Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study

Abstract

The drug concentrations of all first-line anti-TB drugs were markedly below the target therapeutic concentrations in most South African children who received the revised WHO-recommended paediatric weight-based dosages.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

“…Infant INH concentrations also compared well with other pediatric pharmacokinetic studies with similar 2-hour concentrations reported of 4.5, 5.6, and 3.9 to 8.6, following 10 to 15 mg/kg (7,27,38). The effect of acetylator status on INH exposures is not reported here (future work).…”

“…To our knowledge, this is the first study specifically performed in infants on antituberculosis drugs that also incorporated postconceptual age, and we found no remaining influence of prematurity. There is no clear evidence regarding the potential association between low TB drug exposures and concomitant cART (8,13,27,47). In our study, we observed lower PZA and EMB exposures in HIV-infected infants; however, we studied only 5 HIV-coinfected infants.…”

“…Other pediatric studies reported similarly low concentrations of between 0.78 and 2.1 g/ml when dosed at 10 to 20 mg/kg (27,28,32,40,41). Increasing EMB dosage in children has been reported to result in higher peak concentrations (42,43); however, dose-dependent ocular toxicity is a limiting factor in dosing increases (44) especially in young children, in whom clinical evaluation is more challenging.…”

“…Few pediatric studies have reported on hepatotoxicity at the revised WHO dosing recommendations. Hiruy et al documented an ALT range of 9 to 71 U/liter in 31 children younger than 10 years at the revised higher doses (27). Two (3.1%) of 64 children developed hepatitis on the previously recommended lower doses, and 3 (4.8%) of 63 children did so on the revised higher doses in a study conducted in Indian children younger than 15 years of age (32).…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…The pharmacokinetic parameters for standard first-line drugs and for drugs used in both MDR and XDR tuberculosis are shown in table 9, mainly based on publications from South Africa, India, and the USA. [404][405][406][407][408][409][410][411][412][413][414][415][416] Predicting what concentration a patient will achieve is difficult, given the multiple determinants of pharmacokinetic variability. 191 Therefore, to identify the specific concentration-time profile, the drug concentrations should be measured in the patient directly.…”