Pharmacokinetics of First-Line Drugs Among Children With Tuberculosis in Rural Tanzania

Abstract

Background Dosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limited. We evaluated plasma drug concentrations of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) among children undergoing TB treatment in Tanzania when these dosing recommendations were being implemented. Methods At the end of intensive-phase TB therapy, blood was obtained 2 hours after witnessed medication administration to estimate the peak drug concentration (C2h), measured using high-performance liquid chromatography or liquid chromatography–tandem mass spectrometry methods. Differences in median drug concentrations were compared on the basis of the weight-based dosing strategy using the Mann–Whitney U test. Risk factors for low drug concentrations were analyzed using multivariate regression analysis. Results We enrolled 51 human immunodeficiency virus–negative children (median age, 5.3 years [range, 0.75–14 years]). The median C2hs were below the target range for each TB drug studied. Compared with children who received the “old” dosages, those who received the “revised” WHO dosages had a higher median C2h for RIF (P = .049) and PZA (P = .015) but not for INH (P = .624) or EMB (P = .143); however, these revised dosages did not result in the target range for RIF, INH, and EMB being achieved. A low starting dose was associated with a low C2h for RIF (P = .005) and PZA (P = .005). Malnutrition was associated with a low C2h for RIF (P = .001) and INH (P = .001). Conclusions Among this cohort of human immunodeficiency virus–negative Tanzanian children, use of the revised dosing strategy for treating childhood TB did not result in the target drug concentration for RIF, INH, or EMB being reached.

Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty-Related Diseases: A Systematic Review

“…The alterations in drug exposure likely depend on the patient population, as for some drugs relationships could be identified between the type or severity of malnutrition and the effect on drug exposure in these studies. For example, isoniazid and rifampicin exposure was decreased in moderately malnourished patients [59,76,77], potentially due to either reduced absorption or decreased protein binding and, consequently, an increased volume of distribution or elevated drug clearance [59]. On the other hand, isoniazid and rifampicin exposure was increased in severe malnutrition [18,65,66], potentially caused by a more pronounced suppression of enzyme activity in severe malnutrition [65].…”

“…The sample size was small (< 50 participants) in the majority of studies, which can be the reason why a potentially expected effect could not be demonstrated in some of the studies [32,67,[78][79][80][81]. The effect might not be traceable because of the small difference in malnutrition status between patient groups [32,55,76,78,79,81]. In other studies, the number of malnourished patients was unknown [82,83] or malnutrition was poorly diagnosed [84].…”

Food for thought: addressing undernutrition to end tuberculosis

“…Importantly, children who received newer WHO-recommended doses had increased concentrations, but the majority of children still had peak concentrations below target range. 43 In a separate cohort from rural Tanzania, where the median BMI-for-age Z-score was −2.0 (IQR 2.3), full PK exposure was measured in 51 children and of those with a calculable total serum area under the concentration curve (AUC), rifampin was at or above target in 35%, and for isoniazid, in only 4%. 44 PK variability was more frequent among the most undernourished children and despite aggressive treatment of malnutrition in all, mortality remained high, with 8 of 9 deaths (89%) occurring in children with pretreatment BMI-for age Z-score of −2.0 or below (Figure 2).…”

Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness

“…Medication was administered orally as directly observed therapy for the PK visit. Once blood was collected, the vials were centrifuged to separate serum, which was immediately frozen at −80 °C until batch shipment to University of Florida, USA (Gainesville, VA, USA), where concentrations of all four drugs were quantified using validated liquid chromatography-tandem mass spectrometry procedures, including prior testing for confirmation of milligram quantity in fixed dose preparations [ 36 ]. The methods were validated over the concentration ranges 0.4 to 20 µg/ml for isoniazid, 0.5 to 50 µg/ml for rifampin, 2 to 100 µg/ml for pyrazinamide, and 0.2 to 10 µg/ml for ethambutol [ 37 ].…”