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

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: unbound (f) area-under-the-concentration-time-curve (AUC)/minimal inhibitory concentration (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 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 an MIC of 0.5 mg/L was 55% or 97% if patients receiving 300 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 and MIC determination should be performed to control PK/PD target attainment as linezolid shows high variability in its PK in the TB population.

Automated summary

This study found that a dose of 300 mg twice daily of linezolid may not be sufficient to treat patients with multidrug-resistant tuberculosis from a pharmacokinetic/pharmacodynamic perspective. It is therefore recommended to start with a higher dose of 600 mg twice daily to ensure PK/PD target attainment. Therapeutic drug monitoring and MIC determination should be performed to control PK/PD target attainment due to high variability in linezolid's PK in the TB population.