The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement
| Autor: | Casper Rokx, E. van Nood, Annelies Verbon, Pauline D.J. Bollen, H.A.B. Prins, T E M S de Vries-Sluijs, Hannelore I. Bax, Bart J. A. Rijnders, M de Mendonca Melo, David M. Burger, Kirsten Velthoven-Graafland, Jan L. Nouwen, Angela Colbers |
|---|---|
| Přispěvatelé: | Medical Microbiology & Infectious Diseases |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Pyridones 030106 microbiology Drug-drug interaction Human immunodeficiency virus (HIV) HIV Infections Pharmacology medicine.disease_cause Piperazines law.invention 03 medical and health sciences chemistry.chemical_compound All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Randomized controlled trial Pharmacokinetics SDG 3 - Good Health and Well-being law Oxazines Medicine Humans Pharmacology (medical) Drug Interactions 030212 general & internal medicine Trial registration Valproic Acid business.industry lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Infectious Diseases chemistry Pharmaceutical Preparations Dolutegravir lipids (amino acids peptides and proteins) business Heterocyclic Compounds 3-Ring medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy, 76, 1273-1276 Journal of Antimicrobial Chemotherapy, 76, 5, pp. 1273-1276 Journal of Antimicrobial Chemotherapy, 76(5), 1273-1276. Oxford University Press |
| ISSN: | 0305-7453 |
| Popis: | Objectives The dolutegravir/valproic acid drug–drug interaction (DDI) is suggested to be caused by protein displacement. Here, we assess the underlying mechanism. Methods Participants in a randomized controlled trial investigating valproic acid as an HIV latency reversing agent were recruited in a predefined pharmacokinetic substudy if they were on once-daily 50 mg dolutegravir-containing combination ART (cART) for >12 months with a plasma HIV-RNA Results Six of 10 participants on dolutegravir were randomized to receive valproic acid. During 14 days of valproic acid treatment, the GM total dolutegravir concentration decreased sharply from 1.36 mg/L on day 0 to 0.85, 0.31 and 0.20 mg/L on days 0, 1, 7 and 14, respectively, while total dolutegravir concentrations in the controls remained comparable during the same period: 1.27–1.49 mg/L. We observed a parallel increase in unbound dolutegravir fractions ranging from 0.39% to 0.58% during valproic acid administration, compared with 0.25% to 0.28% without valproic acid. Unbound dolutegravir concentrations were above the established in vitro EC90 value for unbound dolutegravir in 85% of the tested samples. Conclusions This study confirms protein displacement as the main mechanism for this DDI, although additional mechanisms might be involved too. If dolutegravir is taken with food, this DDI is probably not clinically relevant. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|