icon-folder.gif   Conference Reports for NATAP  
 
  20th International Workshop
on Clinical Pharmacology of HIV
Hepatitis & Other Antiviral Drugs
May 14-16, 2019. Noordwijk, the Netherlands
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Reported dolutegravir-valproic acid interaction
probably not clinically relevant

 
 
  20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands
 
Mark Mascolini
 
Previously reported lower dolutegravir plasma levels in patients taking valproic acid seem unlikely to be clinically relevant, according to an analysis by University of Nijmegen and Erasmus Medical Center investigators [1]. The interaction, the Dutch team found, probably results from displacement of dolutegravir protein binding by valproic acid.
 
In 2018 Italian researchers reported 2 patients with low dolutegravir concentrations while taking valproic acid, a drug prescribed for bipolar disorder and seizures [2]. Although both patients maintained dolutegravir concentrations above the protein-adjusted 90% inhibitory quotient of 0.064 ug/mL, the authors suggested that the size of the potential drug-drug interaction was clinically concerning. Dolutegravir area under the concentration-time curve (AUC) in these 2 people lay more than 80% below the average reference value for dolutegravir AUC.
 
The Nijmegen/Erasmus investigators suggested three mechanisms that might explain the dolutegravir-valproic acid interaction: valproic acid induction of dolutegravir metabolizing enzymes (although valproic acid is better known as an enzyme inhibitor), impaired dolutegravir absorption resulting from excipients contained in some valproic acid formulations, and binding site competition by dolutegravir and valproic acid since both drugs are highly protein-bound.
 
To measure total and free dolutegravir concentrations in people with HIV, the researchers focused on individuals taking a dolutegravir regimen in the LRAs United as a Novel Anti-HIV strategy (LUNA) study. Participants took 50 mg of dolutegravir daily with or without 30 mg/kg of valproic acid (Depakine enteric) divided over 2 daily doses for 14 days. The researchers measured dolutegravir trough concentrations before valproic acid codosing on day 0, with valproic acid codosing on days 1, 7, and 14, and without valproic acid on day 42. On day 1 researchers collected a 6-hour sample. A LUNA participant taking dolutegravir without valproic acid served as a control patient.
 
The study group included 3 people taking dolutegravir with valproic acid and 1 taking dolutegravir alone. During the study 1 person stopped valproic acid on day 7 because of side effects. Before participants started valproic acid, their total dolutegravir trough on day 0 averaged 1.8 mg/L. On day 42, after valproic acid had stopped, dolutegravir trough averaged 1.5 mg/L.
 
During valproic acid codosing, total dolutegravir troughs fell sharply to 0.79, 0.33, and 0.24 mg/L on days 1, 7, and 14. But the dolutegravir free (unbound) fraction climbed from 0.29-0.30% without valproic acid to 0.53-0.69% with valproic acid. Dolutegravir free fraction began to rise quickly with valproic acid, jumping from 0.30% to 0.40% within the first 6 hours of dosing. All free dolutegravir concentrations lay above the proposed in vitro 90% effective concentration for unbound dolutegravir, 0.9 ug/L.
 
The control patient who did not take valproic acid had total and free dolutegravir concentrations in the same range as the 3 other people before or after they took valproic acid.
 
The researchers proposed that their findings indicate the "rapid and consistent decrease [in total dolutegravir plasma concentration] can be explained by displacement of protein binding of dolutegravir by valproic acid." Thus they concluded that the reported dolutegravir-valproic acid interaction is not clinically relevant.
 
20th Intnl Wrkshp Clin Pharm: Other than dolutegravir, no antiretroviral interactions with valproic acid in 134 people - Mark Mascolini (05/16/19)
 
References
1. Bollen P, Prins H, Velthoven K, et al. The valproic acid-dolutegravir drug-drug interaction is based on displacement of protein binding and unlikely to be clinically relevant. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 44.
2. Palazzo A, Trunfio M, Pirriatore V, et al. Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid. J Antimicrob Chemother. 2018;73:826-827. https://academic.oup.com/jac/article/73/3/826/4735126