Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens

PURPOSE: Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens. METHODS: To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER. RESULTS: The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens. CONCLUSION: The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER

Pooled population pharmacokinetic analysis of tribendimidine for the treatment of Opisthorchis viverrini infections

Opisthorchiasis, caused by the food-borne trematode Opisthorchis viverrini, affects more than 8 million people in Southeast Asia. In the framework of a phase 2b clinical trial conducted in Lao PDR, pharmacokinetic samples from 125 adult and adolescent O. viverrini patients treated with 400 mg tribendimidine were obtained following the design of an sparse sampling scheme at 20 min, 2, 7.75, 8 and 30 h after treatment, using dried blood spot sampling. Pharmacokinetic data for the metabolites dADT and adADT were pooled with data from two previous dose-ascending trials and evaluated using nonlinear mixed-effects modelling. The observed pharmacokinetic data were described using a flexible transit absorption model for the active metabolite dADT followed by one-compartment disposition models for both metabolites. Significant covariates were age, body weight, formulation, and breaking of the enteric coating on the tablets. There were significant associations between O. viverrini cure and both dADT Cmax and AUC (p-values <0.001), with younger age associated with a higher probability of cure. Modelling and simulation of exposures in a patients with different weight and age combinations showed that an oral single dose of 400 mg tribendimidine attained therapeutic success in over 90% of adult patients. Our data confirmed that tribendimidine could be a valuable novel alternative to the standard treatment praziquantel for the treatment of O. viverrini infections