Background: Multidrug-resistant (MDR) tuberculosis (TB) is still a global health threat with close to half a million new cases annually (1). Infection with MDR- or extensively drug resistant (XDR-) TB requires usage of second-line treatment, which is longer, requires costly, more toxic drugs and has a success rate of merely 56% (1). Linezolid is one of the core drugs (group A) used for treatment of MDR- and XDR-TB. Treatment of TB using linezolid is much longer than standard treatment of other indications (maximal 28 days). The long treatment duration has been shown to lead to more serious adverse events (2,3). In order to reduce the risk of developing serious adverse events, model-informed precision dosing (MIPD) (4), guided by patient characteristics, individual plasma drug concentrations and a population pharmacokinetic (PK) or combined pharmacokinetic-pharmacodynamic (PKPD), model can be employed.
Aims: The aim of this work was to develop a population PK model, which in combination with efficacy and safety targets, can be used for MIPD of linezolid in the clinic from the first day of administration. Furthermore, clinical trial simulations were performed to evaluate the most optimal dose on an average level following different dosing regimens.
Methods: A population pharmacokinetic model for linezolid was built using therapeutic drug monitoring (TDM) data from 70 MDR-and XDR-TB patients from the University Medical Center Groningen (UMCG), Groningen, The Netherlands. Linezolid was administered as daily oral doses ranging from 150 mg to 1200 mg for up to 542 days in combination with other anti-TB drugs. Pharmacokinetic parameters were described using the nonlinear mixed-effects modelling software NONMEM (v.7.4.3; Icon Development Solutions, http://www.iconplc.com/technology/products/nonmem, Ellicott City, MD) (5). When building the structural model, one- and two-compartment models were evaluated, as well as absorption delay, non-linear elimination and elimination inhibition. Different residual error models were evaluated, and inter-individual (IIV) and inter-occasion (IOV) variability was tested on each parameter while building the stochastic model. Stepwise covariate modeling (SCM) was used to select statistically and clinically significant covariates. Evaluation of the most optimal dose considering both efficacy and safety targets was performed using simulations of 1000 hypothetical patients per dose group including IIV and IOV.
Results: The final model consisted of a one-compartment model with transit absorption and first-order elimination kinetics with concentration- and time-dependent auto-inhibition of elimination. Covariates included were sex on absorption rate constant, P-glycoprotein inhibitors on mean absorption transit time, and HIV status on oral clearance. Efficacy and safety targets for MIPD were the fAUC0-24h/MIC of 119 and fCmin of 1.38 mg/L, respectively. Simulations of fAUC0-24h/MIC and fCmin in 1000 virtual patients per dose-level at steady-state with covariates and MIC values sampled from the study population, revealed that for 600 mg once daily (QD), 72.4% of the virtual population met the safety target, whereas the efficacy target was met in 74.7% of the population. On average, doses of 300 mg twice daily (BID), 600 mg BID and 1200 mg QD resulted in higher efficacy but also increased safety issues compared to the 600 mg QD regimen.
Conclusion: a one-compartment model with transit absorption, taking into account concentration- and time-dependent auto-inhibition of linezolid elimination, was successfully developed, describing linezolid population PK in MDR- and XDR-TB patients. This work proposes a MIPD approach for linezolid, applicable from the first day of treatment, and suggests that a 600 mg QD regimen results in adequate efficacy and less safety concerns compared to the other studied regimens in most of the patients.
- World Health Organization. Global tuberculosis report 2020. WHO <http://www.who.int/tb/publications/global_report/en/> (2020). Accessed 13 October 2020.
- Millard, J. et al. Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation. J Antimicrob Chemother 73, 1755–1762 (2018).
- World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. WHO <http://www.ncbi.nlm.nih.gov/books/NBK539517/> (2019). Accessed 13 October 2020.
- Keizer, R. J. et al. Model-Informed Precision Dosing at the Bedside: Scientific Challenges and Opportunities. CPT: Pharmacometrics & Systems Pharmacology 7, 785–787 (2018).
- Beal, S., Sheiner, L., Boeckmann, A., and Bauer, R. NONMEM 7.3.0 Users Guides. Hanover, MD: ICON Development Solutions (1989).