Impact of Splitting or Crushing on the Relative Bioavailability of the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single‐Tablet Regimen

Abstract

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is an oral once‐daily single‐tablet regimen for the treatment of human immunodeficiency virus‐1 infection. Different administration modalities for the D/C/F/TAF fixed‐dose combination tablet were explored in this phase 1 randomized, open‐label, 3‐period, 3‐treatment crossover study enrolling 30 healthy adults. The primary objective was to assess the relative bioavailability of each component after a single dose of D/C/F/TAF (800/150/200/10 mg) administered as a split or crushed tablet (tests) versus swallowed whole (reference). Pharmacokinetic parameters (noncompartmental analysis; logarithm‐transformed) for each component were compared using linear mixed‐effects modeling. For the split versus whole tablet, the bioavailabilities (maximum plasma concentration [Cmax] and area under the plasma concentration‐time curve [AUClast]) of each D/C/F/TAF component were comparable. For the crushed versus whole tablet, the bioavailabilities of darunavir, cobicistat, and emtricitabine were comparable, except for a 17% decrease in emtricitabine Cmax; the relative bioavailability of tenofovir alafenamide decreased by 29% and 19% for Cmax and AUClast, respectively. All intakes were safe and generally well tolerated. In summary, there was no clinically relevant impact on the bioavailability of D/C/F/TAF components when administered as a split tablet compared with a tablet swallowed whole. Administration of a crushed tablet resulted in a modest decrease in tenofovir alafenamide bioavailability; the clinical relevance of this change has not been assessed but is expected to be minimal based on the wide therapeutic window for this agent.