Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers

Within the UNIVERSAL project (RIA2019PD-2882) the aim is to develop a paediatric dolutegravir(DTG)/emtricitabine(FTC or F)/tenofovir alafenamide(TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together. This single-dose, open-label, three-period, randomised, cross-over trial in healthy adult volunteers was conducted from November 2022 to March 2023 at the Radboud university medical Center, Nijmegen, the Netherlands. A total sample size of 13 participants was considered sufficient for a power of 80% to show a 30% difference for the area under the curve (AUC) and maximum concentration (Cmax) considering a intrasubject variability for TAF AUC has a coefficient of variation percentage (CV%) of ~35%. The goal was to include a total number of 16 participants to account for dropouts. Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF en tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve and maximum concentration of each compound were within 0.70-1.43, we considered this as no clinically relevant PK interaction. The protocol was approved by our national ethics committee as well as the local ethics committee MREC Oost-Nederland. Data were collected using Castor EDC (Castor Electronic Data Capture CB, Amsterdam, the Netherlands. Concentrations of DTG, FTC, TAF, and TFV in plasma were analysed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method at the laboratory of the Pharmacy of the Radboud University Medical Center. PK parameters were determined by means of non-compartmental analysis using Phoenix 64 WinNonlin (version 8.4).