Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism

Abstract

ObjectivesTo assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations.Methods135 HIV-1 infected patients treated with DRV-based therapy were included in the study and plasma samples were obtained immediately before drug intake in order to determine DRV trough concentrations using an ultra performance liquid chromatography method (UPLC) with diode-array detection (DAD). Noteworthy is the fact that in 16 (11.9%) patients, etravirine (ETR) was combined with DRV. CYP3A5 genotypes were determined using real time PCR method (TaqMan® genotyping assay). The patients were then classified into CYP3A5 expressors (CYP3A5*1 allele carriers) and non-expressors (CYP3A5*3 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed.Results45% of the patients were classified as CYP3A5 expressors. In the whole cohort, mean [DRV]plasma was not different between CYP3A5 expressors and non-expressors (1894ng/ml [CI95%: 1566–2290] versus 1737ng/ml [CI95%: 1468–2057], p = 0.43). However, in the subgroup of the 16 patients receiving DRV combined with ETR, a significantly lower [DRV]plasma was observed for CYP3A5 expressors when compared to non-expressors (1385ng/ml [CI95%:886.3–2165] versus 3141ng/ml [CI95%:2042–4831], p = 0.007).ConclusionsInteraction between DRV and ETR is partly mediated by CYP3A5 polymorphism with lower DRV plasma trough concentrations in CYP3A5 expressors suggesting a specific ETR-driven CYP3A5 activation only in CYP3A5 expressors. Consequently, these patients might be more at risk of infra-therapeutic [DRV]plasma. This potentially important observation is a good illustration of a genotype-based drug interaction, which could also have considerable consequences if translated to other CYP3A5-metabolized drugs. Further investigations are thus needed to confirm this association and to explore its clinical impact, mainly in the African population among whom CYP3A5 expressors are more frequent, before recommending systematic CYP3A5 pre-emptive genotyping for DRV-ETR co-administration.

Optimizing Concentrations of Concomitant Antiretrovirals by Reducing Etravirine Doses: Two Case Reports of Complex Drug-drug Interactions

“…Compared to data with once-daily darunavir/ritonavir/etravirine, CYP3A4 inhibition by cobicistat appears less potent than ritonavir in the presence of inducers, in particular, at the end of the dosing interval [7,9]. Due to a drug-drug-gene interaction, the decrease of darunavir levels by etravirine induction may be accentuated in patients that are CYP3A5 expressers [10]. Unfortunately, pharmacogenetic testing was not available for these patients.…”

Exploration of Reduced Doses and Short-Cycle Therapy for Darunavir/Cobicistat in Patients with HIV Using Population Pharmacokinetic Modeling and Simulations

“…CYP3A5*3 is commonly found in Caucasian individuals, which may result in CYP3A4 being the major isoform responsible for DRV metabolism for that ethnicity, while it is far less frequent in African individuals, in whom both isoforms (CYP3A4 and CYP3A5) may contribute to some extent. Indeed, in subjects receiving etravirine (a known CYP inducer), plasma exposure to DRV was previously found to be lower in carriers of the functional CYP3A5*1 allele compared with CYP3A5*3 carriers, suggesting that CYP3A5 is also involved in DRV biotransformation [ 57 ]. It is also worth noting that race correlated with the presence of the CYP3A4*22 , CYP3A5*3 , and ABCB1 3435C > T alleles in this population.…”

Optimal sampling strategies for darunavir and external validation of the underlying population pharmacokinetic model

“…The validation set was composed of data collected between November 2012 and April 2016 at the Cliniques universitaires Saint-Luc (Brussels, Belgium) as part of a study by Belkhir et al [ 7 ]. Original approval for data collection was granted by the local ethics committee (Comité d’Ethique Hospitalo-Facultaire des Cliniques Saint-Luc, approval number B403201214460).…”