Steady state pharmacokinetics of cycloserine in patients on terizidone for multidrug-resistant tuberculosis.

Abstract

Terizidone/cycloserine (TRD/CS) is included in standard treatment regimens for multidrug-resistant tuberculosis (MDR-TB) in many countries. The steady state pharmacokinetics (PKs) of CS after TRD administration are not known. We recruited in-patients treated with 250-750 mg oral TRD daily as part of standard treatment regimens for pulmonary MDR-TB in Cape Town, South Africa. Plasma CS assays were performed in samples taken pre-dose and at 2, 4, 6, 8 and 10 h post-dose. CS concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Non-compartmental PK analyses were performed. Of 35 participants enrolled, 22 were males, and 20 (57%) were infected with the human immunodeficiency virus; the median age was 37 years. The median duration on TRD at the time of sampling was 33 days (interquartile range [IQR] 28-39). The area under the concentration-time curve at 0-10 h (AUC0-10) was 319 μg.h/ml (IQR 267.5-378.7), and peak concentration was 38.1 μg/ml (IQR 32.6-47.2). On multiple regression, dose (mg/kg) was the only factor independently associated with AUC0-10. Steady state concentrations of CS in patients treated with TRD for MDR-TB were higher than those reported with CS formulations. Our findings support once-daily dosing.