Model-Based Dose Selection of Fostemsavir for Pediatric Populations With Multidrug-Resistant HIV-1 and Relative Bioavailability Assessment in Healthy Adults.

Fostemsavir, a prodrug of the first-in-class HIV-1 attachment inhibitor temsavir, is approved for the treatment of multidrug-resistant HIV-1 in adults; its use in pediatric populations is currently being studied. Population pharmacokinetic modeling across pediatric weight bands was used to guide pediatric fostemsavir dose selection. Dosing simulations demonstrated that twice-daily fostemsavir 600-mg (adult dose) and 400-mg doses met safety and efficacy criteria for 35 kg or greater and 20 or greater to less than 35 kg pediatric weight bands, respectively. Temsavir relative bioavailability of 2 low-dose fostemsavir extended-release formulations (3 × 200 mg; formulations A and B) and reference formulation (600 mg extended release) was assessed in a 2-part, open-label, randomized, crossover study in healthy adults. Part 1 (N = 32) compared single-dose temsavir relative bioavailability, and Part 2 (N = 16) evaluated the impact of fed versus fasted conditions using the selected low-dose formulation. Temsavir geometric mean ratios for the area under the plasma concentration-time curve from time zero to infinity and maximum concentration for formulation B were bioequivalent to the reference formulation. Temsavir maximum concentration for formulation B was similar in fed and fasted states, but area under the plasma concentration-time curve from time zero to infinity geometric mean ratio was increased under fed conditions, consistent with previous results in adults. These analyses demonstrated efficient pediatric dose selection using a model-based approach.

Statistical issues in a modeling approach to assessing bioequivalence or PK similarity with presence of sparsely sampled subjects.

Drug development at different stages may require assessment of similarity of pharmacokinetics (PK). The common approach for such assessment when the difference is drug formulation is bioequivalence (BE), which employs a hypothesis test based on the evaluation of a 90% confidence interval for the ratio of average pharmacokinetic (PK) parameters. The role of formulation effect in BE assessment is replaced by subject population in PK similarity assessment. The traditional approach for BE requires that the PK parameters, primarily AUC and Cmax, be obtained from every individual. Unfortunately in many clinical circumstances, some or even all of the individuals may be sparsely sampled, making the individual evaluation difficult. In such cases, using models, particularly population models, becomes appealing. However, conducting an appropriate statistical test based on population modeling in a form consistent, at least in principle, with traditional 90% confidence interval approach is not so straightforward as it may appear. This manuscript proposes one such approach that can be applied to sparse sampling situations. The approach aims to maintain, as much as possible, the appropriateness of the hypothesis test. It is applied to data from clinical studies to address a need in drug development for assessment of PK similarity in different populations.