Treatment with an updated fixed-dose combination (FDC) of rifampicin/isoniazid/ pyrazinamide may decrease the risk for insufficient exposure to rifampicin among children with tuberculosis (TB) infection, according to results of a prospective study published in Clinical Infectious Diseases.
Between November 2012 and June 2017, investigators conducted a pharmacokinetic study among children aged 12 years or younger with or without HIV infection in South Africa who were receiving first-line treatment for drug-susceptible TB infection in accordance with 2010 World Health Organization (WHO) guidelines. First-line treatment for TB infection comprised 1, 2, 3, or 4 FDC tablets (rifampin/isoniazid/pyrazinamide 75/50/150 mg) daily based on 4 weight bands: 4 to8 kg, 8 to12 kg, 12 to16 kg, and 16 to25 kg, respectively.
Participants included in the study underwent pharmacokinetic sampling 2 weeks after starting treatment during the initial 2-month intensive phase. For children receiving first-line treatment for TB infection, the investigators aimed to achieve drug exposures similar to pharmacokinetic targets for rifampin, isoniazid, and pyrazinamide observed in adult patients. They also created simulations to estimate the effects of 3 dosing strategies: dosing under the 2010 WHO guidelines with currently available FDCs, improved dosing with the currently available FDC tablets to optimize rifampicin exposure, and dosing with an optimized new FDC and optimized weight bands.
Investigators used N-acetyltransferase 2 (NAT2) to measure isoniazid clearance; however, if NAT2 acetylator status was unknown, a mixture model was used to categorize patients as slow, intermediate, or fast acetylators. In addition, they used the root mean square error (RMSE) to compare the achievement of target exposures between current and optimized FDC treatment.
Among a total of 180 children included in the trial, 42% were women, 13.9% had HIV infection, the median age was 1.9 (range, 0.22-12) years, and the median weight was 10.7 (range, 3.20-28.8) kg.
After stratification by weight and age, the investigators found that, compared with adult patients, children had up to a 50% decreased exposure to rifampicin exposure vs. Additionally, children treated with rifampin had a 61% decrease in bioavailability. Of note, fewer than 10% of children aged 5 to8 years achieved a rifampin exposure comparable with exposures observed in adults.
The investigators found that administering an additional FDC tablet among children with TB infection resulted in a median rifampicin exposure that was within the target range, but isoniazid and pyrazinamide exposures were above the target range. Improved exposures to all 3 drugs included in the FDC were observed when investigators administered 1, 2, 3 or 4 FDC tablets of rifampin/isoniazid/pyrazinamide (120/35/130 mg) to children on the basis of weight bands (<6 kg, 6-13 kg, 13-20 kg, and 20-25 kg, respectively). Of note, the investigators found that administering only half of an FDC tablet to children less than 3 months of age who had immature metabolism prevented overexposure to rifampicin and pyrazinamide.
The RMSE was found to be significantly decreased among children who received first-line TB treatment with the optimized new FDC tablets and optimized weight-bands. The investigators noted that the most significant decrease in RMSE was observed in children less than 1 year of age who weighed less than 6 kg. In a simulation model containing patient characteristics from a real-life Kenyan population, the new FDC and optimized weight bands resulted in adequate isoniazid exposure in slow, intermediate, and fast acetylators.
The study was limited by its use of NAT2 acetylator distributions from high-burden regions to establish isoniazid dosing, which may not be generalizable to other geographic regions.
The investigators concluded that “an [additional] 75-mg [dose] of rifampicin in each weight band could be used as a temporary solution against [insufficient] rifampicin exposure.”
Disclosure: One author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Denti P, Wasmann RE, van Rie A, et al. Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis: a prospective population pharmacokinetic study. Clin Infect Dis. Published online October 19, 2021. doi:10.1093/cid/ciab908