Date of report: 22 Jun 2020
Reported case interaction between
Dolutegravir and Valproate

FLS Science

Drugs suspected to be involved in the DDI

Drug A
Dolutegravir (Victim)
Daily Dose
50mg (mg)
Dose adjustment performed
Administration Route
Start date
Nov. 15, 2019
End date
Drug B
Valproate (Perpetrator)
Daily Dose
3000 (mg)
Dose adjustment performed
Administration Route
Start date
Nov. 6, 2019
End date

Complete list of drugs taken by the patient

Antiretroviral treatment
Complete list of all comedications taken by the patient, included that involved in the DDI
Valproate Alfusozin Ciprofloxacin Colecalciferol Desloratidin Haldol Lorazepam Metoprolol Quetiapine Multivitamin

Clinical case description

eGFR (mL/min)
Liver function impairment

A 50-year old patient with a new HIV infection (CD4 count 10; VL 300.000 copies/ml) was admitted to the hospital for respiratory insufficiency due to PJP and Pasteurella infection. Dolutegravir (DTG) with FTC/TDF was started on 14 November 2019. The patient also received valproate for having a history mental disorders and drug abuse. The valproate-DTG interaction is not considered to be clinically relevant. Valproate reduces total DTG concentrations due to protein binding displacement, free DTG fraction increases, leading to therapeutic free DTG plasma concentrations (Bollen P; 20th International Workshop on Clinical Pharmacology of HIV 2019, abstract 44). Several DTG plasma trough concentrations were measured in this patient – displayed in the table below.

We decided to measure free DTG concentrations, because of the extremely low result at 22 Nov 2019. Free DTG fraction did not increase and was thus considered to be potentially subtherapeutic. DTG was given BID instead of QD to increase plasma concentrations from 29 Nov 2019 onwards. DTG trough concentration increased and the free DTG concentration was above the proposed in vitro EC90 value of unbound dolutegravir (0.9 µg/L). This case suggests that the DDI between valproate and DTG might be clinically relevant in some patients.

DTG concentrations

Date Dose Total DTG Free DTG
    mg/L ug/L (% of total DTG)
18-11-2019 1 dd 50mg 0.71 5.8 (0.8)

1 dd 50mg

0.09 0.58 (0.6)
02-12-2019 2 dd 50mg 0.39 1.47 (0.4)


Viral load data

Date VL
07-11-2019 300.000 copies/ml
02-12-2019 600 copies/ml
31-01-2020 900 copies/ml



Loss of efficacy

Drug Interaction Probability Scale (DIPS)

2 - Possible

Editorial Comment