Julie Bertrand*(1), Monidarin Chou (2), Laurence Borand (3), Céline Verstuyft (4), Xavier Blanc (4), France Mentré (1), Anne-Marie Taburet (4) and ANRS 1295-CIPRA KH001 study group
(1) INSERM, Paris, France; (2) University of Health Sciences, Phnom Penh, Cambodia; (3) Institut Pasteur du Cambodge, Phnom Penh, Cambodia; (4) Bicêtre University hospital, Kremlin Bicêtre, France
Objectives: To monitor efavirenz plasma concentrations in Cambodian patients of the CAMELIA-ANRS1295-CIPRA KH001 trial and to explore genetic variations as factors of variability, especially due to concomitant use of rifampicin.
Methods: Analyses included 307 HIV-1 infected patients. All received efavirenz and nucleoside analogs once daily and efavirenz trough plasma concentrations were measured 12h after drug intake at weeks 2 and 6 after the onset of HAART and at weeks 22 and 50 after the tuberculosis treatment onset along with intensive pharmacokinetic profiles (6 samples) in 10 patients.
A one compartment model with delayed zero-order absorption and first-order elimination was used accounting for between and within subject variability on Cl/F and a scale bioavailability parameter F fixed to 1.
Efavirenz is mainly eliminated through CYP2B6 with CYP3A5 and CYP2A6 as alternative pathways and rifampicin is a known inhibitor of the OATP-C transporter as well as an inducer of the PXR transporter which influences CYP3A4 and P-glycoprotein expression levels. Therefore in the present study patients were genotyped for CYP2B6 G516T, CYP2B6 C1459T, CYP3A4*1B, CYP3A5 A6986G, CYP2A6*9, ABCB1 C3435T and OATP1B1 T521C polymorphisms. Due to the duration of study and the related improvement in patient's condition, weight was entered as covariate on Cl/F with an allometric scaling.
Results: Allele frequencies of CYP2B6 516T , OATP1B1 521C , ABCB1 3435T and CYP3A5 6986G (loss-of-function variant) were 0.30, 0.14, 0.36 and 0.36, respectively. Efavirenz F was found to be slightly increased with transaminase levels and CL decreased by 21% and 73% in CYP2B6 516 GT and TT patients, respectively. The anti-TB treatment was associated with increased CL in patients CYP2B6 516 GG, and further decreased CL in patient carriers of the T (non-functional) allele.
Conclusions: Because the first samples were collected following at least 2 weeks of efavirenz on top of 4 weeks of anti-TB treatment, we did not use the auto-induction and concurrent enzyme induction model proposed by Zhu et al. [1]. No other genetic marker than CYP2B6 G516T was found associated to efavirenz CL in the present study, and further analyses are required to fully understand the interaction with the anti-TB treatment.
References:
[1] M. Zhu, S. Kaul, P. Nandy, D. M. Grasela, and M. Pfister, "Model-Based Approach To Characterize Efavirenz Autoinduction and Concurrent Enzyme Induction with Carbamazepine," Antimicrobial Agents and Chemotherapy, vol. 53, 2009, pp. 2346-2353.
Reference: PAGE 21 (2012) Abstr 2573 [www.page-meeting.org/?abstract=2573]
Poster: Infection