Model-Informed Precision Dosing of Linezolid in Patients with Drug-Resistant Tuberculosis

Laurynas Mockeliunas; Lina Keutzer; Marieke G G Sturkenboom; Mathieu S Bolhuis; Lotte M G Hulskotte; Onno W Akkerman; Ulrika S H Simonsson

doi:10.3390/pharmaceutics14040753

Model-Informed Precision Dosing of Linezolid in Patients with Drug-Resistant Tuberculosis

Pharmaceutics. 2022 Mar 30;14(4):753. doi: 10.3390/pharmaceutics14040753.

Authors

Laurynas Mockeliunas¹, Lina Keutzer¹, Marieke G G Sturkenboom², Mathieu S Bolhuis², Lotte M G Hulskotte², Onno W Akkerman^{3

4}, Ulrika S H Simonsson¹

Affiliations

¹ Department of Pharmaceutical Biosciences, Uppsala University, 75124 Uppsala, Sweden.
² Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
³ Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
⁴ Tuberculosis Center Beatrixoord, University Medical Center Groningen, University of Groningen, 9751 ND Groningen, The Netherlands.

Abstract

Linezolid is an efficacious medication for the treatment of drug-resistant tuberculosis but has been associated with serious safety issues that can result in treatment interruption. The objectives of this study were thus to build a population pharmacokinetic model and to use the developed model to establish a model-informed precision dosing (MIPD) algorithm enabling safe and efficacious dosing in patients with multidrug- and extensively drug-resistant tuberculosis. Routine hospital therapeutic drug monitoring data, collected from 70 tuberculosis patients receiving linezolid, was used for model development. Efficacy and safety targets for MIPD were the ratio of unbound area under the concentration versus time curve between 0 and 24 h over minimal inhibitory concentration (fAUC_0-24h/MIC) above 119 and unbound plasma trough concentration (fC_min) below 1.38 mg/L, respectively. Model building was performed in NONMEM 7.4.3. The final population pharmacokinetic model consisted of a one-compartment model with transit absorption and concentration- and time-dependent auto-inhibition of elimination. A flat dose of 600 mg once daily was appropriate in 67.2% of the simulated patients from an efficacy and safety perspective. Using the here developed MIPD algorithm, the proportion of patients reaching the efficacy and safety target increased to 81.5% and 88.2% using information from two and three pharmacokinetic sampling occasions, respectively. This work proposes an MIPD approach for linezolid and suggests using three sampling occasions to derive an individualized dose that results in adequate efficacy and fewer safety concerns compared to flat dosing.

Keywords: auto-inhibition of linezolid elimination; linezolid; model-informed precision dosing; population pharmacokinetics; simulation; tuberculosis.