cThere are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (C max ) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 g/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 g/ ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC 0 -8 ) were 12.1, 24.7, 239.4, and 5.1 g · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed in C max (geometric mean ratio

Although children may experience fewer adverse effects from oral second-line antituberculosis drugs than adults, evidence from prospective studies of the incidence of adverse events in children is limited. Higher doses of second-line drugs, new antituberculosis drugs, and new drug regimens are being evaluated in children: these call for strict pharmacovigilance in children treated in the near future, as adverse effect profiles may change.

Delamanid has been demonstrated to be safe and effective for treatment of adult multidrug-resistant tuberculosis (MDR-TB) and has been approved by the European Commission for treatment of pediatric MDR-TB patients at least 10 kg in weight, making the drug no longer limited to adults. A 10-day phase I age deescalation study was conducted, followed by a 6-month phase II extension study, to assess the pharmacokinetics, safety, tolerability, and preliminary efficacy of delamanid when combined with optimized background regimen (OBR) in children (birth to 17 years) with MDR-TB. Delamanid administered at 100 mg twice-daily (BID), 50 mg BID, and 25 mg BID resulted in exposures in 12- to 17- ( n  = 7), 6- to 11- ( n  = 6), and 3- to 5-year-olds ( n  = 12), respectively, comparable with those in adults at the approved adult dosage (100 mg BID).