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Dosage Individualization of Linezolid - Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity
Dosage Individualization of Linezolid - Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity
Dosage Individualization of Linezolid - Precision Dosing of Linezolid To Optimize Efficacy and Minimize Toxicity
a Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical, Pharmacology, University of Liverpool and Royal Liverpool Broadgreen
University Hospital Trust, Liverpool, United Kingdom
b Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
c Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona, Spain
d Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, España
e Infectious Diseases Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
f Universitat Pompeu Fabra, Barcelona, Spain
g Critical Care Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain
h Critical Illness Research Group (GREPAC), Institut Mar d’Investigaciones Mèdiques, Barcelona, Spain
i Universitat Autònoma de Barcelona, Barcelona, Spain
j Children’s Hospital Los Angeles, University of Southern California. Los Angeles, California, USA
S. Luque and W. Hope contributed equally to the article. Their order was decided by considering the contribution to the article.
KEYWORDS population pharmacokinetics, therapeutic drug monitoring, dose Received 27 November 2020
Returned for modification 25 December
selection, Bayesian, individualized dosing, linezolid, pharmacokinetic software
2020
Accepted 18 March 2021
Accepted manuscript posted online
June 2021 Volume 65 Issue 6 e02490-20 Antimicrobial Agents and Chemotherapy aac.asm.org 1
Luque et al. Antimicrobial Agents and Chemotherapy
clinical effectiveness, and its favorable pharmacokinetic (PK) properties (i.e., high oral bioavaila-
bility and extensive tissue distribution into infection sites with anatomical barriers) (1–3).
Numerous studies have reported a high variability in the plasma drug exposure for patients
RESULTS
Linezolid dosing and PK. A total of 338 acutely hospitalized patients were included in
the study. The demographic and relevant clinical data are summarized in Table 1. Linezolid
was administered at the standard licensed regimen (i.e., 600 mg q12h) in 323/338 of patients
(95.6%), at a dose of 300 mg q12h in 2/338 (0.6%), and at a dose of 600 mg q8h in 13/338
(3.8%) of patients. The intravenous (i.v.) and oral routes were used in 300 (88.8%) and 38
(11.2%) of patients, respectively. The median (range) duration of treatment was 11.0 (3 to 127)
days. A total of 868 linezolid plasma concentrations obtained from 338 patients were included
in the population analysis. The mean (standard deviation [SD]) number of observations per
patient was 2.6 (1.7) with a range of 1 to 15. The means (SD) of the minimum concentration
(Cmin,ss) and maximum concentration (Cmax,ss), both obtained at steady state, were 7.2 (9.5) and
FIG 1 Mean population (A) and individual (B) predicted concentrations versus observed concentrations of linezolid
in plasma. The broken line is the line of identity (i.e., observed = predicted concentrations).
19.7 (12.3) mg/liter, respectively. The first Cmin,ss concentrations were subtherapeutic
(,2 mg/liter) in 43.1% of the patients, in range (between 2 and 8 mg/liter) in only 28% of
them and supratherapeutic (.8 mg/liter) in 28.9%. Figure 1 shows the linezolid plasma
concentration-time profiles for all patients in this study.
Population PK model. A three-compartment pharmacokinetic model that consisted
of absorptive, central, and peripheral compartments was fitted to the data. Linezolid was
administered as a bolus input into the absorptive compartment (gut) and as zero-order
time delimited i.v. input into the central compartment over 1 h. Drug was cleared from the
central compartment, and this was modeled as a first-order process.
Estimates for measures of central tendency, dispersion, and the 95% confidence
intervals for the population PK parameters from the final model are shown in Table 2.
Figure 2 shows the observed-predicted values using the median parameter values both before
and after the Bayesian step. After maximum a posteriori probability-Bayesian estimation, a lin-
ear regression of observed versus predicted values had an intercept and a slope of 20.157
FIG 2 Linezolid plasma concentration-time profiles for patients receiving oral or i.v. linezolid. Sampling was performed
in the majority of cases after the second or third day of treatment.
for all susceptible isolates classified according to EUCAST was estimated to be as high as 2,400
mg q12h, which is four times higher than the maximum licensed linezolid dose. In addition,
the PTAs for achieving trough concentrations within the therapeutic range (between 2 and
8 mg/liter) with different linezolid regimens (300 mg i.v. q12h, 600 mg i.v. q24h, 600 mg
i.v. q12h, 600 mg i.v. q8h, and 1,200 mg i.v. q24) were determined and are shown in Fig. 4.
Validation of the linezolid software dosing controller for predicting individual
FIG 3 PTA for achieving 100% T.MIC and AUC/MIC $ 100 mg · h/liter in plasma of linezolid (600 mg/12 h
administered as a 1-h infusion) during the third day of treatment (from 48 to 72 h after the start of the
treatment).
FIG 4 PTA for achieving trough concentrations within the therapeutic range (between 2 and 8 mg/liter) during the
third day of treatment with different doses of linezolid (from 48 to 72 h after the start of the treatment).
were critically ill, and all of them received a standard regimen of linezolid (600 mg q12h).
Intravenous dosing was used in 9 (90%) patients, and only one received oral administra-
tion. There was a median of three observations (range, two to five) per patient, and the
measured target concentrations of linezolid ranged from 0.8 to 36.6 mg/liter.
The algorithm was able to accurately track the observed PK of each of these 10
patients. The combined individual patient observed-versus-predicted concentrations
of linezolid from all 10 patients are shown in Fig. 5. The r2 value of the linear regression
was 0.998, with a slope of 0.985 and an intercept of 0.175. The median (interquartile
range) bias and percent bias for the predictions of the target concentrations were
20.1 (0.17) mg/liter and 20.5 (1)%, respectively. For the dosage prediction, the bias
and percent bias were 101.5 (237.3) mg and 16.9 (39.6)%, respectively.
Example of the clinical utility of the linezolid dose optimization software. The
FIG 5 Observed-versus-predicted linezolid concentrations of all 10 patients. The solid line is the line
of identity (observed = predicted concentrations), and the dashed line is the linear regression line
fitted to the pooled data with a slope of 0.985, an intercept of 0.175 and a R2 value of 0.998.
FIG 6 Graph showing the potential advantage of a controller for the individualization of linezolid concentrations. A patient receiving a standard linezolid
dose (600 mg i.v. q12h infused over 1 h) was sampled at 1 h (peak or Cmax) and 12 h after linezolid dose administration (trough or Cmin) on two occasions
(past data in red color). The second observed trough concentration is much higher than the superior limit of the therapeutic range (8 mg/liter), being
potentially toxic. The controller predicted two much lower maintenance doses of 394 and 215 mg i.v. q12h (a half of the initial dose) infused over 1 h to
achieve a therapeutic trough concentration of between 5 and 7 mg/liter (future data in green color). The solid line represents the mean predicted
concentration-time profile of the patients.
than desired target concentration and associated with an increased risk of toxicity. The admin-
istration of a lower dose suggested by the algorithm was predicted to rapidly allow for the
achievement of a linezolid trough concentration that was safe and effective (Fig. 6).
DISCUSSION
Therapeutic drug monitoring (TDM) is a well-established adjunct for some antimi-
(21). Algorithms to enable dosage adjustment for linezolid have not been developed or
used, and this has been an impediment for routine use of TDM for linezolid. This study
provides the necessary tools to begin addressing that problem.
Here, an algorithm was developed to achieve concentration targets for linezolid that are
safe and effective. The final PK model was a three-compartment linear model with an absorp-
tive compartment, which is consistent with previously developed PK population models of
linezolid (22, 23). Since our primary aim was to develop an algorithm for dosage individualiza-
tion, we selected the simplest structural model without extensive covariate building.
The algorithm that has been constructed to facilitate individualized dosing needs
to be further characterized in a prospectively study, as has previously been done with
other antimicrobial agents (24, 25). Regimen planning should be performed by an
experienced clinician with due consideration for factors with spurious results (e.g., sub-
optimal compliance and medication errors). However, the software may be a clinically
useful tool for a decision support tool for precision dosing of linezolid as a way to opti-
mize the use of linezolid in patients with serious Gram-positive infections.
Compartments 1, 2, and 3 denote the absorptive, central and peripheral compartments, respectively,
with X(1), X(2), and X(3) representing the amount of drug (mg) in each respective compartment. CL is
clearance from the central compartment (liters per hour); Vc (liters) is the volume of the central compart-
ment, and Kcp and Kpc are first-order intercompartmental transfer rate constants (h21).
Other pharmacokinetic calculations. The plasma AUC for each patient was estimated using the
Bayesian posterior parameter estimates using the trapezoidal method embedded within Pmetrics. The
average AUC0–24 (AUC0–24av) was calculated by dividing the cumulative AUC of each patient by the total
time in hours and multiplying by 24 h.
Targets of linezolid exposure and toxicity. The therapeutic range for linezolid for efficacy has
been defined as a Cmin,ss of 2 to 8 mg/liter (11, 12, 17, 21, 30, 31). An optimal pharmacokinetic/pharmaco-
dynamic (PK/PD) ratio for linezolid antibacterial efficacy has been defined as a 100% time .MIC (i.e.,
Cmin,ss $ MIC) in clinical studies (32). A trough concentration of linezolid of $2 mg/liter is a value often
used in clinical practice and it has been associated with .80% probability of bacterial eradication (20). A
Cmin,ss . 8 mg/liter was used as the upper bound because it has been associated with a higher risk of
thrombocytopenia in clinical studies (11, 12). However, it has to be considered that a much lower cutoff
point (a trough concentration of linezolid of 0.19 mg/liter) has been associated with a 50% maximal mi-
tochondrial toxicity in an in vitro hollow-fiber infection model system (33).
The AUC/MIC has also been identified as the relevant PK/PD index for linezolid in animal and clinical
studies (33, 34). Values of AUC/MIC of 100 and 300 have been suggested for efficacy and toxicity, respec-
tively (34). Again, in the previously described hollow-fiber model a much lower value of AUC of about
150 mg s² h/liter was related to mitochondrial toxicity (33).
Monte Carlo Simulations predicting optimal exposure and probability of toxicity. Monte Carlo
simulations (n = 1,000) of plasma concentrations were used to calculate the 100% time .MIC and the
AUC24/MIC of 100 at steady state (i.e., on day 3 of treatment, from 48 to 72 h posttreatment initiation) af-
ter the administration of a fixed regimen of 600 mg q12h i.v. The simulated AUC from 48 to 72 h were
also compared to the individual predicted AUC after the Bayesian step during the same period of time.
Linezolid software dosing controller construction. The final population PK linezolid model was
incorporated into BestDose (29, 35). This software has been previously validated to individualize dosages of
other antimicrobials such us vancomycin, voriconazole, piperacillin, and antiretroviral therapy (24, 25, 36–39).
The structural mathematical equations of the model relating input (linezolid dosing) to output (line-
zolid plasma concentrations) and the discrete joint probability distribution of pharmacokinetic parame-
ters (support points) were included in the controller. These support points are the prior Bayesian sets of
PK parameters that can be used to explain the future observed concentrations of the patients. The soft-
ware used user-supplied data regarding dosing (dose and timing of drug administration) and the
observed concentrations (past data) to find the least biased and most precise dosage regimen relative
graphically by default as provided by the NPDE R package (version 1.2) using (i) a Q-Q plot (where Q is
quantile) of the NPDE and (ii) a histogram of the NPDE. The normal distribution of NPDEs (P 0.115 in the
Shapiro-Wilk normality test) confirmed the adequacy of the model for dosing simulations.
SUPPLEMENTAL MATERIAL
Supplemental material is available online only.
SUPPLEMENTAL FILE 1, PDF file, 0.4 MB.
ACKNOWLEDGMENTS
S.L. received support from the Instituto de Salud Carlos III (ISCIII; grant BA18/00005),
the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), and the
Spanish Society of Hospital Pharmacy (SEFH). S.L. also received research travel grants.
We thank Roger Jelliffe and Michael Neely, both members of the Laboratory for
Applied Pharmacokinetics (LAPK), for the development of the computer program
“BestDose.”
W.H. holds or has recently held research grants with F2G, AiCuris, Astellas Pharma,
Spero Therapeutics, Matinas Biosciences, Antabio, Amplyx, Allecra, Bugworks, NAEJA-
RGM, AMR Centre, and Pfizer. He holds awards from the National Institutes of Health,
Medical Research Council, National Institutes of Health Research, the FDA and the
European Commission (FP7 and IMI). W.H. has received personal fees in his capacity as a
consultant for F2G, Amplyx, Ausperix, Spero Therapeutics, and BLC/TAZ. W.H. is an
Ordinary Council Member for the British Society of Antimicrobial Chemotherapy. S.G.
has received personal fees from Merck Sharp & Dohme, Angelini Pharma, and Pfizer. J.P.H.
has received personal fees Pfizer, Merck Sharp & Dohme, and Astellas Pharma, and he has
held research grants with Merck Sharp & Dohme. The other authors have nothing to
declare.
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