Pharmacokinetics of cycloserine in an Indian population with multidrug-resistant tuberculosis.
Juan Eduardo Resendiz-Galvan (1), Tester F. Ashavaid (2), Prerna R. Arora (2), Rohan V. Lokhande (2), Amita Gupta (3), Zarir F. Udwadia (2), Lancelot Pinto (2), Jeffrey A. Tornheim (3), Paolo Denti (2), the MUKT Study Team and the Indo-SA Study team.
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. (2) Research Laboratories, P.D. Hinduja National Hospital and Medical Research Centre, Mumbai, India. (3) Center for Clinical Global Health Education, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Introduction: Cycloserine (CYC) inhibits alanine racemase and D-alanine ligase, two essential enzymes for the cell wall synthesis in Mycobacterium tuberculosis [1]. It is part of the WHO Group B of drugs for the treatment of multidrug-resistant tuberculosis (MDR-TB) at a daily dose of 15 to 20 mg/kg [2]. Overdose of CYC increases the probability of neuropsychiatric concentration-dependent toxicity [3]. CYC is partially metabolized, and approximately 60 to 70% is reported to be excreted by the kidneys [4]. The incidence of MDR-TB is increasing worldwide, and India has the highest burden of MDR-TB with 27% [5]. Moreover, there is a limited number of pharmacokinetic studies of CYC. Therefore, we aimed to describe the pharmacokinetics of CYC in an Indian population as a first step for the optimization of its use in clinical settings.
Methods: Patients with MDR-TB were enrolled for a prospective observational study at the P. D. Hinduja National Hospital in Mumbai, India. The study participants received MDR-TB treatment as per national guidelines, including weight-adjusted CYC dose of 250 mg twice or three times daily. Blood was drawn at pre-dose and 1, 2, 4, 6, and 8 h after an observed dose, during the first or second month into treatment. Creatinine clearance was estimated using the Cockcroft-Gault equation [6] as an indicator of renal function. The pharmacokinetic analysis was performed in NONMEM. One- and two-compartment models were tested to describe the pharmacokinetics of CYC. To estimate the between-occasion variability (BOV), each dose and its consecutive samples were considered a separate occasion. A combined proportional and additive error model was used to describe the residual unexplained variability (RUV). Concentrations below the lower limit of quantification (0.78 mg/L) were not censored by the laboratory and were incorporated in the analysis by adapting the M6 method [7].
Results: Data were available from 50 Indian participants contributing 300 observations with only one below the lower limit of quantification. The participants were 66% female, and their median age, weight, fat-free mass, and creatinine clearance were 26 (interquartile range (IQR): 21-32) years, 54 (IQR: 46-64) kg, 39 (IQR: 32-46) kg, and 108 (IQR: 94.4-134) mL/min, respectively. Most participants (n=47, 94%) received 250 mg of CYC three times daily, for a total daily dose of 750 mg. The treatment also included clofazimine (84% of participants), bedaquiline (46%), pyrazinamide (40%), ethambutol (30%), para-aminosalicylic acid (24%), ethionamide (20%), and kanamycin (6%) in various combinations as per the drug susceptibility.
The pharmacokinetics of CYC was best described by a one-compartment model with first-order elimination and transit compartment absorption. Allometry using fat-free mass improved the estimation of disposition parameters. The best model included the assessment of two different elimination pathways, non-renal and renal clearance. The renal clearance was estimated using the renal function and accounted for 60% of the total clearance. The typical values for non-renal clearance, renal clearance, and volume of distribution were 0.65 L/h, 0.96 L/h, and 35.5 L, respectively. The between-subject variability on total clearance was 33%. BOV was estimated for absorption rate constant, mean transit time, and bioavailability at 91, 50, and 15%, respectively. A scaling factor on the BOV of the absorption parameters was estimated to a 2.3-fold increase to account for unreliability of self-reported dosing information (unobserved doses) and the impact on subsequent pre-dose samples.
Conclusion: A one-compartment model described the pharmacokinetics of CYC in an Indian population. The typical renal clearance estimated in our population is higher than that reported in other populations (0.43 [8] and 1.03 [9] L/h) and the overall exposures in this cohort of Indian participants are lower. Evaluation covariates with potential influence on the pharmacokinetics of CYC and simulation of different scenarios (e.g., the combination of weight bands and doses) needs to be evaluated further to estimate the probability of target attainment.
References:
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[2] World Health Organization Operational handbook on tuberculosis. 2020. Module 4: Treatment Drug-resistant tuberculosis treatment.
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[5] World Health Organization. 2020. Global tuberculosis report.
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