Drug Metabolism and Pharmacokinetics 56 (2024) 101019

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Drug Metabolism and Pharmacokinetics

journal homepage: www.journals.elsevier.com/drug-metabolism-and-pharmacokinetics

Insights into drug development with quantitative systems pharmacology: A

prospective case study of uncovering hyperkalemia risk in diabetic
nephropathy with virtual clinical trials
Ryuta Saito *, Tomohisa Nakada
Discovery Technology Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, 227-0033, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: The quantitative systems pharmacology (QSP) approach is widely applied to address various essential questions
Quantitative systems pharmacology in drug discovery and development, such as identification of the mechanism of action of a therapeutic agent,
Model-informed drug discovery and patient stratification, and the mechanistic understanding of the progression of disease. In this review article, we
development
show the current landscape of the application of QSP modeling using a survey of QSP publications over 10 years
Clinical trial simulation
Diabetic nephropathy
from 2013 to 2022. We also present a use case for the risk assessment of hyperkalemia in patients with diabetic
Hyperkalemia nephropathy treated with mineralocorticoid receptor antagonists (MRAs, renin-angiotensin-aldosterone system
Renin–angiotensin–aldosterone system inhibitors), as a prospective simulation of late clinical development. A QSP model for generating virtual patients
inhibitor with diabetic nephropathy was used to quantitatively assess that the nonsteroidal MRAs, finerenone and apar­
Mineralocorticoid receptor antagonist arenone, have a lower risk of hyperkalemia than the steroidal MRA, eplerenone. Prospective simulation studies
using a QSP model are useful to prioritize pharmaceutical candidates in clinical development and validate
mechanism-based pharmacological concepts related to the risk-benefit, before conducting large-scale clinical
trials.

and aimed at improving the quality, efficiency, and cost effectiveness of

1. Introduction
Research and development (R&D) productivity on drug discovery
and development has been halved every 9 years in the 60 years from
1950 to 2010, declining about 80-fold [1]. The results of nonclinical
studies are often not sufficient to quantitatively predict clinical out­
comes and the related signatures in terms of both drug efficacy and
adverse effects. In fact, the success rate of approvals is about 5.9 % of all
pharmaceutical candidates on drug development, and the success rate in
Phase 2 is the lowest, ranging from 15 % to 30 % [2]. Insufficient effi­
cacy is the most frequent cause of failure in Phase 2 trials (51 %), fol­
lowed by safety concerns (20–30 %), and these issues have not improved
in the 20 years from 1990 to 2010 [3,4]. To improve such low R&D
productivity on drug discovery and development, the technologies of
modeling and simulation have been applied to the pharmaceutical in­
dustry to enhance the quality of scientific decision-making, called
model-informed drug discovery and development (MID3). MID3 is
defined as a quantitative framework for prediction and extrapolation,
based on the knowledge and inference generated from integrated
mathematical models of compound-, mechanism-, and disease-level data
decision-making by the European Federation of Pharmaceutical In­
dustries (EFPIA) MID3 workgroup [5]. The integrated mathematical
model and its analysis, which is positioned as the core technology of the
MID3 approach, is called quantitative systems pharmacology (QSP) or
quantitative systems toxicology. QSP mechanistically connects the
pharmacological mechanism of a proposed product, across the hierarchy
of human biology and the variability of patient population, to the
quantitative changes of its pharmacodynamic biomarkers/clinical end­
points following various dosing regimens in healthy participants or
patients, through multiscale spatial and temporal modeling [6].
2. Current landscape of QSP modeling
According to the United States Food and Drug Administration (FDA),
regulatory submissions containing QSP have steadily increased since
2013 [7]. Also, only one article on QSP was found before 2012 in the
MEDLINE database; “quantitative systems pharmacology” OR “quanti­
tative systems toxicology” was used in the paper. Therefore, the land­
scape analysis of scientific papers on QSP in this review paper covered
the period from January 1, 2013 to December 31, 2022 (Fig. 1). QSP has

* Corresponding author. Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, 227-0033, Japan.
E-mail address: saitou.ryuuta@mc.mt-pharma.co.jp (R. Saito).

https://doi.org/10.1016/j.dmpk.2024.101019
Received 30 October 2023; Received in revised form 25 April 2024; Accepted 2 May 2024
Available online 9 May 2024
1347-4367/© 2024 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
R. Saito and T. Nakada Drug Metabolism and Pharmacokinetics 56 (2024) 101019

and C). The co-occurrence analysis used the ontology dictionary VOCab,
Abbreviations developed by SciBite Limited (Cambridge, UK), to correct spelling in­
consistencies. Until 2018, QSP models were mostly applied to specific
ACE angiotensin-converting enzyme central nervous system diseases such as schizophrenia and Alzheimer’s
ANGII angiotensin II disease, and cardiotoxicity such as cardiac arrhythmias. However, since
ARB angiotensin receptor blocker 2019, QSP modeling was adapted to various therapeutic areas. As shown
CV cardiovascular in the survey by the IQ Consortium, there have been several publications
DN diabetic nephropathy on the application of QSP modeling to the area of oncology, such as for
GFR glomerular flow rate triple-negative breast cancer and non-small cell lung cancer, with the
CKD chronic kidney disease progress of immuno-oncology research. Conversely, the application of
MAP mean arterial pressure QSP modeling has increased in the area of infectious diseases due to the
MR mineralocorticoid receptor coronavirus disease 2019 (COVID-19) pandemic, and also has unex­
MRA mineralocorticoid receptor antagonist pectedly continued to be utilized for metabolic disorders such as type 2
PAC plasma aldosterone concentration diabetes mellitus (T2DM), nonalcoholic steatohepatitis, and nonalco­
PRC plasma renin concentration holic fatty liver disease.
QSP quantitative systems pharmacology Recent breakthroughs in artificial intelligence (AI) and machine
RAAS renin-angiotensin-aldosterone system learning (ML) are also expected to accelerate the application of QSP
SCr serum creatinine modeling to drug discovery and development. The integration of QSP
T2DM type 2 diabetes mellitus and ML was reviewed in 2022 [9]. The purposes of the integrated QSP
UACR urinary albumin to creatinine ratio and AI/ML approaches can be grouped into four categories: (1)
parameter estimation and extraction; (2) model structure; (3) dimension
reduction; and (4) uncertainty and virtual populations. As one example
of the need for AI/ML-facilitated dimension reduction, sensitivity
quickly become established as a technical term since 2016. The EFPIA analysis, uncertainty estimation, and virtual population generation
MID3 workgroup published the MID3 white paper in 2016, and more require performing hundreds of thousands of QSP model simulations.
than 50 QSP scientific articles have been published per year since 2019 The hybrid method of QSP and AI/ML shows that small data AI ap­
(Fig. 1A). A cross-industry survey about QSP modeling conducted in proaches can be supplemented by encoding mechanistic principles into
2018 by the QSP working group within the International Consortium for the AI architecture. Thus, the integrated data and mechanistic infor­
Innovation and Quality in Pharmaceutical Development (IQ Con­ mation of hybrid models are important factors for achieving good pre­
sortium) revealed the current state of preclinical QSP modeling in dictive power.
addition to future opportunities at that time [8]. In the IQ consortium QSP modeling has been widely used to address various essential
survey, cancer and autoimmune disorders were identified as focused questions in different stages of drug discovery and development: for
therapeutic areas in which QSP support is expected to grow in the near example, identification or verification of drug target molecules, pre­
future. On the other hand, in the same survey, infectious diseases and diction of clinical efficacy and safety from nonclinical data, decision
metabolic disorders were described as therapeutic areas with low support on clinical trials using biomarkers, differentiation from
growth potential for supporting by QSP modeling. To follow up this competitive drugs, patient stratification for clinical trial design, and
forecast of the near future, we compared the disease or gene names pathophysiological interpretation of clinical data [5]. A recent survey
co-occurring in QSP articles between up to 2018 and after 2019 (Fig. 1B conducted by the IQ Consortium showed that QSP models are mainly

Fig. 1. Trends of scientific publications on QSP and word clouds of co-occurring words with QSP. (A) Number of published papers related to Quantitative Systems
Pharmacology (QSP) were yearly plotted to search the MEDLINE database using “quantitative systems pharmacology” OR “quantitative systems toxicology” as a
search term. (B, C) Word clouds represented co-occurrence frequencies of disease names up to 2018 and after 2019, respectively. (D, E) Word clouds represented co-
occurrence frequencies of gene name up to 2018 and after 2019, respectively.

2
R. Saito and T. Nakada
used to support internal decision-making in preclinical and early phases
of clinical development [10]. We have also reported some retrospective
research examples of the application of QSP models within a pharma­
ceutical company, including the clarification of mechanisms of action of
anticoagulants and endocrine disruptors in nonclinical studies [11,12],
clinical prediction of drug-induced liver injury [13], and the modeling
and simulation of sodium-glucose transport protein 2 inhibitors [14,15].
Therefore, in this review paper, we present a use case for the risk
assessment of hyperkalemia in patients with diabetic nephropathy (DN)
treated with mineralocorticoid receptor antagonists (MRAs), as an
example of prospective research for late clinical development.
3. Prospective use case for the risk assessment of hyperkalemia
3.1. Chronic kidney disease in diabetic patients and treatment advances
Chronic kidney disease (CKD) is a common complication in in­
dividuals with T2DM and is an independent risk factor for cardiovas­
cular disease. The persistent and abnormal activation of the MR by the
hormone aldosterone in T2DM patients has detrimental effects [16]. The
MR is a steroid hormone receptor belonging to the nuclear hormone
receptor superfamily, which activates intracellular receptors and nu­
clear transcription factors. The primary ligand for the MR is aldosterone,
the end product of the renin-angiotensin-aldosterone system (RAAS)
[17]. Aldosterone, a mineralocorticoid steroid hormone, is synthesized
and secreted in response to various factors, including elevated potassium
levels, angiotensin II (ANGII), corticotropin, and sodium depletion,
primarily within the adrenal cortex [18]. It plays a pivotal role in
maintaining the sodium and potassium balance and regulating extra­
cellular fluid volume through its interaction with MRs found in renal
tubular epithelial cells. MRs are not confined to renal tubules but are
also present in other cell types, such as vascular smooth muscle cells and
mesangial cells. This broader distribution suggests that excessive aldo­
sterone production may directly harm both the cardiovascular system
and the kidneys [19]. In individuals with diabetes, heightened aldoste­
rone activity in the kidneys leads to increased hypertension, glomerular
injury, renal vasoconstriction, and proteinuria [20].
Chronic use of medications that inhibit the RAAS can lead to aldo­
sterone breakthrough, where aldosterone levels rebound [21]. This
phenomenon is associated with a faster decline in glomerular filtration
rate (GFR), a key indicator of kidney function. MR overactivity can also
be triggered by mechanisms independent of serum aldosterone, such as
increased MR expression in target tissues and elevated levels of MR
steroid hormone agonists including aldosterone and cortisol [22–24].
Table 1
Drug profiles of nonsteroidal mineralocorticoid receptor antagonists used in this study.
Eplerenone
Chemical structure
In vitro Ki (MR) 84.9 nMa
Plasma protein binding (human) 50 %b
Elimination half-life 3–6 hb
Clinical dosage 25 mg, 50 mgb
Notes.
a
In-house data.
b
US-FDA label of INSPRA tablets.
c
US-FDA label of KERENDIA tablets.
d
Nakamura and Kawaguchi [42].
e
MT-3995-E06 (NCT01756703).
3
Drug Metabolism and Pharmacokinetics 56 (2024) 101019
Overactive MRs can increase cardiovascular and renal risks through
both hemodynamic and metabolic pathways [25,26]. The initial decline
in estimated GFR due to MR activation may ultimately lead to improved
renal function, possibly due to increased tubuloglomerular feedback
[19]. Nonetheless, aldosterone breakthrough can occur in about 40 % of
individuals with diabetic kidney disease and is closely linked to
decreased GFR [27].
To address these issues, several randomized controlled trials have
explored the use of MRAs for the treatment of CKD. Eplerenone, a ste­
roidal MRA, has demonstrated effectiveness not only in DN but also in
hypertension and heart failure. Its beneficial effects include blood
pressure reduction, and in individuals with reduced left ventricular
ejection fraction, blood pressure-independent anti-inflammatory and
antifibrotic effects, leading to reductions in cardiovascular morbidity
and mortality [26]. However, the clinical application of eplerenone is
limited due to the increased risk of hyperkalemia (high serum potassium
levels) [16]. To mitigate this risk, nonsteroidal MRAs (ns-MRAs) with
high MRA selectivity have been proposed. The approval of finerenone by
the FDA in 2021 was followed by the advanced clinical development of
apararenone (MT-3995) [17]. They provide an alternative to epler­
enone, and their features for DN treatment are summarized in Table 1.
These developments in MRAs represent significant progress in managing
the complex interplay between CKD and T2DM [17].
3.2. Hyperkalemia as a major adverse event of MRAs
Hyperkalemia is a major adverse event of MRAs and thus patients
with DN should be closely monitored for this condition when treated
with this class of drugs. Potassium is balanced in the body by matching
food intake with excretion mainly via urine and maintaining the
appropriate distribution between extra- and intracellular fluids in the
body. While 98 % of total body potassium is retained in intracellular
fluid, 2 % of that is in the extracellular space. Serum potassium con­
centrations are precisely maintained between 3.5 and 5.0 mEq/L [28].
Hyperkalemia is an increase in serum potassium concentrations beyond
5.5 mEq/L and is associated with a higher risk of cardiovascular events.
Outpatients with hyperkalemia with serum potassium concentrations
>6.0 mEq/L should undergo cardiac monitoring [28]. Table 2 shows the
frequencies of DN patients with hyperkalemia at their clinical dosage of
the MRAs. Some patients exceeding the potassium thresholds were
observed even in the placebo group of eplerenone [29]. This was likely
attributed to the use of enalapril, an angiotensin-converting enzyme
inhibitor (ACEi), because RAAS inhibitors including ACEi and angio­
tensin receptor blocker (ARB) also elevate serum potassium by
Finerenone Apararenone
1.83 nMa 104 nMa
90 %c 97 %d
2–3 hc 250–300 hd
10 mg, 20 mgc 5 mg, 10 mge
R. Saito and T. Nakada Drug Metabolism and Pharmacokinetics 56 (2024) 101019

Table 2 insulin resistance in T2DM patients is associated with a greater risk of

Comparison of the estimated frequency of exceeding thresholds of serum po­ hyperkalemia because insulin regulates potassium by shifting from the
tassium with the observed values. blood into the intracellular space [30]. Even though studies of MRAs
Drugs Dose Frequency of exceeding Frequency of exceeding have similar eligibility (inclusion/exclusion) criteria, the distribution of
5.5 mEq/L 6.0 mEq/L baseline characteristics among patients such as GFR, serum potassium
Estimated Observed Estimated Observed concentrations, and plasma aldosterone concentrations differs between
a trials, leading to a difference in the frequency of hyperkalemia during
Eplerenone Placebo 0.0 % (N 4.5 % (N 0.0 % (N 3.4 % (N
= 260) = 91) = 260) = 91) the treatment period.
50 mg, 5.5 % (N 4.5 % (N 0.9 % (N 2.2 % (N
qd = 260) = 91) = 260) = 91) 3.3. QSP model for elevated serum potassium caused by MRAs
100 mg, 13.7 % (N 9.8 % (N 4.4 % (N 6.1 % (N
qd = 260) = 86) = 260) = 86)
To address the above challenges, a QSP model for the regulation of
Finerenoneb Placebo 0.0 % (N 0.0 % (N 0.0 % (N 0.0 % (N serum potassium was developed based on the Entelos Hypertension
= 465) = 94) = 465) = 94)
PhysioLab (EHPL) model, which was originally derived from the Guy­
10 mg, 0.9 % (N 0.0 % (N 0.0 % (N 0.0 % (N
qd = 465) = 98) = 465) = 98) ton/Karaaslan model of blood pressure regulation [31,32]. As an
20 mg, 2.6 % (N 1.7 % (N 0.2 % (N 0.0 % (N extension of the Guyton/Karaaslan model, the EHPL model character­
qd = 465) = 119) = 465) = 119) izes relevant biology on the long-term regulation of blood pressure, as
Apararenonec,d 5 mg, 0.2 % (N 4.4 % (N 0.0 % (N 0.0 % (N controlled by the RAAS system at the systemic and glomerular levels;
qd = 301) = 23)c; = 301) = 21)c; kidney function related to the maintenance of blood pressure; renal
0.0 % (N 0.0 % (N hemodynamic regulation (e.g., sodium, water); and disorders of
= 64)d = 64)d
glomerular and tubular functions (Fig. 2A). A previous study on the
10 mg, 1.8 % (N 0.0 % (N 0.2 % (N 0.0 % (N
qd = 301) = 22)c; = 301) = 19)c; EHPL model demonstrated that it is able to accurately recapitulate not
0.0 % (N 0.0 % (N only lowered blood pressure but RAAS markers (ANGII receptor type
= 62)d = 62)d 1-bound ANGII and plasma renin concentration) in hypertensive pa­
Notes: Estimated values represent simulated frequencies with numbers of virtual tients by using different classes of antihypertensive agents: ACEi (ena­
patients in parenthesis. lapril, ramipril), ARB (candesartan, irbesartan, losartan, valsartan),
a
Epstein [29]. calcium channel blocker (amlodipine), direct renin inhibitor (aliskiren),
b
Bakris [39]. diuretic (hydrochlorothiazide), and MRA (eplerenone) [33]. However,
c
MT-3995-E06 (NCT01756703). the EHPL model itself does not cover the mechanism of potassium
d
Wada [43]. regulation.
For our research aim, the EHPL model was extended by incorpo­
decreasing the urinary excretion of potassium via a reduction in aldo­ rating the potassium regulation module, which was created on the
sterone. As aforementioned, ns-MRAs (e.g., finerenone and aparar­ premise of similar regulation systems regarding the reabsorption and
enone) have a lower risk of hyperkalemia than steroidal MRAs (e.g., secretion of sodium and potassium in the kidney [34]. When connecting
eplerenone) (Table 2). It should be noted that study designs (e.g., the potassium module with the EHPL model, it was confirmed that this
inclusion/exclusion criteria of serum potassium concentrations, GFR, connection did not alter the characteristics of normotensive virtual pa­
and blood pressure at baseline status and evaluation period) somewhat tients. The connected module reproduced clinical findings in terms of
differ depending on the study, making it complicated to compare the the following relationships: (i) urinary potassium secretion in the distal
potential of MRAs in terms of hyperkalemia. In particular, the following tubule and the collecting duct according to aldosterone concentrations;
factors are reportedly independent risk factors of hyperkalemia. (1) Low (ii) aldosterone binding to the MR, driving potassium secretion; and (iii)
GFR (<60 mL/min) causes lower urinary potassium excretion, resulting serum potassium concentrations and potassium secretion [35,36].
in the retention of fluid and potassium in the body. (2) Aging is asso­ Furthermore, some key parameters such as GFR, plasma aldosterone
ciated with increased serum potassium concentrations. (3) More severe concentration, and serum potassium concentration were validated with

Fig. 2. Schematic illustration of potassium regulation by aldosterone in the Entelos Hypertension PhysioLab (EHPL). (A) Overall relationship of the RAAS pathway,
blood pressure, and renal electrolyte management in the EHPL. (B) Schematic representation of aldosterone effects on renal potassium and sodium regulation pre-
treatment. MR, mineralocorticoid receptor. PAC, plasma aldosterone concentration. (C) Schematic representation of aldosterone effects on renal potassium and
sodium regulation after MRA treatment. MRA blocks effective aldosterone bound to the MR. This causes reductions in both potassium excretion and sodium
reabsorption, resulting in increased serum potassium.

4
R. Saito and T. Nakada Drug Metabolism and Pharmacokinetics 56 (2024) 101019

clinical results with normotensive subjects under the conditions of
different dietary intakes of sodium and potassium [37]. As illustrated in
Fig. 2B and C, aldosterone plays a complementary but opposite role in
the urinary excretion of both potassium and sodium. Aldosterone binds
to the MR on the distal tubule to cause urinary potassium excretion,
while MR-bound aldosterone causes sodium retention by increasing
sodium reabsorption. Thus, increases in MR-bound aldosterone results
in decreased serum potassium and elevated serum sodium levels, while
MRA reverses such regulation.
The final model captured the interactive effects of aldosterone and
electrolytes (e.g., sodium, potassium). To validate the final model of
serum potassium profiles in patients with DN, a model-based simulation
was compared from the RENAAL study with DN patients administered
losartan and placebo in combination with furosemide [38]. The use of
ARB (e.g., losartan) was reasonable for this model-validation because
ARB acts on RAAS in the same way as MRA. The final model well
captured the elevation in serum potassium level in both the losartan and
placebo groups (Fig. 3A). In addition, we carried out further simulations
of whether the model could characterize the effects of the MRAs
(eplerenone, finerenone, and apararenone) on the clinical outcomes of
mean arterial pressure (MAP), GFR, and the urinary albumin to creati­
nine ratio (UACR). MAP is a clinical indicator of the average blood
pressure in an individual patient through a single cardiac cycle, and both
GFR and UACR are clinical biomarkers representing renal function in DN
patients. These parameters are related with MR-bound aldosterone. As
shown in Fig. 2B and C, serum potassium is closely regulated with PAC
and urinary potassium excretion. When renal function declines, serum
potassium will rise due to reduced excretion of potassium [21]. In
addition, MR-bound aldosterone increases intraglomerular arterial
pressure via stimulation of urinary sodium reabsorption [19]. Based on
each clinical study of 50 and 100 mg eplerenone [29], 10 and 20 mg
finerenone [39], and 5 and 10 mg apararenone (MT-3995-E06,
NCT01756703), we ran simulations with virtual patients (N = 260, 465,
301, respectively) to meet the inclusion/exclusion criteria in terms of
creatinine clearance, GFR, MAP, UACR, and serum potassium concen­
trations in each study (Table 2). Although individual data are not
available and there may be some outliers in these studies, the simulated
results overlapped with the observed data (Fig. 3B). The estimated fre­
quency exceeding the criteria of serum potassium concentrations (i.e.,
5.5 and 6.0 mEq/L) were slightly higher but generally comparable to the
observed data (Table 2). It should be noted that cohort size could affect
the observed frequency. The virtual clinical trial was extended for cohort
size and patient variety compared with an actual clinical study, sup­
porting in-depth evaluation of the hyperkalemia risk.
3.4. Head-to-head comparisons of hyperkalemia risks by QSP among the
MRAs
Normally, it is not straightforward to conduct head-to-head com­
parisons among the same class of drugs due to unmatched study con­
ditions such as cohort size, evaluation period, and recruited population.
However, a QSP model can provide a mechanistic platform to implement
virtual clinical trials to directly compare the performance among drugs
and gain insights into the right doses and patients to mitigate unfavor­
able side effects. As aforementioned, we developed and validated the
QSP model with potassium regulation mechanisms associated with
systemic/renal RAAS systems. Considering the clinical studies for these
MRAs [29,39] (NCT01756703), a virtual clinical trial was designed to
mimic actual studies and was evaluated at 8 weeks after initial admin­
istration of the MRA (Fig. 4A). In the virtual trial, DN virtual patients (N
= 546) were selected with realistic criteria in terms of GFR, UACF, MAP,
and serum potassium concentrations; their distributions are presented in
Fig. 4B.
The model-based simulations demonstrated individual relationships
between increments in serum potassium from baseline after MRA
treatment and GFR at baseline. As described earlier, DN virtual patients
with lower GFR had more significant elevation of serum potassium,
especially those treated with eplerenone (Fig. 5A). Overall, lower in­
crements in serum potassium were found for the ns-MRAs, finerenone
and apararenone, than for eplerenone. Likewise, the maximum serum
potassium concentrations after an 8-week treatment were simulated
according to baseline serum potassium concentrations. Some virtual
patients in the 50 and 100 mg eplerenone groups were simulated to
exceed the threshold of moderate/severe hyperkalemia (>6.0 mEq/L),
whereas virtual patients with serum potassium level greater than 5.5
mEq/L, the threshold of mild hyperkalemia, were found in all groups but
with the lowest proportion in the 5 mg apararenone group (Fig. 5A, B
and 5C). Although patients with a lower GFR and/or higher baseline
value of serum potassium are regarded as the high-risk hyperkalemia
group [30], virtual patients with such characteristics showed less

Fig. 3. Validation results on changes in serum potassium and related measurables after drug treatments. (A) Comparison of simulated serum potassium and observed
concentrations after losartan/placebo treatment. Box plots represent simulated serum potassium of virtual patients who met the inclusion criteria in the RENAAL
study. Symbols and bars represent the mean and standard error of the mean of the observed data from the RENAAL study [38]. (B) Box plots represent the simulated
changes in the MAP, GFR, and UACR of virtual patients who met the inclusion criteria in each clinical study. For the eplerenone (EP) study, symbols and bars
represent the median and 25th to 75th percentile for the observed GFR (mean of the observed MAP and UACR) 8 weeks after treatment [29]. For the finerenone (FN)
study, symbols and bars represent the mean and standard deviation (SD) for the observed MAP and GFR (observed mean and 95 % confidence interval [CI] for the
UACR) 60 days after treatment from the ARTS-DN study [39]. For the apararenone (AP) study, symbols and bars represent mean and SD for the observed MAP and
GFR (observed mean and 95 % CI for the UACR) 8 weeks after treatment from the MT-3995-E06 study (NCT01756703).

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R. Saito and T. Nakada
Fig. 4. Virtual trial design and characteristics of the virtual patients with DN. (A) Virtual patients with type II DN with albuminuria (N = 546) were used to meet the
following criteria at baseline condition: GFR ≥35 mL/min, UACR ≥50 mg/g (5.65 mg/mmol), MAP ≤133 mmHg, serum potassium ≤5.0 mEq/L. EP, Eplerenone (50
mg QD, 100 mg QD). FN, Finerenone (10 mg QD, 20 mg QD). AP, Apararenone (5 mg QD, 10 mg QD). (B) Histogram of the DN virtual patients (N = 546) for MAP,
GFR, UACR, serum potassium, and PAC.
sensitivity to apararenone than finerenone regarding increments in
serum potassium (Fig. 5D). As summarized in Table 1, apararenone has a
much longer half-life than finerenone, leading to the maintenance of
suppression of MR-bound aldosterone with less variation of electrolytes
regulation and feedback effects of RAAS systems [33]. As the underlying
mechanisms, two possible reasons are suggested. Firstly, drugs with
short half-life such as eplerenone and finerenone tend to have higher
Cmax to maintain effective concentrations than apararenone. Secondly,
the drugs such as eplerenone and finerenone, which have a large dif­
ference between peak and trough plasma concentrations, are more likely
to increase serum potassium with repeated administrations because of
the feedback from MR inhibition and the high sensitivity of MR to serum
potassium after the MRA administration.
3.5. Limitations of QSP model for potassium regulation
Hyperkalemia results either from the shift of potassium out of cells or
from abnormal renal potassium excretion [40,41]. Shifting of potassium
from the cells to the extracellular space is a cause of transient hyper­
kalemia, while chronic hyperkalemia indicates an impairment in renal
potassium secretion. In chronic renal failure, the decreased GFR and
secondary decrease in distal delivery cause nephron dropout, less col­
lecting tubule mass to secrete potassium, and/or the reduced mineral­
ocorticoid activity induces chronic hyperkalemia. Hyperkalemia
induced by RAAS inhibitors such as MRAs depends on this chronic
regulatory system of electrolyte regulation. In acute hyperkalemia,
shifting of as little as 2 % of the body’s potassium from the intracellular
to the extracellular space can double the plasma potassium concentra­
tion [40,41]. Acute hyperkalemia occurs with tissue damage, exercise,
catecholamines, insulin deficiency, and metabolic acidosis. Therefore,
the relevant mechanisms of acute hyperkalemia remain to be covered in
the EHPL model extended in this study as a future challenge. Currently,
the EHPL model consists of the mechanisms of electrolyte regulation and
cardio-renal axis, enabling us to quantitatively evaluate the risk of
chronic hyperkalemia induced by RAAS inhibitors. For further appli­
cations to treatments and patient stratification in hyperkalemia beyond
the current scope of this model, in-depth investigation will be warranted
6
Drug Metabolism and Pharmacokinetics 56 (2024) 101019
to incorporate the relevant mechanisms of acute hyperkalemia into this
model and validate it with related data.
4. Conclusions
In this review article, we surveyed QSP publications over 10 years
from 2013 to 2022 to clarify the current landscape of the application of
QSP models in drug discovery and development. Moreover, as an
investigative example of prospective prediction for late clinical devel­
opment, which has not been usually reported in the past, we presented a
use case for the risk assessment of hyperkalemia in patients with DN
treated with an MRA. Clinical trial simulations based on a QSP model
can quantitatively evaluate drug efficacy and/or safety by head-to-head
comparisons of competitive drugs with the same or similar mechanism
of action using virtual patients with the same conditions. The actual
clinical trials require huge resources and costs to evaluate the hypothesis
based on clinical questions, and the QSP model can be used to perform
not only virtual large-scale clinical trial but also patient stratification.
The latter case would suggest an informative platform to design a clin­
ical trial by in-depth understanding what kinds of patients should be
included/excluded to minimize a safety concern without compromising
drug efficacy. With the QSP model validated rightly, the model can be
also reusable for relevant subsequent programs to gain insights into
more promising profiles. In other words, a prospective simulation study
using the QSP model is useful to prioritize pharmaceutical candidates in
clinical development and validate pharmacological concepts related to
the risk-benefit, because it can be performed at no huge additional costs.
Recent breakthroughs of AI/ML technologies are expected to accelerate
the application of QSP models to drug discovery and development, with
the hybrid models of QSP and AI/ML-encoded clinical and experimental
data and mechanistic knowledge having good predictive power. We
would like to improve the low productivity and success rates in drug
discovery and development as much as possible by the applications of
QSP models to prospective prediction, such as the use case presented in
this review article.
R. Saito and T. Nakada Drug Metabolism and Pharmacokinetics 56 (2024) 101019

Fig. 5. Simulated increases in serum potassium after MRA treatments for 8 weeks. (A) Upper panels show maximum increments in serum potassium from baseline 8
weeks after MRA treatments related to baseline GFR. Lower panels show maximum serum potassium concentrations at 8 weeks after MRA treatment related to
baseline serum potassium concentrations. (B) Comparisons of the maximum serum potassium concentrations after 8 weeks among MRAs with one-way analysis of
variance (**, p < 0.01; ***, p < 0.001; NS, not statistically significant). Symbols represent the individual value in each virtual patient. Yellow and red lines represent
serum potassium concentrations of 5.5 and 6.0 mEq/L as criteria of mild and moderate/severe hyperkalemia, respectively [28]. (C) Display of individual virtual
patient to each MRA treatment and their associations among the treatment regarding the maximum serum potassium concentrations after 8 weeks among MRAs. (D)
Difference of maximum increments in serum potassium from baseline 8 weeks between finerenone (FN) 10 mg and apararenone (AP) 5 mg as an example (upper).
Difference of maximum serum potassium concentrations at 8 weeks between FN 10 mg and AP 5 mg as an example (lower). (For interpretation of the references to
colour in this figure legend, the reader is referred to the Web version of this article.)

Role of the funding source Writing – review & editing.

This research received no specific grant from any funding agency in Declaration of competing interest
the public, commercial, or not-for-profit sectors.
Ryuta Saito and Tomohisa Nakada are an employee of Mitsubishi
Authorship contributions Tanabe Pharma Corporation.

Participated in research design: Saito and Nakada. Acknowledgments

Conducted research: Saito and Nakada.
Performed data analysis: Nakada. The authors would like to sincerely thank Dr. Maithreye Rengasw­
Wrote or contributed to the writing of the manuscript: Saito and amy, Krishnakant Dasika, and Dr. Rukmini Kumar (Vantage Research
Nakada. Inc) for their support in the modeling work. We would also like to thank
Dr. Kohei Kikkawa (Mitsubishi Tanabe Pharma Corporation) for valu­
CRediT authorship contribution statement able discussion about pharmacology of RAAS inhibitors.

Ryuta Saito: Conceptualization, Data curation, Funding acquisition, References

Investigation, Methodology, Project administration, Supervision, Vali­
dation, Writing – original draft, Writing – review & editing. Tomohisa
Nakada: Conceptualization, Data curation, Formal analysis, Investiga­
tion, Methodology, Validation, Visualization, Writing – original draft,
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