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

Abstract

AbstractFostemsavir, 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.