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Other than dolutegravir, no antiretroviral
interactions with valproic acid in 134 people
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20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands
Mark Mascolini
HIV outpatients taking an array of integrase inhibitors, protease inhibitors (PIs), or nonnucleosides (NNRTIs) had no concerning interactions with valproic acid,[1] other than the previously reported lower dolutegravir exposure with valproic acid [2], which came into question at this Pharmacology Workshop [3].
University of Torino researchers noted that growing rates of comorbidities in people with HIV expose them to more potential interactions between antiretrovirals and comedications. The Torino group recently reported lower dolutegravir concentrations with versus without valproic acid, an anticonvulsant prescribed for seizures and bipolar disorder [2]. These investigators wondered if valproic acid has potentially dangerous interactions with other frequently used antiretrovirals, especially raltegravir.
The researchers focused on outpatients taking antiretroviral therapy who had plasma samples available for drug monitoring. They searched medical records to determine which patients took their antiretrovirals with valproic acid. Then they used standard assays to measure antiretroviral concentrations and compared antiretroviral plasma exposures to peak or trough concentrations or 90% confidence intervals of people taking the same antiretrovirals without valproic acid, stratified by 2-hour intervals from dosing.
This process yielded 134 people taking valproic acid with antiretrovirals. Seventy-eight people (58%) were men, median age stood at 49.7 years (interquartile range [IQR] 45 to 56), and median body mass index measured 23.4 kg/m2 (IQR 20.8 to 26.3). Most people took nucleos(t)ides with integrase inhibitors (29 dolutegravir, 27 raltegravir), PIs (24 atazanavir, 13 darunavir, 4 lopinavir), NNRTIs (10 etravirine, 7 rilpivirine, 3 nevirapine, 2 efavirenz), or an entry inhibitor (17 maraviroc).
No significant or clinically meaningful interaction emerged between valproic acid and any antiretroviral other than dolutegravir (median trough 145 ng/mL). For raltegravir, median levels of the integrase inhibitor with versus without valproic acid were 349 and 746 ng/mL 2 to 4 hours after dosing (P = 0.202) and 384 and 216 ng/mL 10 to 14 hours after dosing (P = 0.513).
A Dutch study reported separately by NATAP confirmed decreasing total dolutegravir troughs with ongoing valproic acid dosing, but an increasing dolutegravir free (unbound) fraction with longer valproic acid use [3]. The researchers proposed that the falling total dolutegravir plasma concentration "can be explained by displacement of protein binding of dolutegravir by valproic acid." Therefore they deduced that the reported dolutegravir-valproic acid interaction is not clinically relevant.
References
1. Calcagno A, Cusato J, Ferrara M, et al. Valproic acid co-administration is not associated with lower non-dolutegravir antiretrovirals' exposures. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 43.
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
3. 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.
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