Influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1.
OBJECTIVE
The metabolic pathways of dolutegravir and nevirapine suggest a potential pharmacokinetic interaction between these drugs. The objective of this study was to investigate the influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1.


METHODS
This study was an investigator-initiated trial registered at ClinicalTrials.gov under identifier NCT02067767. Dolutegravir (50 mg once daily) was added to the antiretroviral regimen (400 mg of nevirapine once daily + 600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravir + abacavir/lamivudine was continued. Full pharmacokinetic profiles were assessed on the day of nevirapine discontinuation and 2 weeks after discontinuation of nevirapine. The pharmacokinetic parameters of dolutegravir were calculated by non-compartmental analysis. The log-transformed values of these parameters were compared between periods with and without nevirapine co-administration.


RESULTS
The co-administration of nevirapine led to a significant decrease (P < 0.05) in the area under the plasma concentration-time curve for dolutegravir from the time the dose was administered until the end of the dosing interval (-19%, P = 0.011), as well as decreases in trough plasma concentration (-34%, P = 0.018) and terminal half-life (-15%, P = 0.039), and a significant increase (P < 0.05) in apparent oral clearance for dolutegravir (+23%, P = 0.011).


CONCLUSIONS
The decrease in dolutegravir exposure in combination with nevirapine suggests that the metabolism of dolutegravir is induced by nevirapine. According to therapeutic drug monitoring for dolutegravir, some patients may need a higher dose than 50 mg of dolutegravir once daily to maintain the therapeutic plasma concentration throughout the dosing interval.
Clinical Pharmacology Department, University Hospital of Nantes, Nantes, France EA 3826 Thérapeutiques Cliniques et Expérimentales des Infections, University of Nantes, Nantes, France eric.dailly@chu-nantes.fr.
Eric
E
Dailly
Infectious Diseases Department, University Hospital of Nantes, Nantes, France.
Clotilde
C
Allavena
Clinical Pharmacology Department, University Hospital of Nantes, Nantes, France EA 3826 Thérapeutiques Cliniques et Expérimentales des Infections, University of Nantes, Nantes, France.
Matthieu
M
Grégoire
Infectious Diseases Department, University Hospital of Nantes, Nantes, France.
Véronique
V
Reliquet
Clinical Pharmacology Department, University Hospital of Nantes, Nantes, France.
Régis
R
Bouquié
Infectious Diseases Department, University Hospital of Nantes, Nantes, France.
Eric
E
Billaud
Clinical Pharmacology Department, University Hospital of Nantes, Nantes, France.
Hélène
H
Hernando
Infectious Diseases Department, University Hospital of Nantes, Nantes, France.
Sabelline
S
Bouchez
Clinical Pharmacology Department, University Hospital of Nantes, Nantes, France.
Guillaume
G
Deslandes
Infectious Diseases Department, University Hospital of Nantes, Nantes, France.
Nolwenn
N
Hall
Clinical Pharmacology Department, University Hospital of Nantes, Nantes, France.
Pascale
P
Jolliet
Infectious Diseases Department, University Hospital of Nantes, Nantes, France.
François
F
Raffi
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000008:administration & dosage*; D010078:Oxazines; D010879:Piperazines; D011446:Prospective Studies; D011728:Pyridones; D000099226:Dolutegravir
D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D019829:Nevirapine; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir