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

• Published in: Clinical pharmacokinetics Vol. 63; no. 5; pp. 721 - 728
• Main Authors: Bevers, Lisanne A. H., Kamphuis, Anne E. M., van der Wekken-Pas, L. C. Wendy, Leisegang, Rory, Burger, David M., Colbers, Angela
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2024; Springer Nature B.V
• Subjects: Adenine - administration & dosage; Adenine - analogs & derivatives; Adenine - blood; Adenine - pharmacokinetics; Adolescent; Adult; Adults; Alanine - administration & dosage; Alanine - pharmacokinetics; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - blood; Anti-HIV Agents - pharmacokinetics; Antiretroviral drugs; Area Under Curve; Bioavailability; Biological Availability; Clinical outcomes; Cross-Over Studies; Drug Combinations; Drug dosages; Drug interactions; Emtricitabine - administration & dosage; Emtricitabine - pharmacokinetics; Female; Healthy Volunteers; Heterocyclic Compounds, 3-Ring - administration & dosage; Heterocyclic Compounds, 3-Ring - blood; Heterocyclic Compounds, 3-Ring - pharmacokinetics; HIV; Human immunodeficiency virus; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Original; Original Research Article; Oxazines - administration & dosage; Oxazines - pharmacokinetics; Pediatrics; Pharmacology/Toxicology; Pharmacotherapy; Pharmacy; Piperazines - pharmacokinetics; Plasma; Pyridones - pharmacokinetics; Tablets; Tenofovir - administration & dosage; Tenofovir - analogs & derivatives; Tenofovir - pharmacokinetics; Young Adult; Netherlands
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-024-01365-4

Background and objective Within the UNIVERSAL project (RIA2019PD-2882) we aim 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. Methods 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, and 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 (AUC) and maximum concentration ( C max ) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction. Results A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC 0–∞ and C max fell outside our acceptance criteria of 0.70–1.43. Conclusions Although TAF AUC and C max 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.