Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis.

BACKGROUND: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharmacokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. OBJECTIVES: To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. METHODS: We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. RESULTS: A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransferase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC. CONCLUSIONS: Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses >10 mg/kg. The safety implications of these phenomena remain unclear.

Effect of Isoniazid Intake on Ethionamide Pharmacokinetics and Target Attainment in Multidrug-Resistant Tuberculosis Patients.

Ethionamide is recommended as part of regimens to treat multidrug-resistant and rifampicin-resistant tuberculosis. This study was conducted to (i) describe the distribution of ethionamide MICs, (ii) describe the pharmacokinetics of ethionamide, and (iii) determine the probability of attaining target area under the concentration-time curve from 0 to 24 h (AUC0-24)/MIC values associated with suppression of resistant subpopulation and microbial kill. Participants received 15 to 20 mg of drug/kg of body weight of ethionamide daily (in 500- or 750-mg doses) as part of a multidrug regimen. Pretreatment MICs of ethionamide for Mycobacterium tuberculosis sputum isolates were determined using Sensititre MYCOTB MIC plates. Plasma concentrations of ethionamide (measured predose and at 2, 4, 6, 8, and 10 h postdose) were available for 84 patients. A one-compartment disposition model, including a liver compartment capturing hepatic extraction, best described ethionamide pharmacokinetics. Clearance and volume were allometrically scaled using fat-free mass. Isoniazid coadministration reduced ethionamide clearance by 31%, resulting in a 44% increase in AUC0-24. The median (range) MIC (n = 111) was 2.5 mg/liter (<0.3 to >40 mg/liter). Simulations showed increased daily doses of ethionamide (1,250 mg, 1,500 mg, and 1,750 mg for patients weighing ≤45 kg, 46 to 70 kg, and >70 kg, respectively) resulted in the probability of attaining an area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of a drug (fAUC0-24)/MIC ratio of ≥42 in more than 90% of patients only at the lowest MIC of 0.3 mg/liter. The WHO-recommended doses of ethionamide do not achieve target concentrations even for the lowest MIC measured in the cohort.

Neuropsychiatric toxicity and cycloserine concentrations during treatment for multidrug-resistant tuberculosis.

BACKGROUND: Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited. METHODS: A prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma. RESULTS: A total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01). CONCLUSIONS: A high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.

Population Pharmacokinetics of Cycloserine and Pharmacokinetic/Pharmacodynamic Target Attainment in Multidrug-Resistant Tuberculosis Patients Dosed with Terizidone.

Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis (TB). Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine when administered as terizidone and predict the doses of terizidone attaining cycloserine exposures associated with efficacy. The plasma cycloserine level was measured 2 to 6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. The pretreatment MICs of cycloserine were determined for the clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. The median pretreatment MIC was 16 mg/liter. A one-compartment disposition model with two clearance pathways, nonrenal (0.35 liters/h) and renal (0.43 liters/h), described cycloserine pharmacokinetics well. Nonrenal clearance and the volume of distribution were allometrically scaled using fat-free mass. Smoking increased nonrenal clearance by 41%. Simulations showed that with daily doses of terizidone (750 mg and 1,000 mg for patients weighing ≤45 kg and >45 kg, respectively), the probability of maintaining the plasma cycloserine concentration above the MIC for more than 30% of the dosing interval (30% T>MIC) (which is associated with a 1.0-log10-CFU/ml kill in vitro) exceeded 90% at MIC values of ≤16 mg/liter, but the proportion of patients achieving 100% T>MIC (which is associated with the prevention of resistance) was more than 90% only at MICs of ≤8 mg/liter. Based on a target derived in vitro, the WHO-recommended doses of terizidone are effective for cycloserine MICs of ≤8 mg/liter, and higher doses are required to prevent the development of resistance.