Evaluation of cycloserine dose regimens in an Indian cohort with multidrug-resistant tuberculosis: a population pharmacokinetic analysis.

Abstract

Cycloserine is recommended for inclusion in regimens for multidrug-resistant tuberculosis (MDR-TB). Its efficacy is time dependent and relies on the concentration remaining above the minimum inhibitory concentration (MIC); however, there is a concentration-dependent risk of neurotoxicity. Limited pharmacokinetic (PK) data are available in individuals of Indian origin, despite the high burden of MDR-TB in India. We enrolled adults and adolescents receiving cycloserine for MDR-TB at a tertiary hospital in Mumbai, India, in a prospective cohort. Total daily doses ranged from 500 to 750 mg, and participants underwent serial PK sampling on multiple visits starting 1 month after treatment initiation. PK data were analyzed using non-linear mixed-effect modeling. A total of 180 participants (117 females) were enrolled, with a median age of 27 years (interquartile range [IQR] 21-35), weight of 56.0 kg (IQR 46.0-65.9), and fat-free mass of 38.6 kg (IQR 32.3-47.1). Cycloserine PK was best described by a one-compartment model with first-order elimination and transit compartment absorption. Allometric scaling by fat-free mass provided the best adjusment for body size. Serum creatinine improved the model fit and allowed separate estimation of renal and non-renal clearances, whose typical values were 0.589 and 0.901 L/h, respectively. Simulations showed median exposure of 308 mg·h/L after 250 mg twice daily (BID), which is lower than reported in literature. Monte Carlo simulations suggested that doses of 500 or 750 mg BID are required to reach efficacy targets of ≥30% and ≥64% time within dose interval above MIC. The reasons behind the low exposure identified in this Indian population require further investigation.