Abstract
BACKGROUND: Anti-TB drugs dosing based on weight alone may contribute to suboptimal drug concentrations and poor treatment outcomes in malnourished children. We examined the effect of malnutrition on the pharmacokinetics (PK) of first-line anti-TB drugs in children.METHODS: Drug concentrations were measured in Ghanaian children during the intensive phase of TB treatment. Weight-for-age (WFA), height-for-age (HFA), weight-for-height (WFH) and body mass index-for-age (BFA) were calculated and children with Z-scores < -2 SD (standard deviations) were considered as having malnutrition. PK differences of anti-TB drugs were compared by nutritional status.RESULTS: Of 100 participants, 24/48 (50.0%) of those younger than 5 years had wasting, 58/86 (67.4%) were underweight, and 56/99 (56.6%) had stunting; 22/51 (43.1%) children aged ≥5 years had low BFA. Children with stunting were more likely than controls to have lower mean peak concentration (C(max)) and area under the curve (AUC(0-8h)) of rifampin (RIF) and pyrazinamide (PZA), as well as a higher frequency of C(max) below the normal range. Wasting and underweight were associated with lower mean ethambutol (EMB) C(max) and AUC(0-8h).CONCLUSIONS: The current WHO-recommended dosages were associated with lower plasma exposure of RIF, PZA and EMB in children with stunting, wasting and underweight. Anti-TB drugs dosing models for children may need to include height.