Population pharmacokinetics and target attainment analysis of linezolid in multidrug-resistant tuberculosis patients

Br J Clin Pharmacol. 2021 Oct 7. doi: 10.1111/bcp.15102. Online ahead of print.

ABSTRACT

AIM: This study investigates the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of linezolid in patients infected with multidrug-resistant (MDR) tuberculosis (TB).

METHODS: A pharmacometric model was developed including 244 timed linezolid concentration samples from 39 patients employing NONMEM® 7.4. The probability of target attainment (PTA, PK/PD target: fAUC/MIC of 119) as well as a region-specific cumulative fraction of response (CFR) were estimated for different dosing regimens.

RESULTS: A one-compartment model with linear elimination with a clearance (CL) of 7.69 L/h (Interindividual variability (IIV): 34.1%), a volume of distribution (Vd) of 45.2 L and an absorption constant (KA) of 0.679 h-1 (Interoccasion variability: 143.7%) allometric scaled by weight best described the PK of linezolid. The PTA at a minimal inhibitory concentration (MIC) of 0.5 mg/L was 55% or 97% if patients receiving 300 mg or 600 mg twice daily, respectively. CFRs varied greatly among populations and geographic regions. A desirable global CFR of ≥90% was achieved if linezolid was administered at a dose of 600 mg twice daily but not at a dose of 300 mg twice daily.

CONCLUSION: This study showed that a dose of 300 mg twice daily of linezolid might not be sufficient to treat MDR-TB patients from a PK/PD perspective. Thus, it might be recommendable to start with a higher dose of 600 mg twice daily to ensure PK/PD target attainment. Hereby, therapeutic drug monitoring (TDM) and MIC determination should be performed to control PK/PD target attainment as linezolid shows high variability in its PK in the TB population.

PMID:34622478 | DOI:10.1111/bcp.15102