Clin Pharmacokinet (2018) 57:1267–1293

https://doi.org/10.1007/s40262-018-0650-9

SYSTEMATIC REVIEW

Complex Drug–Drug–Gene–Disease Interactions Involving

Cytochromes P450: Systematic Review of Published Case Reports
and Clinical Perspectives
Flavia Storelli1,2 • Caroline Samer1,3,4 • Jean-Luc Reny3,5 • Jules Desmeules1,2,3,4 •

Youssef Daali1,2,3,4

Published online: 17 April 2018

Ó Springer International Publishing AG, part of Springer Nature 2018

Abstract Drug pharmacokinetics (PK) is influenced by renal impairment, cirrhosis, and/or inflammation. Current
multiple intrinsic and extrinsic factors, among which con- knowledge on the impact of each of these factors on drug
comitant medications are responsible for drug–drug inter- exposure and DDIs is summarized and future perspectives
actions (DDIs) that may have a clinical relevance, resulting for the management of such complex DDIs in clinical
in adverse drug reactions or reduced efficacy. The addition practice are discussed, including the use of advanced
of intrinsic factors affecting cytochromes P450 (CYPs) Computerized Physician Order Entry (CPOE) systems, the
activity and/or expression, such as genetic polymorphisms development of model-based dose optimization strategies,
and diseases, may potentiate the impact and clinical rele- and the education of healthcare professionals with respect
vance of DDIs. In addition, greater variability in drug to personalized medicine.
levels and exposures has been observed when such intrinsic
factors are present in addition to concomitant medications
perpetrating DDIs. This variability results in poor pre-
Key Points
dictability of DDIs and potentially dramatic clinical con-
sequences. The present review illustrates the issue of
Complex drug–drug interaction (DDI) scenarios
complex DDIs using systematically searched published
involving intrinsic factors are becoming increasingly
case reports of DDIs involving genetic polymorphisms,
frequent.
Genetic polymorphisms and diseases such as renal
Electronic supplementary material The online version of this impairment, cirrhosis, and inflammation affect drug
article (https://doi.org/10.1007/s40262-018-0650-9) contains supple- disposition and DDIs, resulting in increased
mentary material, which is available to authorized users.
variability and poor predictability of DDIs.
& Youssef Daali Further scientific research is needed to integrate
youssef.daali@hcuge.ch
intrinsic factors in the prediction of DDIs, together
1
Division of Clinical Pharmacology and Toxicology, Geneva with the development of advanced integrated
University Hospitals, University of Geneva, Geneva, e-patient medical dossiers and education of
Switzerland healthcare professionals with respect to personalized
2
Geneva-Lausanne School of Pharmacy, University of medicine.
Geneva, Geneva, Switzerland
3
Faculty of Medicine, University of Geneva, Geneva,
Switzerland
4
Swiss Center for Applied Human Toxicology, Geneva,
Switzerland
5
Department of Internal Medicine, Rehabilitation and
Geriatrics, Geneva University Hospitals, University of
Geneva, Geneva, Switzerland
1268
1 Introduction
With the increase of life expectancy and population aging,
patients tend to have multiple chronic diseases, such as
diabetes, hypertension, hypercholesterolemia, and depres-
sion. Polymorbidity in elderly patients often involves the
prescription of several concomitant drug treatments,
increasing the risk of potentially harmful drug–drug inter-
actions (DDIs), which are a major cause of adverse drug
reactions (ADRs), frequently leading to hospitalization
[1–4]. Indeed, the risk of DDIs increases with the number
of concomitant prescriptions: from 13% with two con-
comitant drugs, to 38% with four concomitant durgs and
82% with eight or more concomitant drugs [5]. To note, it
was reported that the frequency of elderly patients taking
eight or more concomitant medications was [ 10% [6].
The nature of DDIs can be pharmacokinetic (PK, affecting
the disposition of the drug) and/or pharmacodynamic (PD,
affecting the effect of the drug without affecting its con-
centration). Regarding the latter, a drug can affect the
absorption, distribution, metabolism and elimination of
another drug. Of particular interest, cytochromes P450
(CYPs) are involved in the metabolism of a large number
of drugs, in particular those belonging to families 1, 2 and
3. Their importance in clinical practice and drug develop-
ment lies in the large interindividual variability of both
their expression and activity, which might be explained by
intrinsic factors (age, disease, sex, weight, and genetics)
and/or extrinsic factors (xenobiotics).
In the last decades, CYP-related DDIs have been
extensively studied. Currently, clinically relevant DDIs can
be detected by both the prescribers and the delivering
pharmacists through interaction alert software such as
Lexi-Interact [7], ePocrates [8], and Theriaque [9], thus
allowing for the identification, management and prevention
of DDI-related ADRs and therapeutic inefficiency. Because
the association of two interacting drugs cannot always be
avoided, increasing efforts have been provided to develop a
mechanistic model to quantitatively predict DDIs, allowing
for prospective dose adjustment [10]. Such models include
basic static, mechanistic static, and dynamic physiologi-
cally-based PK (PBPK) models. However, complex DDI
scenarios are becoming increasingly frequent, partly
because our scientific knowledge is constantly developing
and partly because of patients’ increasingly complex clin-
ical features (aging and polymorbidity) and treatments, and
still remain difficult to predict. These complex DDI sce-
narios may include drug-related complexities such as
simultaneous involvement of multiple enzymes and trans-
porters, simultaneous inhibition and induction, mechanisms
of autoinhibition/induction, time-dependent inhibition,
inhibition/induction caused by major metabolites,
F. Storelli et al.
association of multiple perpetrators, and patient-related
complexities such as involvement of genetic variants and
diseases affecting drug disposition.
Interaction trials are often performed on early-stage
clinical development with healthy volunteers or preselected
patients. Nevertheless, genetic variants of CYP isoforms of
clinical interest are not rare and ‘real life’ patients often
have comorbidities that may affect drug disposition, such
as renal failure, liver dysfunction, or inflammation. While
each individual factor may not have a major impact on the
PK and PD of drugs, the consequence of their combined
effect might be clinically significant and deleterious.
This review aims to focus on DDIs involving patient-
related complexities, namely genetic polymorphisms and
diseases affecting drug disposition from a clinical per-
spective. First, published case reports of DDIs complicated
by genetic variants, renal failure, cirrhosis, or inflammation
are described, and the effect of genetic polymorphisms and
diseases on drug disposition and their implication on DDIs
are then discussed. Finally, clinical perspectives regarding
the management of such complex DDI scenarios are
presented.
2 Case Reports Review
2.1 Methods
Case reports involving CYP-related DDIs and genetic
polymorphisms, cirrhosis, renal failure, or inflammation
were searched using the PubMed database and reviewed
systematically. The PubMed database search algorithm is
described in the electronic supplementary material and
contains terms related to CYPs (families 1, 2 and 3), drug
interactions, and case reports. Language was restricted to
English and French, but there were no restrictions on the
year of publication. Search results were first screened based
on title and abstract in order to rule out off-topic publica-
tions, and full-texts of selected publications were then
reviewed in order to verify if they fulfilled all the following
eligibility criteria: coherent PK interaction involving CYP,
information on CYP genotype, renal function, cirrhotic
status, or inflammatory state. Renal function and inflam-
matory state had to be assessed by biomarkers, such as
serum creatinine/glomerular filtration rate (GFR) and
C-reactive protein (CRP)/interleukin (IL)-6/white blood
cell count, respectively.
2.2 Results
The systematic search workflow is presented in Fig. 1.
Overall, 877 records were output from the PubMed search
performed on 13 July 2017. Of these, 769 were excluded
Complex Drug–Drug–Gene–Disease Interactions
Fig. 1 Systematic search in
accordance with the PRISMA
workflow. PRISMA Preferred
Reporting Items for Systematic
Reviews and Meta-Analyses,
DDGI drug–drug–gene
interaction, DDDI drug–drug–
disease interaction, DDGDI
drug–drug–gene–disease
interaction
based on the title and abstract because they were off-topic.
Of the 108 selected records, 46 were excluded because they
did not fulfill the eligibility criteria described in the
Methods section.
Eligible publications were dated from 1998 to 2017.
Among the 62 eligible publications, only one was in
French, while all others were in English. Language
restrictions were not considered to have a deleterious effect
on the quality of the present review, with its aim being
illustrative rather than quantitative. Moreover, it has not
been proven that language restriction has any notable im-
pact on the results of meta-analyses [11].
The 62 eligible publications presented 34 cases of drug–
drug–gene interactions (DDGIs), 25 cases of drug–drug–
disease interactions (DDDIs), and 4 cases of drug–drug–
gene–disease interactions (DDGDIs), which are summa-
rized in Tables 1, 2 and 3, respectively.
DDIs found in the selected literature included 33 victim
drugs and 44 perpetrator drugs. The most cited CYP
1269
substrates were simvastatin, tacrolimus, colchicine and
voriconazole, while the most cited CYP perpetrators were
the inhibitors clarithromycin, ritonavir, and diltiazem (see
Tables 4 and 5 for a complete list of victim and perpetrator
drugs). There were only a few induction-related DDIs,
which were perpetrated by the CYP inducers carbamaza-
pine and rifampin.
The mechanisms of these complex DDIs are numerous:
(1) enhancement of the magnitude of interaction due to a
genetic variant directly impacting the CYP isoform of
interest [12, 13]; (2) increased vulnerability to phenocon-
version (i.e. the phenomenon that occurs when a perpe-
trator drug of DDIs is strong enough to modify the
phenotype of an individual [14, 15]) caused by a genetic
variant or disease directly affecting the inhibited/induced
metabolic pathway [16–62]; (3) increased exposure of the
perpetrator drug due to genetic polymorphisms
[21, 25, 26, 60, 63–68]; and (4) modification of the relative
contribution of a minor pathway by a genetic variant or
Table 1 Reported case reports of complex drug–drug interactions involving genetic polymorphisms
1270

Interacting drugsa Patient characteristics Effect of interaction Comment Reference

Victim Perpetrator Age, Sex Relevant genotype Other relevant
years information

Atorvastatin 20 mg/day Pantoprazole 75 M CYP2C19*2/*2 SLCO1B1 521CC C: Rhabdomyolysis and acute renal [66]
20 mg/day ABCB1 3435TT failure 3 weeks after statin initiation
Clomipramine Citalopram 28 F CYP2D6*1/*4 PK: Css desmethylclomipramine : CYP2D6 phenotype: [16]
75–100 mg/day 40 mg/day 82% (although clomipramine daily PM
Thioridazine dose was reduced from 100 to
5 mg/day 75 mg), plasma level 8-hydroxy-
desmethylclomipramine ; 42%
4 days after the addition of
citalopram
Clomipramine Modafinil 60 F CYP2D6 *4A/*4A PK: Css clomipramine and [69]
75–100 mg/day 200–400 mg/day desmethylclomipramine : 22% and
14%, respectively, after the addition
of modafinil 200 mg/day (although
clomipramine daily dose was
reduced from 100 to 75 mg), and
63% and 116%, respectively, when
modafinil daily dose was : to
400 mg/day
C: : of liver function tests
Clozapine 750 mg Fluvoxamine 31 M CYP1A2*1F/*1F (UM) CYP1A2 high PK: Clozapine and norclozapine Caffeine MR [13]
3 9/day 25–50 mg/day activity (caffeine concentrations : 2.18-fold and 1.44- decreased 50%
MR 17.9) fold, respectively, within 1 week of with fluvoxamine
fluvoxamine 25 mg/day 50 mg/day
C: Marked improvement in psychosis
with fluvoxamine 50 mg/day
Codeine 10–20 mg/4 h Fluoxetine NR F CYP2D6 *2/*4 UGT2B7 *1/*2 PK: Total codeine 840 lg/L, free Patient was involved [30]
Bupropion codeine 348 lg/L, morphine-3- in a car accident
glucuronide 17 lg/L, morphine-6-
Promethazine
glucuronide 3 lg/L and free
Valproic acid morphine not detectable
Dextromethorphan Amitriptyline 60 M CYP2D6*4/*4 PK: Accumulation of [62]
30 mg 3 9/day 50 mg/day dextromethorphan,
reaching [ 100 ng/mL after 3 days
C: Somnolence after 3 days of
dextromethorphan
Efavirenz 600 mg/day Fluconazole 33 F CYP2B6: 516TT PK: Efavirenz levels: 59.4 mg/L [71]
400 mg/day (approximately 30-fold more than
Ritonavir 100 mg the normal limit)
2 9/day C: Severe psychosis
F. Storelli et al.
Table 1 continued
Interacting drugsa Patient characteristics Effect of interaction Comment Reference
Victim Perpetrator Age, Sex Relevant genotype Other relevant
years information

Fluvastatin 40 mg/day Telmisartan 39 M CYP2C9*1/*3 ABCC2 -24CT C: Twofold : of creatine kinase levels [32]
20 mg/day with myalgia, cramps and
fasciculation in the legs
Fluticasone 27.5 lg/day per Ritonavir 6 F CYP3A4 *1B/*1G C: Cushing syndrome within a few [33]
nostril 80 mg/day CYP3A5 *3/*3 weeks after starting fluticasone
Haloperidol 9 mg/day 59 M CYP2D6*5/*10 C: Neuroleptic malignant syndrome [18]
Levomepromazine 100 mg/day
Chlorpromazine 250 mg/day
Hydrocodone 30 mg over Clarithromycin 5 M CYP2D6*2A/*41 PK: Hydrocodone fatal concentration The child received [20]
Complex Drug–Drug–Gene–Disease Interactions

24 h Valproic acid 0.14 lg/mL twice the

250 mg 2 9/day Hydromorphone \ 0.008 lg/mL recommended dose
Valproic acid 43 lg/mL (within the
therapeutic range)
C: Death
Lopinavir 180 mg 2 9/day Ritonavir 45 mg 6/12 F CYP2D6 UM PK: Plasma level of ritonavir and Ritonavir dose was [65]
2 9/day lopinavir not detectable increased threefold
C: Treatment failure up to 150 mg
2 9/day, and
lopinavir dose was
kept at 75 mg
2 9/day, resulting
in a
detectable plasma
level and
therapeutic
efficacy
Metoprolol 200 mg/day Terbinafine 63 M CYP2D6 *1/*4 C: Sinus bradycardia, confusion, falls [31]
250 mg/day
Metoprolol 200 mg/day Propafenone 66 F CYP2D6*4/*9 PK: MR metoprolol/a- [27]
600 mg/day hydroxymetoprolol 104.3 (PM
phenotype) 3 h after metoprolol
intake
After propafenone withdrawal: 1.4
(phenotype EM)
C: Tiredness and dyspnea on exertion
Nortriptyline 75 mg/day Fluoxetine 24 F CYP2D6*1/*81 VKORC1*3/*3 PK: C12h 1830 nmol/L (therapeutic [28]
60 mg/day (truncated protein) range 200–600 nmol/L)
CYP2C19*1/*2D C: Minimal adverse effects apart from
1271

dry mouth
Table 1 continued
1272

Interacting drugsa Patient characteristics Effect of interaction Comment Reference

Victim Perpetrator Age, Sex Relevant genotype Other relevant
years information

Oxycodone 40–60 mg/day Rifampin 300 mg 60 M CYP2D6*1/*4 CYP3A5*3/*3 PK: Oxycodone not detected; Patient was [72]
oxymorphone not detected free, suspected of lack
190 lg/L conjugated; noroxycodone of compliance
700 ug/mL free because of
C: Not adequate pain relief negative
oxycodone testings
Risperidone 6 mg/day Carbamazepine 50 M CYP2D6*4/*5 PK: Plasma levels of risperidone and [70]
titrated up to active metabolite ; 3.67- and 2.73-
800 mg/day over fold, respectively, after 4 weeks of
5 days carbamazepine
C: Exacerbation of psychotic
symptoms (auditory hallucinations,
paranoid delusions, ideas of
reference, and mild excitement
Risperidone 4 mg/day Haloperidol 6 mg 17 M CYP2D6*4/*4 PK: 8 days after haloperidol initiation, [17]
2 9/day risperidone Css : from 29–37 to 59
ug/L, 9-hydroxyrisperidone Css :
from 12–13 to 18 lg/L, and active
moiety Css : from 41–50 to 77 lg/L
C: Severe akathisia
Simvastatin 20 mg/day Cyclosporin 55 F CYP3A5*3/*3 C: Rhabdomylosis and elevation of [24]
350–500 mg/day CYP3AP1*3/*3 liver function tests
according to TDM
Simvastatin 40 mg/day for Diltiazem 90 mg 63 F CYP3A5 *3/*3 Other genetic C: : of creatine kinase and alanine [22]
4 weeks, then 80 mg/day 2 9/day variants: aminotransferase levels
SLCO1B1 521T/
C and ABCB1
2677TT
Tacrolimus 0.06 mg/kg/day Itraconazole 51 F CYP3A5*3/*3 PK: Tacrolimus C0 : 2.8-fold 2 days [19]
200 mg/day after introduction of itraconazole
Tacrolimus 1 mg/day Itraconazole 53 F CYP2C19*1/*2 PK: : in tacrolimus blood Voriconazole levels [25]
100 mg/day CYP3A5*3/*3 concentration after antifungal switch 5.5 lg/mL
replaced by from 6.1 to 34.2 ng/mL (reference
voriconazole 400 1.4–1.8 lg/mL)
mg/day
F. Storelli et al.
Table 1 continued
Interacting drugsa Patient characteristics Effect of interaction Comment Reference
Victim Perpetrator Age, Sex Relevant genotype Other relevant
years information

Tacrolimus 9 mg 2 9/day, Omeprazole started 17 NR CYP2C19*2/*2 ABCB1 1236TT, PK: C0 with a 9 mg 2 9/day regimen: [26]
days 1–4, then 7 mg on day 5 CYP3A5*3/*3 677TT and 19.6 ng/ml at day 3 and 29.2 ng/ml
2 9/day from day 5 3435TT at day 4
C0 with a 7 mg 2 9/day regimen:
92 ng/mL day 6
C: Acute nephrotoxicity (serum
creatinine 160 lmol/L associated
with proteinuria)
Tacrolimus 17 mg/day Lansoprazole 34 M CYP2C19*1/*2 PK: Tacrolimus C0 : 30% 1 day after [63]
Complex Drug–Drug–Gene–Disease Interactions

30 mg/day lansoprazole introduction, and

Tacrolimus 22 mg/day
Tacrolimus 2 mg/day
Tramadol 4.5 g (intentional
overdose)
Venlafaxine 112.5 mg/day
continued to increase although the
tacrolimus dose was gradually
decreased
Lansoprazole 57 F CYP2C19*1/*2 PK: Tacrolimus C0 : 1.57-fold 3 days [67, 68]
30 mg/day after lansoprazole initiation
Lansoprazole 51 M CYP2C19*2/*3 PK: Tacrolimus C/D ratio : Interaction occurred [64]
30 mg/day CYP3A5*3/*3 approximately twofold after switching
from omeprazole
to lansoprazole
Ketoconazole 22 F CYP2D6*1/*1X2 PK: Tramadol initial concentration Tramadol/O- [73]
(plasma 3.1 mg/L at admission (low value desmethyltramadol
concentration at considering the dose intake) MR 2.54
admission 200 ng/ Tramadol/N-
mL) desmethyltramadol
MR 11.4
Cotrimoxazole 46 F CYP2C19*1/*2 CYP2D6 and PK: Css,plasma venlafaxine ? O- Tremor is probably [74]
800 ? 160 mg/day CYP3A4 desmethylvenlafaxine : from 344 to the consequence of
phenotypes: EM 444 ng/mL with the introduction of both PK and PD
cotrimoxazole (therapeutic interaction (known
recommended range: 100–400 ng/ side effect of
mL) cotrimoxazole)
N-desmethylvenlafaxine was not
modified: Css 8 ng/mL (expected
17–37 ng/mL)
C: Severe bilateral resting tremor of
the hands
1273
Table 1 continued
1274

Interacting drugsa Patient characteristics Effect of interaction Comment Reference

Victim Perpetrator Age, Sex Relevant genotype Other relevant
years information

Voriconazole 400 mg day Carbamazepine 62 F CYP2C19*17/*17 PK: C0 \ 0.3 mg/L at day 5 and [23]
1, then 200 mg 2 9/day, 200 mg 2 9/day 0.5 mg/L at day 9 (therapeutic range
day 2.5, then 510 mg IV 1–5 mg/L)
loading dose followed by C: Therapeutic failure
425 mg 2x/day
Voriconazole 400 mg Esomeprazole 43 F CYP2C19*1/*2 PK: 7.8 mg/L (therapeutic range [21]
2x/day day 1, followed by 1–5 mg/L; target 1.5 mg/L)
200 mg 2 9/day C: Hallucinations 7 days after
voriconazole initiation, : of liver
function tests
Voriconazole 2.5–5.5 mg/ Esomeprazole 35 F CYP2C19*1/*17 CYP2C19 PK: Subtherapeutic levels of [12]
kg/12 h IV 40 mg 2 9/day IV phenotype: voriconazole (B 0.5 ug/L), : up to
Ritonavir omeprazole 3.5 lg/L with concomitant
100 mg/day metabolic ratio administration of esomeprazole and
10.5 (CYP2C19 ritonavir (although voriconazole
activity dose reduced from 5.5 to 2.5 mg/kg/
decreased) 12 h)
Voriconazole 450 mg day Haloperidol 1 mg 43 M CYP2C19*2/*2 PK: Voriconazole C0 : from 3931 ng/ [75]
1, followed by 3 9/day from day mL at day 6 to 11,063 ng/mL at day
300 mg/day days 2–12 8 18
and 250 mg/day days C: : of liver function tests
13–18
Voriconazole 200 mg Ritonavir 50 M CYP2C19 *1/*2 PK: Overtherapeutic level of [34]
2 9/day 100 mg/day voriconazole requiring 25% dose
decrease
Warfarin 5 mg/day Amiodarone 73 M CYP2C9*3/*3 PD: INR 10.7 with 5 mg daily dose, [29]
400 mg/day 6.8 with 2.5 mg daily dose
C/D concentration over dose ratio, C clinical outcomes, Css concentration at steady-state, EM extensive metabolizer, INR international normalized ratio, MR metabolic ratio, NR not reported,
PK pharmacokinetic outcomes, PD pharmacodynamic outcomes, PM poor metabolizer, UM ultrarapid metabolizer, M male, F female, CYP cytochrome P450, TDM therapeutic drug
monitoring, IV intravenously, C12h concentration at 12 h, C0 trough concentration, : indicates increase, ; indicates decrease
a
If the dosage is not specified, the data could not be found in the case report. If not specified, the administration route is orally
F. Storelli et al.
Complex Drug–Drug–Gene–Disease Interactions 1275

Table 2 Reported case reports of complex drug–drug interactions involving diseases affecting drug disposition
Interacting drugsa Patient characteristics Effect of interaction Comment Reference
Substrate Perpetrator Age, Sex Relevant disease
years

Budesonide Amiodarone 100 mg/day 81 M Chronic RI C: Cushing’s syndrome [36]

6 mg/day (serum
creatinine
196–207 lmol/
L)
Budesonide Ritonavir 100 mg/day 75 M Chronic kidney C: Cushing’s syndrome [50]
3 mg Atazanavir 300 mg/day disease (serum
3 9/day creatinine
1.6 mg/dL)
Colchicine Clarithromycin 500 mg 23 F RI (dialysis) C: Nausea, vomiting, [41]
0.5 mg 2 9/day Mediterranean weakness, abdominal pain,
2 9/day fever (CRP diarrhea, pancytopenia
8.05 mg/dL
Colchicine Clarithromycin 500 mg 61 M RI (serum C: Nausea, vomiting, [41]
0.5 mg 2 9/day creatinine diarrhea, worsening of
2 9/day 3.1 mg/dL) renal function (creatinine
clearance 10 mL/min)
Colchicine Clarithromycin 73 M Chronic RI C: Neuromyopathy [42]
0.5 mg/day
Colchicine Clarithromycin 500 mg 48 M Chronic RI C: Rhabdomyolysis [46]
0.6 mg/day 2 9/day
Colchicine Cyclosporin 175 mg/day 60 M Chronic RI PK: C36h,serum colchicine [44]
1 mg/day (dialysis) serum 7 ng/mL (reference
range 1–4 ng/mL)
Cyclosporin blood
concentration : from 130
to 475 ng/mL (reference
range 100–150 ng/mL)
C: Vomiting, diarrhea,
neutropenia,
rhabdomyolysis
Clozapine Valproic acid 500 mg/day 49 M Probable PK: C8h clozapine 1130 ng/ Non-smoker [55]
300 mg/day Escitalopram 10 mg/day inflammation dL, norclozapine 297 ng/ Past history of
(WBC 13,000 dL (ratio 3.81:1) chronic
Aripiprazole 15 mg/day
cells/mm3) C: Somnolence moderate
renal
insufficiency
Fentanyl Diltiazem 85 M RI (creatinine C: Hypoactive delirium [49]
25 lg/h IV 2.0 mg/dL)
drip
Fluticasone Fluconazole 100 mg/day 9 F Cystic fibrosis C: Cushing’s syndrome [52]
110 lg/ and cirrhosis
actuation
Glibenclamide Sorafenib 800 mg/day 70 M Cirrhosis PD: Severe hypoglycemia [54]
3.5 mg (Child–Pugh (blood glucose 37 mg/dL)
2 9/day A) C: Acute nocturnal
eGFR 55 mL/ disorientation and
min somnolence
Nifedipine Clarithromycin 500 mg 77 M Chronic RI C: Reduced consciousness [40]
60 mg 2 9/day with response to stimuli,
2 9/day hypotension (80/
40 mmHg), bradycardia
(40 bpm)
1276 F. Storelli et al.

Table 2 continued
Interacting drugsa Patient characteristics Effect of interaction Comment Reference
Substrate Perpetrator Age, Sex Relevant disease
years

Nifedipine, Clarithromycin 78 M Chronic kidney C: Hypotension (96/ Patient was [57]

diltiazem disease 38 mmHg), bradycardia also taking
(44 bpm), loss of carvedilol
consciousness
Repaglinide Cotrimoxazole 76 M RI (serum C: Symptomatic [47]
1 mg 800 ? 160 mg/day creatinine hypoglycemia (blood
3 9/day 1.84–2 mg/dL) glucose 34 mg/dL)
Simvastatin Amiodarone 1 mg/day 80 M Chronic RI C: Severe rhabdomyolysis, [51]
40 mg/day (serum elevation of liver function
creatinine tests 4 days after
2.2 mg/dL, amiodarone initiation
eGFR 31)
Simvastatin Azithromycin 500 mg/day and 73 M Chronic kidney C: Acute kidney injury and Comorbidity: [53]
80 mg/day 250 mg/day days 2–5 disease rhabdomyolysis obesity
(;CYP3A4
activity by
40%)
Simvastatin Clarithromycin 500 mg 64 M Severe RI C: Rhabdomyolysis [37]
80 mg/day 2 9/day
Simvastatin Colchicine 0.5 mg 2 9/day 70 M Chronic RI C: Rhabdomyolysis and : of [38]
aspartate aminotransferase
levels
Simvastatin Tacrolimus, sirolimus (dosage 56 M RI (serum C: Rhabdomyolysis and [45]
10 mg/day unknown) creatinine acute renal failure
2.33 mg/dL) resulting in patient’s death
Simvastatin Telaprevir 750 mg 3 9/day 46 M Hepatitis C: Rhabdomyolysis and : of [56]
80 mg/day C-related liver function tests
cirrhosis
Sirolimus Erythromycin 500 mg 2 9/day 70 M Chronic RI PK: Sirolimus C0 38.2 ng/ [39]
1 mg/day (hemodialysis) mL (target range 5-10 ng/
mL)
Sirolimus Fluconazole 100 mg/day IV for 60 M RI PK: Sirolimus C0 : greater [39]
2 mg/day 10 days, then 200 mg PO than fourfold (up to
48.44 ng/mL)
Sorafenib Felodipine 5 mg 2 9/day 80 M Cirrhosis PK: Sorafenib Css, plasma : [48]
400 mg (competition) (Child–Pugh threefold 15 days after
2 9/day A) felodipine introduction
Tacrolimus Diltiazem 5–10 mg/h 24 h 38 M RI (serum PK: Tacrolimus C0 : to [35]
8 mg infusion followed by 30 mg/ creatinine 55 ng/mL
2 9/day 8 h orally 2.1 mg/dL) C: Delirium, confusion and
Ciprofloxacin agitation
Venlafaxine 75 mg/day 55 F Cirrhosis C: Acute respiratory failure [43]
Propanolol 160 mg/day (Child–Pugh
C)
bpm beats per minute, C clinical outcome, C8h concentration every 8 h, C0 trough concentration, CRP C-reactive protein, Css concentration at
steady state, CYP cytochrome P450, eGFR estimated glomerular filtration rate, F female, IV intravenous, M male, PD pharmacodynamic
outcome, PK pharmacokinetic outcome, PO orally, RI renal insufficiency, WBC white blood cells, : indicates increase, ; indicates decrease
a
If the dosage is not specified, the data could not be found in the case report. If not specified, the administration route is orally
Complex Drug–Drug–Gene–Disease Interactions 1277

Table 3 Reported case reports of complex drug–drug interactions involving both genetic polymorphisms and any disease affecting drug
disposition
Interacting drugsa Patient characteristics Effect of interaction Comment Reference
Substrate Perpetrator Age, Sex Relevant Relevant
years disease genotype

Codeine 25 mg Clarithromycin 62 M RI CYP2D6 PK: High levels of Comorbidity: [58]

3 9/day Voriconazole UM morphine (80 ng/ chronic
Valproic acid mL) and lymphocytic
1500 mg/day morphine-6- leukemia
glucuronide
(136 ng/mL)
C: Respiratory
depression, coma
Dextromethorphan Metoprolol 64 M Chronic renal CYP2D6*1/ PK: High [59]
30 mg 40 mg/day failure *10 dextromethorphan
(peritoneal blood level
dialysis) (2.68 ng/mL) 60 h
after a 30 mg dose
C: Myoclonus
Escitalopram Esomeprazole 46 F Child–Pugh C CYP2C19*2/ PK: Day 3: Escitalopram level [60]
10 mg 2 9/day 40 mg/day cirrhosis *2 Escitalopram 3 days before
from day 1 CYP2D6*5*/ serum level ARV initiation
Darunavir 600 *10 619 nmol/L was in the
mg 2 9/day (: 12 9) therapeutic range
and ritonavir Day 8: Escitalopram (52 nmol/L)
100 mg serum level:
2 9/day from 695 nmol/L
day 4 (: 13 9)
Expected
therapeutic range
40–250 nmol/L
Estimated half-life
67–69 h
(literature:
27–33 h)
C: Serotonin
syndrome at day 8
Haloperidol 1 mg Ciprofloxacin 66 M Cirrhosis of CYP2D6*6/ C: Severe UGT2B7-161CT [61]
2 9/day alcoholic *6 extrapyramidal
origin symptoms
Acute
inflammation
(leukocytes
26.72 9 109/
L, CRP
108.48 mg/L)
ARV antiretrovirals, C clinical outcome, CRP C-reactive protein, F female, M male, PK pharmacokinetic outcome, RI renal insufficiency, UM
ultrarapid metabolizer, : indicates increase
a
If the dosage is not specified, the data could not be found in the case report. If not specified, the administration route is orally

disease affecting another major pathway negligible effects on CYP activity at therapeutic doses,
[58, 60, 61, 69–75]. such as colchicine, felodipine, pantoprazole, propanolol,
Interestingly, complex DDIs were perpetrated by drugs tacrolimus, azithromycin (CYP3A), amitriptyline, meto-
with CYP-inhibiting/inducing potencies ranging from weak prolol (CYP2D6), haloperidol (CYP3A), and aripiprazole
to strong. In some cases, drugs described as having null to (CYP2D6, CYP3A) might have been capable of inhibiting
1278 F. Storelli et al.

Table 4 Victim drugs Victim drug No. of occurrences CYP-related metabolic pathways References
implicated in the selected case
reports Atorvastatin 1 3A [76]
Budesonide 2 3A [77]
Chlorpromazine 1 1A2, 2D6 [78, 79]
Clomipramine 2 1A2, 2C19, 2D6, 3A [80]
Clozapine 2 1A2, 2D6, 3A [81]
Codeine 2 2D6, 3A [76]
Colchicine 5 3A [82]
Dextromethorphan 2 2D6, 3A [76]
Diltiazem 1 2D6, 3A [83–85]
Efavirenz 1 1A2, 2B6, 3A [86]
Escitalopram 1 2C19, 2D6, 3A [87]
Fentanyl 1 3A [76]
Fluticasone 2 3A [88]
Fluvastatin 1 2C9 [76]
Glibenclamide 1 2C9, 3A [89–91]
Haloperidol 2 1A2, 2D6, 3A [76]
Hydrocodone 1 2D6, 3A [92]
Lopinavir 1 3A [93]
Metoprolol 2 2D6 [76]
Nifedipine 2 3A [76]
Nortriptyline 1 1A2, 2C19, 2D6, 3A [94, 95]
Oxycodone 1 2D6, 3A [96]
Repaglinide 1 2C8, 3A [97]
Risperidone 2 2D6, 3A [76]
Simvastatin 7 3A [76]
Sirolimus 2 3A [76]
Sorafenib 1 3A [98]
Tacrolimus 7 3A [76]
Tramadol 1 2B6, 2D6, 3A [99]
Venlafaxine 2 2C19, 2D6, 3A [100]
Voriconazole 5 2C9, 2C19, 3A [101]
Warfarin 1 1A2, 2C8, 2C19, 2C9, 3A [102]
CYP cytochrome P450

CYP pathways due to either increased vulnerability to
phenoconversion caused by genetic or disease particulari-
ties, or enhanced exposure related to genetic
polymorphisms.
Victim drugs were affected by CYP inhibitors and
inducers either through major or minor metabolic path-
ways. In the latter case, inhibition of a major metabolic
pathway by a genetic variant or disease allowed boosting of
the minor pathway relative contribution to overall drug
metabolism (fm). The fm value has a high impact on the
magnitude of DDIs. When a major elimination pathway is
inhibited, the contribution of the minor pathway is
enhanced; therefore, the magnitude of DDIs can be dra-
matically increased when multiple elimination pathways
are inhibited. Whereas the effect of inhibition of the minor
pathway would not be significant in most individuals, it
might become clinically relevant when the major pathway
is non-functional.
3 Genetic Polymorphisms
CYPs are subject to genetic polymorphisms, defined as
stable variations in a given locus of the genetic sequence,
which are detected in 1% or more of a specific population
[129]. Among these CYPs, the most polymorphic genes are
CYP2C9, CYP2C19 and CYP2D6; however, genetic vari-
ants of other enzymes, such as CYP1A2, CYP3A4,
CYP3A5, and CYP2B6, have also been described. Variant
alleles of CYP-coding genes may either lead to
Complex Drug–Drug–Gene–Disease Interactions 1279

Table 5 Perpetrator drugs implicated in the selected case reports

Perpetrator No. of occurrences Inhibited/induced pathways References

Amiodarone 3 2C9, 3A: strong inhibition [76, 103]

Amitriptyline 1 2D6: possible weak inhibition (competitive substrate) [76]
Aripiprazole 1 2D6, 3A: possible weak inhibition (competitive substrate) [104]
Atazanavir 1 3A: strong inhibition [105]
Azithromycin 1 3A: weak inhibition [106]
Bupropion 1 2D6: strong inhibition [76]
Carbamazepine 2 2C9, 3A: induction [76]
Chlorpromazine 1 2D6: moderate inhibition [107–109]
Ciprofloxacin 2 3A: moderate inhibition [110]
Citalopram 1 2D6: moderate inhibition [111]
Clarithromycin 8 3A: strong inhibition [76]
Colchicine 1 3A: possible weak inhibition (competitive substrate) [82]
Cotrimoxazole 2 2C8, 2C9: moderate inhibition [76]
Cyclosporin 2 3A: strong inhibition [112]
Darunavir 1 3A: strong inhibition [113]
Diltiazem 4 3A: moderate inhibition [76]
Erythromycin 1 3A: moderate inhibition [76]
Escitalopram 1 2D6: moderate inhibition [87]
Esomeprazole 3 2C19: strong inhibition [76]
Felodipine 1 3A: possible weak inhibition (competitive substrate) [76]
Fluconazole 3 2C9, 3A: strong inhibition [76]
Fluoxetine 2 2C19, 3A: moderate inhibition [76]
2D6: strong inhibition
Fluvoxamine 1 2C9, 3A: moderate inhibition [76, 114]
1A2, 2C19: strong inhibition
Haloperidol 3 CYP3A: weak inhibition [115, 116]
2D6: strong inhibition
Itraconazole 2 3A: strong inhibtion [76]
Ketoconazole 1 3A: strong inhibition [76]
Lansoprazole 3 2C19: strong inhibition [76, 117]
3A: possible weak inhibition (competitive substrate)
Levomepromazine 1 2D6: strong inhibition [118]
Metoprolol 1 2D6: weak inhibition (competitive substrate) [76]
Modafinil 1 2C19: moderate inhibition [119]
Omeprazole 1 2C19: moderate inhibition [76]
Pantoprazole 1 2C19: weak inhibition [76]
Promethazine 1 2D6: inhibition [120]
Propafenone 1 2D6: strong inhibition [27]
Propanolol 1 2D6: weak inhibition (competitive substrate) [121]
Rifampin 1 1A2, 2B6, 2C8, 2C9, 2C19, 3A: induction [76]
Ritonavir 7 3A: strong inhibition [76]
Sorafenib 1 3A: weak inhibition [98, 122]
Tacrolimus 1 3A: weak inhibition (competitive substrate) [76]
Telaprevir 1 3A: strong inhibition [123, 124]
Telmisartan 1 2C9: moderate inhibition [125]
Terbinafine 1 2D6: strong inhibition [76]
Thioridazine 1 2D6: strong inhibition [126]
Valproic acid 3 2C9, 3A: inhibition [127]
Voriconazole 1 3A: strong inhibition [128]
1280
significantly decreased or increased enzyme activity, or
regulated gene expression leading to lack of or overex-
pression of coded enzymes [130].
The impact of CYP genetic variants on the PK of sub-
strate drugs (such as CYP2C9 for vitamin K antagonists,
CYP2C19 for clopidogrel, and CYP2D6 for opioid anal-
gesics, tamoxifen, and antidepressants) have been exten-
sively studied in the last decades. Genetic-based dosing
guidelines constitute a useful tool for the management of
gene–drug interactions (GDIs) in clinical practice. When a
GDI cannot be avoided through modification of therapeutic
entity, dose adjustment or safety/efficacy monitoring might
be proposed to manage such interactions and avoid thera-
peutic failure and/or ADRs. The clinical relevance of pre-
emptive genotyping is supported by recent studies that
estimate the proportion of the population carrying at least
one actionable pharmacogenetic variant to be over 90%
[131–133]. The clinical benefit of pre-emptive genotyping
of the major genes involved in the PK and PD of drugs is
currently assessed in several prospective implementation
studies [134–139]. A recent study by an American genetic
testing laboratory with more than 22,000 patients reported
that among all patients with at least one drug interaction in
their medication list (69% of the cohort), 53% were DDIs,
25% were GDIs, and 22% were DDGIs [140].
The simultaneous presence of both GDIs and DDIs may
be responsible for greater clinical relevance (efficacy/
safety) of such interactions, as reported in the case reports
described herein. In addition, the complexity of the latter
type of drug interactions results in greater variability in
drug levels and difficulty of DDI predictions. The impact of
genetic polymorphisms on CYP-mediated DDIs has been
highlighted in several studies in the past years. Bahar and
colleagues recently published a comprehensive systematic
review on DDGIs involving the most polymorphic
enzymes (CYP2C9, CYP2C19 and CYP2D6) that sum-
marized the available clinical studies on this topic [141].
The present review adds clinical illustrations of such drug
interactions.
Among the DDGI cases described in the present study,
some had severe or fatal outcomes. In a psychotic 50-year-
old patient with inactive CYP2D6 (CYP2D6*4/*5), the
addition of carbamazepine to a stable risperidone regimen
resulted in a significant decrease of active moiety levels,
leading to an exacerbation of psychotic symptoms [70].
Severe psychosis related to toxic levels of efavirenz
resulted from the coadministration of efavirenz, ritonavir
and fluconazole in a 33-year old HIV-positive woman
carrying the CYP2B6 516TT genetic variant. In this case,
the inhibition of CYP3A by fluconazole, which normally
has a modest effect on efavirenz exposure, became sig-
nificant because of the altered CYP2B6 major pathway
[71]. A case of a DDGI explained by both increased
F. Storelli et al.
vulnerability to phenoconversion and increased exposure of
the perpetrator was well-described in a 17-year-old trans-
plant recipient, with overtherapeutic tacrolimus levels
becoming even higher and resulting in acute nephrotoxicity
after omeprazole initiation despite a dose reduction of the
immunosuppressant [26]. Genotyping revealed that the
patient was a non-expressor of CYP3A5, the major enzyme
involved in tacrolimus metabolism. In addition, the patient
was a poor metabolizer (PM) of CYP2C19 (CYP2C19*2/
*2) and carried non-functional variants of ABCB1 coding
for P-glycoprotein (P-gp). In this case, omeprazole likely
inhibited tacrolimus elimination through competition with
the CYP3A4 pathway (minor metabolic pathway of
omeprazole) due to genetic polymorphisms of both
CYP2C19 (major pathway of omeprazole elimination) and
CYP3A5 (preferred metabolic pathway of tacrolimus). As
a last example of dramatic outcomes of DDGIs, lethal
levels of hydrocodone were found in a 5-year-old child
who received twice the recommended dose of hydrocodone
(30 mg over 24 h). In this case, the fatal outcome was a
consequence of overdose, reduced CYP2D6 activity
(CYP2D6 genotype *2A/*41), and concomitant adminis-
tration of CYP3A inhibitors (clarithromycin and valproic
acid) [20].
Two scenarios can be considered when assessing the
impact of DDGIs: (1) introduction of a perpetrator drug in
a patient stabilized with a victim drug; and (2) addition of a
victim drug in a patient treated by a perpetrator. In the first
case, one may consider the magnitude of DDIs relative to
genotype, while, in the second case, the point of view may
focus on genotype-related vulnerability to phenoconversion
and on the superposition of mechanisms of both DDIs and
GDIs.
In the first case, the dose of the victim drug is probably
already modified according to the genetic variant before
introduction of the perpetrator, and the magnitude of the
DDI will depend on the genotype-relative contribution of
the inhibited/induced CYP pathway. As previously dis-
cussed, the impact of the fm value of the inhibited clearance
pathway to the extent of DDI is well known and the effect
of even slight variations in fm values can be clinically
important, especially when the fm value approaches 1
[142]. In the case of CYP inhibition, the higher the con-
tribution of the enzymatic pathway, the higher the magni-
tude of DDIs [108, 143–145]. A PM of a specific CYP
isoform will not be greatly affected by an inhibitor of the
variant isoform of interest. In healthy CYP2D6 PM Cau-
casian subjects, no increase in the AUC of metoprolol was
observed when coadministered with dronedarone, a mod-
erate CYP2D6 inhibitor [146]. In CYP2D6 PM psychiatric
patients, the MR of debrisoquine, a historical phenotyping
probe of CYP2D6, remained unchanged when increasing
the thioridazine dose [147]. In a clinical study with healthy
Complex Drug–Drug–Gene–Disease Interactions
Japanese subjects, inhibition of aripiprazole metabolism by
paroxetine was significantly greater in extensive metabo-
lizers (EMs) than in intermediate metabolizers (IMs).
There was no marked difference with fluvoxamine, a less
potent inhibitor [143]. In Korean subjects, the frequent
CYP2D6*10 allele, which leads to decreased activity of
CYP2D6, showed an impact on the extent of CYP inhibi-
tion by paroxetine, a strong time-dependent inhibitor [144].
Another study highlighted the differential inhibition extent
of haloperidol metabolism by chlorpromazine in Japanese
schizophrenic patients in relation to CYP2D6*5 and *10
alleles [108]. The interaction between fluconazole
200–400 mg/day and flurbiprofen was studied in a clinical
study with healthy volunteers, which demonstrated that
changes in flurbiprofen apparent oral clearance caused by
fluconazole coadministration were gene dose-dependent,
with only modest change occurring in CYP2C9 PM sub-
jects [148]. When a major metabolic pathway is inhibited
by a genetic variant, such as CYP2C9 for warfarin, the
contribution of other pathways increases. This has been
demonstrated in CYP2C9-genotyped patients treated with
warfarin [149] for which the coadministration of simvas-
tatin (a substrate of CYP3A) required an approximately
29% dose reduction in PMs compared with 5% in EMs
[149]. In such cases, an inhibitor of the minor pathway that
would not have any significant impact in a wild-type
patient can cause severe DDIs in patients with a gene-
related defect of the major clearance pathway.
In the second scenario, where a victim drug is initiated
in a patient treated with a perpetrator drug, the impact of
the interaction results from the superposition of GDI and
DDI mechanisms. In the absence of an inhibitor/inducer,
dose adjustment of a CYP substrate with a genetic variant
might be performed during treatment initiation. In the case
of concomitant administration of a perpetrator of DDIs,
dose adjustment is complicated and requires taking into
account both GDIs and DDIs. A genetic variant decreasing
the activity of a specific CYP isoform will result in
increased vulnerability to DDIs. IM subjects are thought to
be more vulnerable to phenoconversion than EMs, while
ultrarapid metabolizers (UMs) were less vulnerable
because of higher basal CYP activity. Indeed, a higher
proportion of subjects in an IM population will be con-
verted to PMs (and will therefore not be able to clear
substrate drugs of the polymorphic enzyme) than in a UM
population, whose basal capacity of drug metabolism is
higher. For example, in patients treated for depression by
any known inhibitor of CYP2D6, phenoconversion to PM
was observed in 24% of patients. After stratification of
study subjects by their genotype, it appeared that conver-
sion to the PM phenotype occurred in 21% of genetic EM
subjects and in only 3% of genetic UM subjects [150]. In
patients taking acenocoumarol, the presence of genetic
1281
variants of CYP2C9 increased the risk of overanticoagu-
lation in the presence of CYP2C9 inhibitors, from 52 to
78% [151]. We recently performed a prospective clinical
trial that aimed at assessing the risk of phenoconversion in
CYP2D6 genetically predicted EMs and found a higher
rate of phenoconversion to PMs with paroxetine in
heterozygous carriers of a non-functional allele compared
with homozygous carriers of two functional alleles [152].
Therefore, the lower the CYP basal activity, the higher the
incidence of phenoconversion and levels of drugs with
concomitant administration of a CYP inhibitor. This might
have clinical consequences when victim drugs have a
narrow therapeutic window.
Complexity is even greater if the magnitude of a DDI
and its clinical impact is modified when a genetic variant
affects the concentrations of a perpetrator. This has been
demonstrated with healthy volunteers genotyped for
CYP2C19 and receiving concomitant administration of
voriconazole and tacrolimus. In this case, genetic defects of
CYP2C19 were associated with increased exposure to
voriconazole and corresponding interaction with the
CYP3A substrate tacrolimus, which was greater in
CYP2C19 PMs than EMs [153]. Among the case reports
described herein, many were related to the interaction
between tacrolimus and proton pump inhibitors (PPIs).
Lansoprazole and omeprazole may affect the elimination of
tacrolimus through competition for the CYP3A pathway. In
the presence of a genetic defect of CYP2C19, the exposure
of PPIs increases, which directly affects the magnitude of
interaction between the concomitantly administered drugs.
This was described in patients carrying homozygous and
heterozygous non-functional CYP2C19 alleles, such as *2
and *3 [63, 64, 67, 68]. This interaction may even be
worsened by the addition of other genetic variants affecting
tacrolimus elimination, such as CYP3A5*3 (no expression
of the CYP3A5 enzyme) or loss-of-function mutations of
the ABCB1 gene coding for the efflux transporter P-gp.
To sum, complex DDGIs involve several mechanisms:
effect on the exposure of the perpetrator, effect on the
exposure of the victim drug, and effect on the magnitude of
DDIs. These three mechanisms may be concomitant and
cause unexpected serious ADRs.
In recent years, there has been growing interest for the
prediction of such complex DDGIs. Tod et al. published a
mechanistic static approach to predict the magnitude of
DDIs involving CYPs and several genotypes. This
approach takes into account the contribution of each indi-
vidual isoenzyme to the clearance of the drug (CR), the
impact of genetic variation on the residual CYP activity,
and the potency of perpetrator drugs. [154] The DDI sim-
ulator ‘DDI Predictor’, available online at www.
ddipredictor.org, is based on this quantitative prediction
[155]; however, this static approach does not take into
1282
account the genetic-related changes in perpetrator drug
exposure. By defining drug-dependent and system-depen-
dent parameters in a single prediction model, PBPK
modeling offers the needed tools to allow for accurate
prediction of complex DDGIs. Vieira and colleagues have
recently shown that the additive impact of genetic poly-
morphisms of CYP2D6 on the interaction between
risperidone and fluoxetine could be successfully predicted
by PBPK modeling [156].
4 Renal Failure
Chronic kidney disease (CKD) is an increasing burden
worldwide, with a consistent estimated global prevalence
of between 11 and 13% [157]. CKD is defined by a
decrease in kidney function, shown by a GFR \ 60 mL/
min/1.73 m2 and/or markers of kidney damage of at least
3 months’ duration [158]. The primary pathological fea-
tures of most CKDs are interstitial fibrosis, tubular atrophy,
and glomerulosclerosis, and are mainly caused by ever-
increasing pathologies such as diabetes and hypertension
[158]. Acute kidney injury (AKI) arises from various eti-
ologies such as tubular, glomerular, and vascular damages
[159, 160].
It is well accepted and intuitive that the clearance of
drugs whose elimination mainly depends on renal filtration
and/or renal transporters is decreased in CKD and AKI. In
addition, an increasing number of in vitro [161–165] and
in vivo (in rats [164, 166, 167] and humans [168, 169])
studies published in the last 15 years revealed that CKD
and end-stage renal disease (ESRD) may decrease the non-
renal clearance of drugs eliminated by metabolizing
enzymes and transporters. These data have been incorpo-
rated in a PBPK model of renal impairment in which CYP
abundance was reduced by 15–85% depending on CYP
isoform and renal disease severity compared with healthy
controls [170]. In a survey by the US FDA, it was reported
that for over 23 new drugs for which applications included
renal impairment studies, 13 exhibited an increased expo-
sure in patients with renal impairment (50% on average)
compared with healthy volunteers. Yeung and colleagues
reported 76 drugs that exhibited altered non-renal clearance
in patients with CKD [171], most of which were eliminated
by CYP-mediated hepatic metabolism. Based on these
data, both the FDA and the European Medicines Agency
(EMA) currently recommend performing PK studies of
non-renally cleared drugs in ESRD patients [172, 173]. To
date, underlying mechanisms of a drug non-renal clearance
decrease in CKD patients are unclear but seem to be related
to downregulation of CYP gene expression and/or direct
inhibition of CYP by the accumulation of uremic toxins
(urea, parathyroid hormone, indoxyl sulfate, and
F. Storelli et al.
inflammatory cytokines) [174]. However, despite accu-
mulating evidence, trends in the impact of renal impair-
ment on CYP abundance and/or CYP intrinsic clearance
are not consistent [160]. Physiological changes that occur
in kidney diseases may alter the clearance of non-renally
eliminated drugs. In particular, hypoalbuminemia and drug
displacement by endogenous compounds (e.g. hippuric
acid) that accumulate in patients with impaired renal
function reduce albumin binding and therefore raise the
non-renal clearance of drugs through an increase in the
unbound fraction [171]. Thus, a lack of change in total
clearance may obscure reduced enzyme activity and/or
abundance in case of concomitant change of the unbound
fraction. Therefore, further investigations are needed to
understand the net effect of renal disease on CYP activity
and expression.
Based on these considerations, kidney disease may
affect the clinical impact of DDIs by two mechanisms
affecting either the exposure of the victim drug or the
extent of the DDI: (1) alteration of the elimination of drugs
whose clearance partially or mainly depends on renal
function; and (2) inhibition of CYP activity induced by the
disease. In addition, the extent of the DDI is impacted by
exposure of the perpetrator, which may increase in cases of
renal dysfunction. Moreover, by affecting both renal and
CYP-mediated hepatic clearance, kidney disease alters the
relative contributions of CYP enzymes and therefore the
magnitude of CYP-related DDIs.
Among the 29 cases of DDDIs, 21 involved renal fail-
ure. Simvastatin, whose elimination is mainly cleared by
CYP3A with negligible renal participation (\ 0.5% is
recovered unchanged in urine), exhibits reduced non-renal
clearance in CKD patients [171]. Indeed, patients with
severe renal failure (GFR \ 30 mL/min) showed twofold
higher plasma concentrations after a single dose compared
with healthy volunteers [175]. The present review descri-
bed six cases of simvastatin toxicity related to DDDIs
(rhabdomyolysis, elevation of liver function tests, renal
failure). The perpetrators were not only well-known strong
CYP3A inhibitors, such as clarithromycin and amiodarone,
but also weak inhibitors of CYP3A, such as azithromycin,
and drugs metabolized by the CYP3A pathway that might
competitively alter the CYP3A-mediated metabolism of
simvastatin, such as colchicine, tacrolimus, sirolimus, and
telaprevir. In those cases, the association of both kidney
disease and DDIs probably resulted in the development of
ADRs. Of note, in three of these cases the daily dose of
simvastatin was 80 mg, which is associated with a four-
and tenfold higher risk of elevation of liver function tests
and creatine kinase, respectively, compared with moderate
dosing [176].
Colchicine is predominantly eliminated by biliary
excretion and is a substrate of P-gp. CYP3A-mediated
Complex Drug–Drug–Gene–Disease Interactions
hepatic metabolism and renal elimination account only for
5–20 and 10–20%, respectively, of drug disposition in
normal conditions [82]; however, their impact might
become critical in cases of DDIs or genetic variants
affecting P-gp [82]. The present review describes five cases
of colchicine toxicity—four with clarithromycin and one
with cyclosporin. The two perpetrators are both CYP3A
and P-gp inhibitors. Colchicine toxicity was precipitated by
the superposition of three mechanisms: reduction of biliary
excretion by inhibition of P-gp, inhibition of CYP3A-me-
diated metabolism, and alteration of renal elimination
related to kidney disease. The disposition of clarithromycin
is dependent on renal elimination, and kidney dysfunction
may have led to increased exposure of the perpetrator,
therefore worsening the DDI.
Overall, renal impairment was found to be a concomi-
tant disease in more than 20 cases of DDIs. The drugs
involved in the DDDIs were primarily cleared by non-renal
routes. Renal impairment probably acted as a compounding
factor of DDIs, leading to clinical toxicity by increasing the
victim drug’s exposure through inhibition of renal elimi-
nation and/or decrease of CYP expression and/or activity.
In addition, the magnitude of DDIs may have been wors-
ened by an increase in the inhibitor’s exposure.
System-dependent parameters such as enzyme abun-
dance, gastric emptying time, binding proteins in plasma,
and hematocrit have been incorporated in renally impaired
virtual populations in PBPK software (SimCYPÒ, Certara,
Princeton, NJ, USA). Provided that a PBPK model is
capable of predicting comparable PK changes observed
in vivo by both individual intrinsic (renal impairment) and
extrinsic (interacting drugs) factors, it can be used to pre-
dict the combined effect of those factors in common
complex scenarios. However, this is not always the case, as
shown in the simulated interaction between telithromycin
and ketoconazole that yielded a predicted AUC ratio lower
than that observed in vivo [177]. These limited observa-
tions (derived from only two subjects) warrant further
development and validation of current PBPK models.
5 Hepatic Impairment: Cirrhosis
The liver plays a major role in the absorption, distribution,
and elimination of many drugs and their active and inactive
metabolites. Liver diseases, particularly cirrhosis, result in
numerous physiological changes that may influence drug
PK [178]. Liver cirrhosis is characterized by the progres-
sive loss of functional hepatocytes, with concomitant for-
mation of connective tissues and nodules [179].
Progression of the disease might be classified using the
Child–Pugh score, which defines the severity of the disease
(A, B, C) and the estimated prognosis. Cirrhosis results in
1283
the reduction of liver blood flow, the presence of portal-
systemic shunting, and a reduction in the number and
activity of hepatocytes, as well as in impaired production
of drug-binding proteins [178]. In addition, renal function
might often become impaired in advanced liver disease,
often corresponding to hepatorenal syndrome [180].
For drugs metabolized primarily in the liver, the total
clearance of a compound is the hepatic clearance, which is
the product of liver blood flow (QH) and the hepatic
extraction ratio (EH), the latter being dependent on the
unbound fraction of the drug in blood (fu,B), the unbound
intrinsic clearance (CLu,int), and the liver blood flow, as
illustrated in Eq. 1:
fu;B  CLu;int
CLH ¼ QH  EH ¼ QH  : ð1Þ
QH þ fu;B  CLu;int
The hepatic clearance of drugs with high extraction
ratios (EH [ 0.7) is limited by hepatic blood flow;
therefore, the latter has a high impact on the clearance of
highly extracted drugs. Oppositely, hepatic clearance of
drugs with low extraction ratios (EH \ 0.3) is considered to
be limited by the metabolic capacity. Their clearance is
therefore impacted by changes in protein binding and
intrinsic hepatic clearance, both occurring in liver disease.
Finally, drugs with intermediate extraction ratios
(0.3 \ EH \ 0.7) can be impacted by alterations of one
of the three components of the equation, i.e. liver blood
flow, protein binding, and intrinsic hepatic clearance.
As a result of a reduced first-pass effect, the bioavail-
ability of intermediate to highly extracted drugs is signifi-
cantly increased in cirrhotic patients. In addition, the
impaired production of albumin and a-glycoprotein related
to liver dysfunction causes an increase in the unbound
fraction of drugs. This change particularly affects the PK of
highly bound drugs (fu,B \ 0.1), impacting both their dis-
tribution (increased volume of distribution) and clearance
(only the unbound fraction is cleared by the liver). The
intrinsic metabolic capacity is also altered in liver disease.
Indeed, it appears that the expression and activity of CYP
are selectively reduced in liver disease. The extent of
impairment of metabolic activity and enzyme expression
depends on CYP isoform, and the type and severity of liver
disease [181]. In addition, the impairment of renal function
in advanced cirrhosis might explain the impact of cirrhosis
in the PK of drugs with predominant renal elimination.
It was postulated that the reduction of hepatic blood flow
in cirrhosis may lead to an increased sensitivity of flow-
limited clearance drugs with high extraction ratios to the
action of enzymatic inhibitors. Indeed, flow-limited drugs
might become capacity-limited with reduction of hepatic
blood flow [182]; however, it seems that the magnitude of
DDIs decreases as the liver dysfunction progresses. Indeed,
the clearance of lidocaine, a flow-dependent drug with a
1284
high extraction ratio, was decreased by 60% in healthy
volunteers, and by 44 and 9% in Child–Pugh A and C
cirrhotic patients, respectively, when coadministered with
fluvoxamine, an inhibitor of CYP1A2 and CYP3A [183].
The magnitude of the decrease of theophylline clearance by
fluvoxamine was also dependent on liver function, with
inhibition of 65, 55 and 14% in healthy volunteers and
Child–Pugh A and C cirrhotic patients, respectively [184].
The impact of clearance inhibition of the CYP3A substrate
quinine by erythromycin was also decreased in cirrhotic
patients but to a lesser extent, probably because of addi-
tional mechanism of competition for protein binding with
erythromycin that may mask the decrease in hepatic
clearance [182]. Therefore, it seems that decreased uptake
of the CYP inhibitor in hepatocytes, together with
decreased enzyme expression (and thus decreased contri-
bution of the latter to drug clearance) are responsible for
the decreased extent of CYP inhibition on liver cirrhosis.
The mechanism of inhibition, whether reversible or irre-
versible, might also play a role in the liver status-depen-
dency of DDIs [184].
Regarding CYP induction, it was demonstrated in rats
that severe liver dysfunction reduces the expression of the
aryl hydrocarbon receptor (AhR), and consequently the
expression and inducibility of CYP1A enzymes [185]. To
our knowledge, no human clinical study was properly
designed to assess the impact of liver dysfunction on CYP
induction.
Because the impact of liver dysfunction on drug PK and
DDIs was mostly described with cirrhosis, only the latter
was selected in the present review. Seven cases of DDDIs
involved cirrhosis as a concomitant disease. Given previ-
ous considerations related to the impact of liver dysfunc-
tion on the extent of DDIs, it seems that cirrhosis only
represents a compounding factor through elevation of basal
circulating levels of the victim drugs and not through an
increase of the magnitude of DDIs. While cirrhosis might
minimize the magnitude of DDIs, in the cases reported
herein, it was responsible for the decreased clearance of
victim drugs even before addition of the perpetrator, so that
the toxic range was more easily reached in DDI conditions.
Interestingly, the steady-state plasma levels of sorafenib,
a CYP3A substrate whose liver metabolism is minor
(\ 30%) [186], were increased threefold 2 weeks after the
introduction of felodipine, another substrate of CYP3A, in
a patient with hepatocellular carcinoma. While ketocona-
zole did not increase the AUC of single-dose sorafenib in
healthy volunteers [187], the introduction of the CYP3A
substrate felodipine resulted in a clinically significant
increase in sorafenib steady-state levels. The explanation
for such significant DDIs may involve other routes of
elimination (sorafenib is also a substrate of UDP-glu-
curonyltransferases [48]), as well as alteration of sorafenib
F. Storelli et al.
metabolism due to hepatocellular carcinoma and cirrhosis.
Indeed in vitro maximal velocities of sorafenib oxidation
and glucuronidation were reduced by 25- and 2-fold,
respectively, in tumor liver microsomes compared with
control hepatic microsomes [188]. Moreover, among hep-
atocellular carcinoma patients, those with Child–Pugh B
cirrhosis showed 20% higher sorafenib exposure compared
with Child–Pugh A cirrhosis [98].
To summarize, cirrhosis is associated with decreased
CYP expression, liver blood flow, and hepatic uptake,
which lead to alteration of drug hepatic clearance. It might
also affect renal function through hepatorenal syndrome.
This might result in the achievement of toxic levels of
drugs, potentially leading to clinically relevant conse-
quences. Regarding the magnitude of DDIs, current
knowledge indicates that the impact of CYP inhibitors
might be reduced by liver dysfunction. Therefore, while the
addition of a CYP inhibitor might require dose adaptation
in the presence of a CYP inhibitor in healthy volunteers, it
might not be the case for advanced cirrhotic patients. Static
[189] and dynamic models [179, 190] have been proposed
to predict the exposure of drugs in cirrhotic patients based
on the Child–Pugh classification. When incorporating cir-
rhosis-related physiological changes into the semi-mecha-
nistic PBPK models, predicted drug concentrations
corroborated with observed data [179, 190]. However,
recent work indicates underprediction of lopinavir expo-
sure changes in cirrhotic patients by PBPK modeling,
which highlights the need to provide additional efforts to
address knowledge gaps in virtual hepatic impairment
populations before being able to predict complex DDIs
involving liver diseases with PBPK modeling [191].
6 Inflammation
Systemic inflammation markers have been identified in a
number of diseases, such as advanced cancer, inflammatory
diseases (rheumatoid arthritis, psoriasis), and infection
(influenza infection, sepsis) [192]. In addition, inflamma-
tion is the result of oncologic treatment by recently mar-
keted immunotherapy agents [193, 194]. With the recent
development of such immunotherapies, closer scientific
attention has been brought to the reduction of CYP-medi-
ated drug metabolism and transport in inflammatory con-
ditions [194].
The underlying mechanisms of reduced CYP activity
and expression have been investigated in vitro [195–200]
and are not only related to transcriptional suppression but
also in part to post-translational protein modification
caused by proinflammatory cytokines, with the most potent
being IL-6, tumor necrosis factor (TNF)-a, IL-1b, and
interferon (IFN)-c [201]. In rheumatoid arthritis patients,
Complex Drug–Drug–Gene–Disease Interactions
tocilizumab, a humanized, monoclonal, antihuman IL-6
receptor (IL-6R) antibody, reversed IL-6-induced sup-
pression of CYP3A4 activity, as demonstrated by a
decrease of simvastatin exposure of approximately 60 and
38% 1 and 5 weeks after tocilizumab infusion, respectively
[202]. Similarly, sarilumab, a human monoclonal antibody
blocking IL-6R, also provoked a decrease in simvastatin
exposure of approximately 50% 7 days after a single-dose
administration [203]. Using a cocktail approach, the
activity of CYP3A (probe midazolam), CYP2C19 (probe
omeprazole), and CYP2C9 (probe warfarin) was increased
after sirukumab administration in rheumatoid arthritis
patients [204]. Consequently, PBPK models were devel-
oped in order to predict the impact of elevated IL-6 levels
on CYP3A4 and the treatment effect of tocilizumab and
sirukumab in rheumatoid arthritis patients [205, 206].
Moreover, cancer immunotherapy agents have also been
associated with IL-6-mediated CYP suppression. [193]
While the impact of IL-6 as a marker of systemic inflam-
mation on CYP3A repression now appears to be clear,
additional knowledge is required in order to assess the
impact of disease-related inflammatory response on drug
exposure.
The effect of inflammation on DDIs has only been
investigated in relation to CYP induction, and it was evi-
denced in human hepatocytes that proinflammatory
cytokines such as IL-6 or TNFa inhibit the b-naph-
thoflavone-mediated induction of CYP1A enzymes and the
rifampin-mediated induction of CYP3A [207]. The
inducibility of CYP2B6 and CYP2C was also decreased by
IL-6, probably through negative regulation of the nuclear
constitutive androstane receptor (CAR) and the pregnane X
receptor (PXR) gene expression [208].
In the present case reports review, only three cases of
DDIs in inflammatory status patients were retained from
the literature search, mainly because inflammatory markers
such as CRP, IL-6, or white blood cell count were rarely
reported in reviewed publications. As reported in advanced
cancer patients, CRP, IL-6, a1-acid glycoprotein, and
TNFa seem to be the inflammatory markers that have the
greatest correlation between inflammatory response and
decreased CYP-mediated drug clearance [192].
In two of these cases, inflammation was a compounding
factor of DDI-related ADRs, in addition to renal impair-
ment, cirrhosis, or genetic polymorphisms. As an example,
severe extrapyramidal symptoms were related to haloperi-
dol toxicity when comedicated with the moderate CYP3A
inhibitor ciprofloxacin in a patient, combining four com-
pounding factors: CYP2D6*6/*6 (PM) and UGT2B7 -161
CT (IM) genotypes, cirrhosis, and acute inflammation as
reported by high CRP levels [61].
Although significant advances have been proposed in
the field of inflammation-induced CYP repression, clinical
1285
evidence is still scarce and is mostly limited to the impact
of IL-6 on CYP3A activity. Further research is needed in
order to investigate the impact of both chronic and acute
inflammation on other CYPs and transporters. Nonetheless,
available population PK (PopPK) and PBPK models have
shown their ability to simulate interactions between
inflammatory diseases and the PK of CYP substrates,
which paves the way for model-informed drug exposure
predictions and dose-finding strategies. As with the other
diseases described in the present review, PBPK might
represent a useful tool in order to predict complex sce-
narios of DDIs in the context of systemic inflammation,
provided that the PK changes related to inflammatory sta-
tus that are fed into the model are validated. Moreover, the
impact of surrogate markers of systemic inflammation
other than IL-6 on CYP activity and/or expression, as well
as their combination, remains to be investigated.
7 Clinical Perspectives
Computerized physician order entry (CPOE) systems cur-
rently include DDI checking tools, most of which are
integrating alert systems [209]. In some advanced systems,
renal and hepatic functions can also be incorporated, and
dose adaptation might be recommended according to the
estimated GFR and/or liver functional status [210]. A
recent meta-analysis highlighted the discrepancy between
the high prevalence of potential DDIs and the low preva-
lence of actual DDIs leading to clinical harm [211]. DDI
checking tools included in CPOE systems only have poor
positive predictability and may cause annoyance and
frustration through overexposure to prescription alerts
[212], especially when prescription assistance is lacking.
While therapeutic drug monitoring might represent the
gold standard for assessing drug exposure, the approach is
not feasible for all drugs and patients, it is resource-con-
suming, and it cannot predict exposure prior to the actual
drug dosing. Phenotyping of drug-metabolizing enzymes
has the major advantage of taking into account both
intrinsic and extrinsic factors influencing enzyme activity
and expression, and is currently often used in Geneva
University Hospitals in order to support the management of
complex drug interaction scenarios [213]. However, this
approach is not yet performed routinely and requires time
for analysis and administration of xenobiotics, even at low
doses. The management of complex drug interaction sce-
narios involving intrinsic (genetic polymorphisms and/or
diseases affecting drug disposition) and extrinsic (con-
comitant medications) factors is thus challenging and relies
on several prerequisites.
First, the prescriber needs to be aware of concomitant
medications, diseases, or medical conditions that may
1286
affect the PK of the prescribed treatment. Therefore, pre-
and post-graduate education of physicians to PK, pharma-
cogenetics, and DDIs is highly recommended to ensure that
prescribers are aware of intrinsic and extrinsic factors
leading to drug safety and efficacy issues. In addition, the
use of advanced CPOE systems that integrate a DDI
checking tool, laboratory data (genetic results, liver func-
tion tests, creatinine clearance/GFR, biomarkers of sys-
temic inflammation), and clinical information (known
allergies, pregnancy, weight, sex) may represent a great
asset to gather all relevant data needed to optimize drug
prescription.
Moreover, the main issue remains the ability to accu-
rately predict the clinical outcome of such complex drug
interactions. In clinical practice, the prescriber may not
have sufficient PK knowledge and confidence to adjust
drug dosage based on the patients’ characteristics, and may
refer to a clinical pharmacology consultancy. Although
pharmacogenetics is expanding in clinical practice, the
prescriber is often confused when interpreting a pharma-
cogenetic result. A US survey reported that 98% of
physicians agree that genetics may predict drug response;
however, only 10% feel adequately informed to actually
use genetic tests [214]. Therefore, providing more focus on
pharmacogenetics, which is expected to grow bigger and
bigger in future years with the paradigm shifting from
universal to personalized medicine, in the education of
Fig. 2 Integrated PBPK model-based informed dose adaptation for
the management of complex drug interactions in clinical practice.
CPOE Computerized Physician Order Entry, DMET drug-
F. Storelli et al.
healthcare professionals, seems necessary. Pharmacoge-
netic education to physicians allowed the successful
adoption of healthcare models of pre-emptive pharmaco-
genetic testing [215]. In addition, the clinical validation of
pharmacogenetic markers is an important prerequisite for
further implementation. Pharmacogenomics data may not
be sufficient to reliably predict a clinical response to a
drug, particularly when the impact of genetic variants on
the PD outcome is moderate [216] or when the relation
with clinical outcome is affected by other patients’ char-
acteristics or clinical settings [217].
Current knowledge does not yet allow for the manage-
ment of complex drug interactions, even though static
mechanistic models and dynamic PBPK models have been
developed to address this issue. While a static prediction
tool might present the advantage of simplicity and appli-
cability in a clinical setting, PBPK modeling seems more
able to handle such complex scenarios, as demonstrated
with DDIs involving genetic polymorphisms or race-re-
lated changes in CYP abundance [156, 218]. In the past
years, model-informed approaches have been successively
used to optimize drug dosing in special populations and
appear to be efficient tools for improving the efficacy and
safety of a drug treatment for an individual patient by
integrating its own characteristics in the model [219].
While a few issues currently hamper their widespread use
in clinical practice, including limited evidence of efficacy,
metabolizing enzymes and transporters, GFR glomerular filtration
rate, PBPK physiologically-based pharmacokinetics
Complex Drug–Drug–Gene–Disease Interactions
weak awareness of the approach in the clinical community,
and lack of cost–benefit analysis, we think that future
implementation of such comprehensive tools may help to
manage complex clinical scenarios in relation to drug
dosing (see Fig. 2). The development of international
guidelines for the management of complex drug interac-
tions is however a prerequisite for further clinical
implementation.
8 Conclusions
More than 60 case reports of complex DDIs were identified
from our systematic literature search. The analysis of these
reports on DDIs involving intrinsic factors such as genetic
polymorphisms or diseases showed their association with
drug exposure. Although the additive role of intrinsic
factors in the clinical relevance of DDIs is not clearly
demonstrated in some case reports presented in this sys-
tematic review, there is evidence suggesting that both
intrinsic and/or extrinsic factors have an impact on the
extent of DDIs and the severity of clinical outcomes.
Indisputably, the presented case reports are real-life illus-
trations of the issue of complex DDIs in clinical practice.
Further research and dedicated clinical trials are needed to
appraise the clinical relevance of complex drug interactions
involving extrinsic and intrinsic factors. Current data
indicate a greater variability in drug levels and exposure
when such complex DDIs are present, compared with
simple DDIs. This variability results in poor predictability
of the DDIs and to the potentially dramatic clinical con-
sequences that were described in the present review. In
clinical practice, the management of such complex sce-
narios of DDIs is currently empiric due to the lack of
prediction tools. The future development of such tools
available for clinical practice, including PBPK model-
based precision dosing tools, is expected to bring more
confidence in the management of complex scenarios and
therefore to decreasing the rate of DDI-related adverse
reactions.
Compliance with Ethical Standards
Funding No funding was received for the preparation of this
manuscript.
Conflict of interest Flavia Storelli, Caroline Samer, Jean-Luc Reny,
Jules Desmeules and Youssef Daali declare no conflicts of interest.
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