PHARMACOLOGY

Dosage Individualization of Linezolid: Precision Dosing of

Linezolid To Optimize Efficacy and Minimize Toxicity
S. Luque,a,b,c W. Hope,a L. Sorli,c,d,e,f R. Muñoz-Bermudez,c,g,h N. Campillo,b,c J. Barceló-Vidal,b,c F. Álvarez-Lerma,g,h,i
J. P. Horcajada,c,d,e,i J. R. Masclans-Enviz,c,g,h,i M. Neely,j S. Graub,c,d,i

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.

ABSTRACT The high interindividual variability in the pharmacokinetics (PK) of linezolid

has been described, which results in an unacceptably high proportion of patients with
either suboptimal or potentially toxic concentrations following the administration of a
fixed regimen. The aim of this study was to develop a population pharmacokinetic
model of linezolid and use this to build and validate alogorithms for individualized dos-
ing. A retrospective pharmacokinetic analysis was performed using data from 338 hospi-
talized patients (65.4% male, 65.5 [614.6] years) who underwent routine therapeutic

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drug monitoring for linezolid. Linezolid concentrations were analyzed by using high-per-
formance liquid chromatography. Population pharmacokinetic modeling was performed
using a nonparametric methodology with Pmetrics, and Monte Carlo simulations were
employed to calculate the 100% time .MIC after the administration of a fixed regimen
of 600 mg administered every 12 h (q12h) intravenously (i.v.). The dose of linezolid
needed to achieve a PTA $ 90% for all susceptible isolates classified according to
EUCAST was estimated to be as high as 2,400 mg q12h, which is 4 times higher than
the maximum licensed linezolid dose. The final PK model was then used to construct Citation Luque S, Hope W, Sorli L, Muñoz-
Bermudez R, Campillo N, Barceló-Vidal J,
software for dosage individualization, and the performance of the software was assessed Álvarez-Lerma F, Horcajada JP, Masclans-Enviz
using 10 new patients not used to construct the original population PK model. A three- JR, Neely M, Grau S. 2021. Dosage
compartment model with an absorptive compartment with zero-order i.v. input and individualization of linezolid: precision dosing of
linezolid to optimize efficacy and minimize
first-order clearance from the central compartment best described the data. The dose toxicity. Antimicrob Agents Chemother 65:e02490-
optimization software tracked patients with a high degree of accuracy. The software 20. https://doi.org/10.1128/AAC.02490-20.
may be a clinically useful tool to adjust linezolid dosages in real time to achieve prespe- Copyright © 2021 American Society for
Microbiology. All Rights Reserved.
cified drug exposure targets. A further prospective study is needed to examine the
Address correspondence to S. Luque,
potential clinical utility of individualized therapy. sluque@parcdesalutmar.cat.

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

L inezolid is an oxazolidinone antibacterial agent that is used for the treatment of

infections caused by Gram-positive bacteria. The use of linezolid has increased in
recent years because of its activity against drug-resistant organisms, its demonstrated
5 April 2021
Published 18 May 2021

June 2021 Volume 65 Issue 6 e02490-20 Antimicrobial Agents and Chemotherapy aac.asm.org 1
Luque et al. Antimicrobial Agents and Chemotherapy

TABLE 1 Demographic and clinical characteristics of the included patients

Parametera Result
Total patients, n 338
Male, n (%) 221 (65.4)
Median age, yr (range) 68 (21–98)
Median body wt, kg (range) 75 (37.5–193)
Median BMI, kg/m2 (range) 26.7 (13.4–70.8)
Critically ill patients, n (%) 225 (66.6)

Initial linezolid dose, n (%)

300 mg q12h i.v. 2 (0.6)
600 mg q12h oral 38 (11.2)
600 mg q12h i.v. 285 (84.3)
600 mg q8h i.v. 13 (3.8)

Median serum creatinine, mg/dl (range)*† 1.08 (0.17–13.6)

Median GFR, ml/min/1,73m2 (range)*† 63.2 (3.3–196.5)
GFR , 90 ml/min/1.73 m2, n (%)* 211 (62.4)
GFR . 130 ml/min/1.73 m2, n (%)* 19 (5.6)
Renal replacement therapy, n (%) 39 (11.5)
Serum albumin, g/dl (range) 2.6 (1.4–5.1)
Median total serum protein, g/dl (range) 5.3 (3–8.4)
Median total leukocytes, cells
109/liter (range) 12.9 (0.32–102.5)

Liver cirrhosis, n (%) 25 (7.4)

Child Pugh A 4 (1.2)
Child Pugh B 13 (3.8)
Child Pugh C 8 (2.4)

Median hospital stay, days (range) 40.0 (3–753)

Mortality during linezolid treatment, n (%) 27 (8.0)
In-hospital mortality, n (%) 91 (26.9)
glomerular filtration rate. *, values at the beginning of linezolid treatment; †, estimated using the Chronic
aGFR,

Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (40).

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

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receiving a standard fixed regimen of linezolid (600 mg every 12 h [q12h]) (4–7). Some of the
PK variability of linezolid can be explained by fixed effects (e.g., body weight, renal and/or he-
patic function, and the severity of illness) (4, 5, 7–9). However, a large portion of the observed
variance remains unexplained. Variability in drug exposure leads to concentration-dependent
therapeutic failure in some patients and an increased probability of toxicity in others (9–12).
Precision dosing is potentially a way that clinical outcomes can be further optimized.
The principal aim of this study was to develop a population PK model of linezolid
using a large number of hospitalized patients and then use this model to build algo-
rithms that can individualize the dosing of linezolid. The performance of this algorithm
was characterized in a separate cohort of 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

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Dosage Individualization Software of Linezolid Antimicrobial Agents and Chemotherapy

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

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and 0.959, respectively, and a coefficient of determination of 0.96. The bias and imprecision
were both acceptable (bias = 1.16 mg/liter; imprecision = 19 mg/liter). Covariates such as age,
body weight, the presence of liver cirrhosis, and critical illness did not significantly improve
the fit of the model to the data and were not considered for further model building.
Probability of target attainment. After the administration of the standard dose of
linezolid (600 mg i.v. q12h), the probability of target attainment (PTA) for achieving
100% total drug T.MIC in plasma for the different tested MIC values is shown in Fig. 3.
With this fixed dose, an optimal PTA could only be achieved for isolates with a MIC of
0.5 mg/liter when estimating the 100% T.MIC and for isolates with a MIC of 1 mg/liter when an
AUC/MIC of $100 mg s² h/liter was considered. In any case, an optimal exposure could not be
achieved for isolates with a MIC value of 4 mg/liter, which is the current susceptibility break-
point according to EUCAST (13). The regimen of linezolid needed to achieve a PTA of $90%

TABLE 2 Population pharmacokinetic parameters of linezolida

Parameter Mean SD Median 95% CI
CL (liters/h) 7.720 7.191 5.126 3.809–6.267
Vc (liters) 33.690 17.697 31.493 29.047–35.218
Ka (h21) 7.036 10.314 1.900 1.236–2.457
F 0.804 0.207 0.880 0.841–0.901
Kcp (h21) 4.418 8.531 0.243 0.217–0.437
Kpc (h21) 7.633 11.980 0.546 0.306–1.079
aCL,clearance; Vc, volume of the central compartment; F, bioavailability; Ka, first-order absorption rate constant.
Kcp and Kpc are the first-order intercompartmental rate constants. CI, confidence interval.

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Luque et al. Antimicrobial Agents and Chemotherapy

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

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concentrations and dosage individualization. The test data set from 10 patients that
were used to assess the performance of the controller had the following demographic
and clinical characteristics. Eight patients (80%) were male with a median (range) age
of 74.5 (59 to 88) years. The median (range) body weight and body mass index (BMI)
were 72.5 (60.0 to 100 kg) and 26.1 (21.3 to 31.6) kg/m2, respectively. Six patients (60%)

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).

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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

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potential utility of the controller is illustrated in Fig. 6, which depicts a typical patient for
whom the standard linezolid regimen resulted in a trough concentration significantly higher

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.

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Luque et al. Antimicrobial Agents and Chemotherapy

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-

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crobial classes such as the glycopeptides and aminoglycosides (14). More recently,
TDM has been used for other classes of drugs, such as the beta-lactams, to improve
antimicrobial activity (especially in special populations), and to minimize the emergence of
AMR (15). Despite numerous studies of linezolid PK demonstrating significant PK variability
(16–19) and knowledge about drug exposures that are associated with safety and efficacy,
active dose adjustment of linezolid is usually not considered (18).
Monte Carlo simulations performed with the PK model used to build the control
software suggested that the use of the standard fixed regimen of linezolid (600 mg
q12h) did not allow the achievement of pharmacodynamic targets for isolates with an
MIC up to 4 mg/liter, which is the ECOFF value for S. aureus and E. faecium. For these
strains, higher dosages may be required to achieve favorable clinical outcomes.
However, dosage escalation may lead to potentially toxic drug exposures in more than 30%
of the patients. This limitation provides the principal justification for considering dosage indi-
vidualization to achieve drug exposures of linezolid that are safe and effective.
Some clinicians support routine TDM of linezolid as a potential strategy to ensure
an effective and safe use of this agent (20, 21). Although linezolid is generally well tol-
erated and may cause only mild gastrointestinal adverse events, its use has been also
related to hematological toxicity, particularly in prolonged linezolid courses, in patients
with liver disease, renal failure, or with a reduced baseline platelet count. Pea et al. con-
cluded in a study that TDM may be useful for improving safety outcomes in adult patients
with infections that require prolonged treatment with linezolid and that dosage adjust-
ments based on plasma concentrations may help to avoid drug-induced adverse events

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(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.

MATERIALS AND METHODS

Study design. All patients $18 years and receiving linezolid for . 72 h undergoing routine TDM in
the Hospital del Mar, Barcelona, Spain, between January 2011 and June 2018 were eligible for inclusion.
The study was approved by the Comitè Etic d’Investigació Clínica del Parc de Salut Mar (2016/6987/I).
Treatment with linezolid. Patients received linezolid because of a documented or suspected infec-
tion with a Gram-positive pathogen. Linezolid was used at the discretion of the treating physician. All
patients initially received the standard recommended dosage (600 mg every 12 h, i.v. and/or orally).
Therapeutic drug monitoring of linezolid. TDM of linezolid plasma concentrations was performed
as a part of routine clinical practice. In the majority of our patients, the first plasma sampling was
obtained at $48 h after treatment initiation, when the steady state has been presumably achieved.
Blood samples (4 ml) were collected immediately prior to the administration of the next dose (Cmin,ss)
and then 30 min after the end of a 1-h i.v. infusion or at 2 h after oral dosing (Cmax,ss). In some patients,
an intensive plasma sampling was performed. According to the TDM results, the initial dose of linezolid
was modified to obtain a Cmin,ss within the therapeutic range of efficacy 2 to 8 mg/liter.
Bioanalysis of linezolid concentrations. Blood samples were collected in heparinized tubes, which
were immediately centrifuged (3,000
g for 10 min at 4°C) to obtain plasma, which was then stored at
280°C until bioanalysis. Linezolid concentrations were determined using a validated high-performance
liquid chromatography (HPLC) method with minor modification of a previously described method (26).
Briefly, for each plasma sample, 100 m l was mixed with 100 m l of methanol and then vortexed for
10 s. The mixture was then centrifuged for 5 min at 15,000
g in a refrigerated centrifuge. A total of 50 m l of

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the supernatant was injected. The HPLC equipment was an Alliance e2695 (Waters Cromatografía, S.A.,
Barcelona, Spain). The mobile phase consisted of a mixture of sodium acetate buffer (pH 3.4) and acetonitrile
(80:20 vol/vol) delivered in an isocratic flow at 1.3 ml/min. The chromatogram run time was 10 min, and the
ultraviolet detector wavelength was set at 250 nm. The assay response was linear (coefficient of linearity
.0.99) over the dynamic range of the assay (0.5 to 30 mg/liter in plasma). The limit of quantification was
0.5 mg/liter in plasma. Imprecision values were ,15% over the entire range of calibration standards, and ac-
curacy was within the range of 85 to 115% for all concentrations.
Data collection. The following data were collected from each included patient: age, gender, weight,
renal function (serum creatinine and serum urea at the start of linezolid treatment), albumin, total serum
protein, the presence of liver cirrhosis and severity (Child Pugh score) (27), the need for renal replace-
ment therapies, and linezolid data (dose, route of administration, and TDM data).
Population pharmacokinetic modeling. Population pharmacokinetic modeling was performed
using the nonparametric adaptive grid (NPAG) algorithm embedded within Pmetrics (28, 29). One-, two-,
and three-compartment models were fitted to the data. Elimination from the central compartment and
intercompartmental transfer were modeled as first-order processes. Data were weighted using the
inverse of the estimated assay variance and additional process noise.
Age, gender, actual body weight, serum creatinine, serum urea, serum albumin, total serum proteins,
the presence of liver cirrhosis, critical illness, or the need of renal replacement therapies were evaluated
as covariates using stepwise linear regression. Potential covariates were separately entered into the
model and retained if their inclusion resulted in a statistically significant improvement in the log-likeli-
hood value and/or in the observed-predicted plots.
The fit of each model to the data was assessed using a linear regression of observed-predicted val-
ues both before and after the Bayesian step. The mean prediction error and the mean bias-adjusted
squared prediction error were used to assess bias and imprecision, respectively. Models were compared
by calculating twice the difference in log-likelihood values.
A three-compartment linear model, with an absorption compartment, and first-order input and
clearance from the central compartment, best described the data. The structure of the final PK mathe-
matical model fitted to the study data was described by the following equations.

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Luque et al. Antimicrobial Agents and Chemotherapy

dXð1Þ=dt ¼ 2Ka
Xð1Þ

dXð2Þ=dt ¼ Ka
Xð1Þ – Kcp
Xð2Þ 1 Kpc
Xð3Þ – ðCL=Vc Þ
Xð2Þ

dXð3Þ=dt ¼ Kcp
Xð2Þ – Kpc
Xð3Þ

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

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to a target concentration (future dosage), as previously described (25). The nonparametric collection of
discrete support points for linezolid obtained from the previously designed population pharmacokinetic
model was used as a “population prior” distribution of the values of the PK parameters. This distribution
is the basis for the individualization of the linezolid dose by a multiple-model stochastic control. When
information about a new patient (dosing history of linezolid and measured concentrations) is entered to
BestDose, the probabilities of each support point are updated to new “Bayesian posterior” probabilities
depending on the ability of each point to describe the PK behavior. After that, the software is able to cal-
culate the dose that minimized the weighted squared error between the real target concentration from
the parameter values of each point in the Bayesian posterior and the target.
Linezolid software dosing controller validation. To validate the performance of the software, a
separate data set obtained from 10 patients receiving linezolid and undergoing TDM was used. We
included all measured linezolid concentrations of each patient except the last one, which was used to
assess the predictive performance of the controller and used as the target concentration for dosage
identification.
The performance of the model was first tested by visually comparing the observed versus last predicted
concentrations of each individual patient. In addition, all combined observed versus predicted concentrations
from all 15 patients were plotted, and a linear regression analysis was performed. In a second stage, the pre-
dicted optimal dosage calculated by BestDose to obtain the last target concentrations was compared to the
real administered dose of linezolid, which was 600 mg in the majority of our patients.
Finally, the bias and percent bias for both target concentrations and target dose were calculated.
The bias target was equal to the predicted concentration or dose minus the actual concentration or
dose. The percent bias target was calculated as follows: (predicted concentration or dose – actual target
concentration or dose)/actual target concentration or dose.
The final model was also evaluated graphically and statistically by visual predictive checks (VPCs)
and normalized prediction distribution errors (NPDE) (see Fig. S1 and S2 in the supplemental material). A
total of 1,000 data sets were simulated using the final population model parameters. For the VPCs, the
5th, 50th, and 95th percentiles of the simulated concentrations were processed using the R platform,
plotted against elapsed time, and compared to observed concentrations. NPDE results were summarized

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Dosage Individualization Software of Linezolid
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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