Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV- Negative Adults in Malawi

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Af-rica. A total of 47Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51%were male, their mean age was 34 years, and 65%were HIV-positive with a mean CD4 count of 268 cells/l. Anti-tuberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-perfor-mance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parame-ters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (Cmax) of 4.129g/ml (2.474 to 5.596g/ml), area under the curve from 0 to 24 h (AUC0–) of 21.32g/ml · h (13.57 to 28.60g/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, Cmax of 3.97g/ml (2.979 to 4.544g/ml), AUC0–24 of 22.5 (14.75 to 34.59g/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, Cmax of 34.21g/ml (30.00 to 41.60g/ml), AUC0–24 of 386.6g/ml · h (320.0 to 463.7g/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, Cmax of 2.278g/ml (1.694 to 3.098g/ml), AUC0–24 of 20.41g/ml · h (16.18 to 26.27g/ml · h), and half-life of 7.507 (6.517 t