Background
Current dosing of tuberculosis drugs in children is largely based on extrapolation from adult data, and does not correctly account for physiological differences between the two populations (1). Additional factors, including malnutrition, HIV and concomitant medications, may further alter drug exposure in children (2,3). Pharmacokinetic studies in children, particularly those with malnutrition, are limited by the need for frequent blood draws. We conducted a prospective study in Port-au-Prince, Haiti, to assess the effects of malnutrition and HIV on the pharmacokinetics of first-line tuberculosis drugs in children under five, and to evaluate a new capillary blood collection device against the standard intravenous method.
Methods
We enrolled HIV-positive and HIV-negative children treated for drug-sensitive tuberculosis at GHESKIO’s pediatric clinic in Port-au-Prince, Haiti, using WHO weight-band dosing. Between 2 – 8 weeks after treatment initiation, blood was collected at 0, 1, 2, 6, and 24 hours post-dose for pharmacokinetic testing. Population pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol were analyzed using nonlinear mixed-effects modelling in NONMEM.
Results
Data for 39 children were analyzed, 17 with malnutrition, and 22 without malnutrition. Median baseline weight (IQR) was 8.22 (6.94-10.4) kg and age 1.46 (1.02 – 1.86) years. 8 children were living with HIV. A one-compartment disposition model with first-order elimination best described rifampicin and pyrazinamide data, while a two-compartment model with first-order elimination best described isoniazid and ethambutol data. Allometric scaling and maturation of clearance and bioavailability (except pyrazinamide) improved the model fit to the data for all drugs. We did not find a significant impact of HIV status. Malnutrition was found decrease pyrazinamide absorption by 32%. The correlation between the drug concentrations observed in plasma and capillary and venous whole blood was high, with r2 values ranging between 0.94 and 0.98.
Conclusion
The pharmacokinetics of 1st-line tuberculosis drugs in this cohort are in line with previous reports (2,4). Lastly, and importantly, tuberculosis drug concentrations were comparable between samples collected via capillary sampling versus venous sampling, thus making the capillary sampling technique an attractive alternative for PK studies and monitoring of TB drug concentrations in children.
References
- World Health Organization. WHO Consolidated Guidelines on Tuberculosis, Module 4: Treatment – Drug-Susceptible Tuberculosis Treatment. 2022.
- Galileya LT, Wasmann RE, Chabala C, Rabie H, Lee J, Njahira Mukui I, et al. Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis. PLOS Med. 2023;20(11):e1004303.
- Gafar F, Wasmann RE, McIlleron HM, Aarnoutse RE, Schaaf HS, Marais BJ, et al. Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis. Eur Respir J. 2023 Mar;61(3):2201596.
- Tikiso T, McIlleron H, Abdelwahab MT, Bekker A, Hesseling A, Chabala C, et al. Population pharmacokinetics of ethambutol in African children: a pooled analysis. J Antimicrob Chemother. 2022 Jun 29;77(7):1949–59.
