Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis.

Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on cycloserine in tuberculosis (TB) patients. We pooled several studies into a large PK data set to estimate the population PK parameters for cycloserine in TB patients. We also performed simulations to provide insight into optimizing the dosing of cycloserine. TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC of ≥30% and ≥64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve ≥90% of PTA. Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA were achieved as the total daily dose was increased. The highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/liter. For MICs of >16 mg/liter, doses of at least 500 mg three times daily or 750 mg twice daily were needed. In conclusion, the current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs of >16mg/liter. Further studies are needed regarding the efficacy and tolerability of daily doses of >1,000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimizing exposure, which can potentially reduce adverse drug effects.

d-Cycloserine Pharmacokinetics/Pharmacodynamics, Susceptibility, and Dosing Implications in Multidrug-resistant Tuberculosis: A Faustian Deal.

Background: d-cycloserine is used to treat multidrug-resistant tuberculosis. Its efficacy, contribution in combination therapy, and best clinical dose are unclear, also data on the d-cycloserine minimum inhibitory concentration (MIC) distributions is scant. Methods: We performed a systematic search to identify pharmacokinetic and pharmacodynamic studies performed with d-cycloserine. We then performed a combined exposure-effect and dose fractionation study of d-cycloserine in the hollow fiber system model of tuberculosis (HFS-TB). In parallel, we identified d-cycloserine MICs in 415 clinical Mycobacterium tuberculosis (Mtb) isolates from patients. We utilized these results, including intracavitary concentrations, to identify the clinical dose that would be able to achieve or exceed target exposures in 10000 patients using Monte Carlo experiments (MCEs). Results: There were no published d-cycloserine pharmacokinetics/pharmacodynamics studies identified. Therefore, we performed new HFS-TB experiments. Cyloserine killed 6.3 log10 colony-forming units (CFU)/mL extracellular bacilli over 28 days. Efficacy was driven by the percentage of time concentration persisted above MIC (%TMIC), with 1.0 log10 CFU/mL kill achieved by %TMIC = 30% (target exposure). The tentative epidemiological cutoff value with the Sensititre MYCOTB assay was 64 mg/L. In MCEs, 750 mg twice daily achieved target exposure in lung cavities of 92% of patients whereas 500 mg twice daily achieved target exposure in 85% of patients with meningitis. The proposed MCE-derived clinical susceptibility breakpoint at the proposed doses was 64 mg/L. Conclusions: Cycloserine is cidal against Mtb. The susceptibility breakpoint is 64 mg/L. However, the doses likely to achieve the cidality in patients are high, and could be neurotoxic.

Bioequivalence assessment of closerin capsule to dura seromycin capsule of cycloserine after a single oral dose administration to healthy male volunteers.

AIM: A bioequivalence study of the closerin capsules to the dura seromycin capsules was conducted. PATIENTS AND METHODS: Twenty-four healthy male Korean volunteers received each medicine at the cycloserine dose of 250 mg in a 2 x 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of cycloserine were monitored by a high-performance liquid chromatography for over a period of 72 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax, and untransformed Tmax. RESULTS: There were no significant differences between the medications in AUCinf and Cmax. The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were, in point estimate (90% confidence interval), 0.992 (0.950 approximately 1.037) and 1.051 (0.965 approximatly 1.144), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of Tmax was 0.000 (-0.250 approximatly 0.125). Moreover, the modified Pitman-Morgan's adjusted F test and equal variance test (one-sided) indicated that the 2 medications were comparable in intra- and inter-individual variability in cycloserine bioavailability. CONCLUSION: Therefore, these results indicate that the 2 medications of cycloserine are bioequivalent and, thus, may be prescribed interchangeably.