HIV+ women have increased cognitive vulnerabilities to anticholinergic, anxiolytic/anticonvulsant, and opioid medications. Potential synergy between these medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider these specific types of medications as a contributor to impaired cognitive performance in HIV+ women and assess the cost/benefit of treatment dosage for underlying conditions.

Rationale: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms but clarity on the optimal dosing approach is lacking. Objectives: In this individual participant data meta-analysis of rifapentine pharmacokinetics, we characterize rifapentine population pharmacokinetics, including autoinduction, and determine optimal dosing strategies for short-course rifapentine-based regimens for latent tuberculosis infection. Methods: Rifapentine pharmacokinetic studies were identified though a systematic review of literature. Individual plasma concentrations were pooled, and non-linear mixed effects modeling was performed. A subset of data was reserved for external validation. Simulations were performed under various dosing conditions including current weight-based methods and alternative methods driven by identified covariates. Measurements and Main Results: We identified 9 clinical studies with a total of 863 participants with pharmacokinetic data (n=4301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentration. The maximum effect was a 72% increase in clearance and was reached after 21 days. Drug bioavailability decreased by 27% with HIV infection, decreased by 28% with fasting, and increased by 49% with a highfat meal. Body weight was not a clinically relevant predictor of clearance. Pharmacokinetic simulations showed that current weight-based dosing leads to lower exposures in low weight individuals, which can be overcome with flat dosing. In HIV-positive patients, 30% higher doses are required to match drug exposure in HIV-negative patients. 2 Conclusions: Weight-based dosing of rifapentine should be removed from clinical guidelines and higher doses for HIV-positive patients should be considered to provide equivalent efficacy.

No abstract

No abstract

Background Moxifloxacin is a priority recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics, QT-interval prolongation and evaluate optimal dosing in children with RR-TB. Methods Pharmacokinetic data were pooled from two observational studies in South African children 0-17 years of age with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. Results Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were <2 years of age, and 8 (9%) were HIV-positive. The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16 kg child. Stunting and HIV infection increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥ 500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (inter-individual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children. Conclusions Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when co-administered with other QT-prolonging agents.