Antiretroviral concentrations in the presence and absence of valproic acid.

An unexpected drug-drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential underlying mechanisms, plasma protein displacement has been suggested. The aim of this study was to assess plasma concentrations of several antiretrovirals when administered with or without valproic acid. We performed a therapeutic drug monitoring registry analysis and identified patients concomitantly taking antiretrovirals and valproic acid and without clinical affecting conditions or interacting drugs. One hundred and thirty-four patients were identified. Median (IQR) age and BMI were 49.7 years (45-56) and 23.4 kg/m2 (20.8-26.3) and 78 were male (58.2%). Despite small groups, we observed no major effect on antiretroviral exposure, even when considering highly protein-bound compounds (such as etravirine), with the exception of dolutegravir trough concentrations [median (IQR) = 132 ng/mL (62-227) in individuals on valproic acid versus 760 ng/mL (333-1407) in those not receiving valproic acid]. Valproic acid does not have a major effect on antiretrovirals other than dolutegravir. The mechanism of this unexpected drug-drug interaction may be the combination of protein displacement, reduced absorption and CYP3A4 induction.

Calcagno A ，Cusato J ，Ferrara M ，De Nicolò A ，Lazzaro A ，Manca A ，D'Avolio A ，Di Perri G ，Bonora S ... -  《-》

Management of the Drug-Drug Interactions Between Valproic Acid and Dolutegravir-A Case Study.

Preliminary evidence shows that concomitant administration of valproic acid can reduce the exposure to dolutegravir with limited clinical impacts. Here, we describe a male living with HIV who experienced a drastic reduction in dolutegravir trough concentrations a few weeks after starting valproic acid treatment as identified by therapeutic drug monitoring. Concomitantly, pharmacists recommended a supplementation of magnesium to improve insomnia. A 62-year-old man with HIV on antiretroviral therapy with dolutegravir and lamivudine recently added valproic acid to clonazepam and sertraline to treat severe sleep disturbances. An 84% reduction in dolutegravir trough concentrations was observed compared with the previous outpatient visit (418 versus 2714 ng/mL), with values close to the minimum effective drug concentration (300 ng/mL). Considering this, we strongly discourage the use of magnesium. We are confident that our findings can contribute to a better understanding of the clinical problems that infectious disease physicians encounter in their daily management of people with HIV and how therapeutic drug monitoring may add value in this context. This case also highlights the importance of multidisciplinary services for the optimal management of polypharmacy in people with HIV.

Cattaneo D ，Giacomelli A ，Calvagna N ，Bonini I ，Ridolfo AL ，Gervasoni C ... -  《-》

Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid.

Palazzo A ，Trunfio M ，Pirriatore V ，Milesi M ，De Nicolò A ，Alcantarini C ，D'Avolio A ，Bonora S ，Di Perri G ，Calcagno A ... -  《-》

The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement.

The dolutegravir/valproic acid drug-drug interaction (DDI) is suggested to be caused by protein displacement. Here, we assess the underlying mechanism. 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 <50 copies/mL (trial registration: ClinicalTrials.gov NCT03525730). Participants were randomized to receive 30 mg/kg/day valproic acid orally (divided into two equal doses) for 14 days or not. Total and unbound dolutegravir concentrations were measured on day 0 (before intake of valproic acid and 6 h after intake of valproic acid) and on days 1, 7, 14 and 42. Intra- and inter-subject dolutegravir concentrations and geometric means (GMs) were evaluated. 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. 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.

Bollen PDJ ，Prins HAB ，Colbers A ，Velthoven-Graafland K ，Rijnders BJA ，de Vries-Sluijs TEMS ，van Nood E ，Nouwen J ，Bax H ，de Mendonca Melo M ，Verbon A ，Burger DM ，Rokx C ... -  《-》

Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.

Calcagno A ，Moltó J ，Borghetti A ，Gervasoni C ，Milesi M ，Valle M ，Avataneo V ，Alcantarini C ，Pla-Junca F ，Trunfio M ，D'Avolio A ，Di Giambenedetto S ，Cattaneo D ，Di Perri G ，Bonora S ... -  《-》