부산대학교 도서관

Background: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. Methods and findings: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. Conclusions: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug–drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. Trial registration: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542 Lufina Galileya and colleagues pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. Author summary: Why was this study done?: Recent pharmacokinetic studies in children on 2010 World Health Organization (WHO)-recommended first-line tuberculosis treatment found variable exposures of rifampicin, isoniazid, and pyrazinamide, with rifampicin being the drug achieving the lowest exposures. Findings of the association of human immunodeficiency virus (HIV) with the exposures of first-line tuberculosis drugs are inconsistent, and the relationships of HIV, antiretrovirals, formulation, demographics, and different sample processing and analysis methods are unclear. To rapidly mitigate the low rifampicin exposures, policymakers have been looking to investigate if taking the existing fixed dose combination tablet along with an additional 75 mg or 150 mg tablet of rifampicin alone (top-up) would be a good way to optimize rifampicin doses in children. What did the researchers do and find?: We pooled individual pharmacokinetic data from 3 large studies, which gave us a total of 387 children through whom we investigated the association of HIV, antiretrovirals, and formulation, and investigated the exposures achieved after increasing rifampicin doses by 75 mg or 150 mg. Age affected drug bioavailability and clearance and there was an association between body size and both the volume of distribution and drug clearance of first-line tuberculosis drugs. HIV had no association with the exposures of first-line tuberculosis drugs; rather, the antiretroviral lopinavir/ritonavir increased rifampicin exposure and reduced isoniazid and pyrazinamide exposure. Increasing rifampicin doses can lead to rifampicin exposures comparable to those observed in adults, and we report large differences between rifampicin and isoniazid formulations with reduced exposures in some formulations. What do these findings mean?: There are opportunities to rapidly improve first-line pediatric tuberculosis treatment through increasing rifampicin doses, which can be done through a rifampicin tablet top-up to the current fixed dose combination tablet as part of the WHO guidelines. Future studies investigating the association of HIV with tuberculosis drug exposures should explore the relationship of different antiretroviral therapies with tuberculosis-drug exposures, including drug–drug interactions due to administration of the drugs at the same time. Where possible, children on HIV and tuberculosis co-treatment should be closely monitored for possible toxicities or reduced efficacy arising from drug–drug interactions. The main limitation of our study is the small study design differences among the pooled studies, which led to some unattributable associations that we classified as site or study associations. [ABSTRACT FROM AUTHOR]