Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection.

Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC0-8), maximum concentration (Cmax), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P < 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC0-8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC0-8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).

Pharmacokinetics of First-Line Antituberculosis Drugs Using WHO Revised Dosage in Children With Tuberculosis With and Without HIV Coinfection.

BACKGROUND: Pharmacokinetic data on the first-line antituberculosis drugs using the World Health Organization (WHO) revised dosages for children are limited. We investigated the pharmacokinetics of these drugs in children who were mostly treated with revised dosages. METHODS: Children with tuberculosis on first-line therapy for at least 4 weeks had blood samples collected at predose, 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography mass spectrometry methods, and pharmacokinetic parameters were calculated using noncompartmental analysis. Factors associated with plasma peak concentration (Cmax) and the area under the time-concentration curve 0-8 hours (AUC0-8h) of each drug was examined using univariate and multivariate analysis. RESULTS: Of the 62 children, 32 (51.6%) were male, 29 (46.8%) were younger than 5 years old, and 28 (45.2%) had human immunodeficiency virus (HIV) coinfection. Three patients had undetectable pyrazinamide and ethambutol concentrations. The median (interquartile range) AUC0-8h for isoniazid was 17.7 (10.2-23.4) µg·h mL-1, rifampin was 26.0 (15.3-36.1) µg·h mL-1, pyrazinamide was 144.6 (111.5-201.2) µg·h mL-1, and ethambutol was 6.7 (3.8-10.4) µg·h mL-1. Of the children who received recommended weight-band dosages, 44/51 (86.3%), 46/56 (82.1%), 27/56 (48.2%), and 21/51 (41.2%) achieved target Cmax for isoniazid, pyrazinamide, ethambutol, and rifampin, respectively. In multivariate analysis, age, sex, HIV coinfection status, and drug dosage in milligrams per kilogram were associated with the drugs' plasma drug Cmax or AUC0-8h. CONCLUSIONS: The revised dosages appeared to be adequate for isoniazid and pyrazinamide, but not for rifampin or ethambutol in this population. Higher dosages of rifampin and ethambutol than currently recommended may be required in most children.