Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis

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 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

Antiretroviral Medication Prescription Errors and Associated Factors among HIV Infected Children in Selected Health Facilities in Nairobi, Kenya

Thesis (Master's)--University of Washington, 2018University of Washington Abstract Antiretroviral Medication Prescription Errors and Associated Factors among HIV Infected Children in Selected Health Facilities in Nairobi, Kenya Irene Njahira Mukui Chair of Committee: Carey Farquhar Background: Access to life saving antiretroviral therapy (ART) in many resource-limited settings has increased, yet more than 30% of children on ART do not achieve viral suppression. Multiple factors contribute to viral suppression including patient, drug and health system factors. Infants and children require continuous medication dose adjustments in response to changing pharmacodynamics and inappropriate dosing may contribute to viral non-suppression. This study sought to determine the magnitude of prescription dosing errors and associated factors. Methods: We conducted a cross sectional study among HIV Infected children aged ≤11 years receiving ART in four public health facilities. Demographic, clinical and prescription data were abstracted from the medical charts of children receiving ART for the last clinical visit. Descriptive statistics were used to summarize participant characteristics. Logistic regression was conducted to determine factors associated with prescription dosing errors. Results: A total of 196 children were included in the study; among these, 52.6% were male and the median age was 7.9 years (IQR 4.8, 10.0). The most commonly used ART regimen was abacavir/lamivudine/lopinavir/ritonavir taken by 31.1% (61/196) of children. Overall, 43.6% (85/196), 45.9% (90/196) and 46.9% (92/196) of children lacked data on specific ARV formulation, dosage and frequency of dosing, respectively. Among 104 children with complete prescription information, the dosing error rate was 36.5% (38/104). In a multivariable model, being on non-nucleoside reverse transcriptase inhibitors was independently associated with prescription dosing errors (adjusted odds ratio 8.8; 95% confidence interval 2.1-36.3). Conclusion: Half of children receiving antiretroviral therapy had inadequate prescription information and among those with adequate information, one third had prescription dosing errors. These findings calls for urgent measures to address health care prescribing practices and knowledge. In addition, further evaluation should be conducted to determine associations with viral suppression