Atazanavir and ritonavir pharmacokinetics with telaprevir-based HCV treatment (ANRSHC26)

Background: The ANRSHC26-TelapreVIH clinical trial enrolled HIV-HCV coinfected patients, non responders to Peg-interferon+ribavirin (PR) therapy. The objective was to estimate virological response rate when telaprevir was added to the standard bitherapy. Antiretroviral therapy was in most patients ritonavir boosted atazanavir with tenofovir/emtricitabine fixed dose combination. The pharmacokinetic (PK) parameters of atazanavir and ritonavir administered with PR bitherapy (at week 0) or after addition of telaprevir (at week 8), were estimated in a subgroup of patients.
Methods: Sixteen patients agreed to participate and 12 completed all samples for PK analysis. Atazanavir and ritonavir were assayed by a validated LC/MS/MS method. Pharmacokinetic parameters were estimated by non compartmental method. Geometric mean ratio (GMR) and 90% confidence interval (90%CI) were constructed for the ratio of each parameter for antiretroviral drug (ARV) combined to telaprevir+ PR / ARV +PR. Unless otherwise indicated, results are presented as median (IQR or range).
Results: Median (IQR) age and weight were 49 (38-61) years and 74 (53-90) kg respectively. Plasma HCV-RNA was 6.04 (5.46-7.30) log10 UI/mL. HIV-RNA was < 50cp/mL in 11 patients. Median CD4 were 452 (152-671) cells/µL. Median total bilirubin and unconjugated bilirubin were 41 (20-200) µmol/L and 33 (15-91) µmol/L respectively. Pharmacokinetic parameters as median (range) were:

 ARV +PRARV+PR+TelaprevirGMR (90%CI)
Cmax-ng/mL3169 (1176-4333)2779 (1331-4387)0.91 (0.73-1.13)
Cmin-ng/mL487 (137-2062)945 (289-1960)1.79 (1.30-2.47)
AUC-ng.h/mL32235 (13965-66420)33179 (20749-72531)1.14 (0.92-1.41)
Cmax-ng/mL1115 (736-1934)857 (422-1135)0.70 (0.62-0.80)
Cmin-ng/mL48 (21-226)51 (17-106)0.80 (0.61-1.05)
AUC-ng.h/mL7979 (6001-18170)6100 (2731-10712)0.65 (0.56-0.76)
[Pharmacokinetic parameters]

Unconjugated bilirubinemia increased by 1.21 fold when atazanavir was combined with telaprevir. A significant relationship between unconjugated bilirubinemia and atazanavir Cmin was observed (p=0.0015).
Conclusions: Atazanavir Cmin increased by 79% when coadministered with telaprevir in HCV-HIV coinfected patients despite a lower exposure to ritonavir. This drug-drug interaction was associated with a mild increase in bilirubin levels.

A. Barrail-Tran1,2, J. Braun3, C. Vincent3, M.-A. Valentin4, D. Vittecoq5, I. Fournier3, J.-P. Aboulker3, B. Chauvin1, J.-M. Molina6, A.-M. Taburet1, L. Cotte7
1Hôpital Bicêtre, AP/HP, University Paris-Sud, Clinical Pharmacy, Kremlin Bicêtre, France, 2University Paris-Sud, EA 4123, Faculty of Pharmacy, Chatenay Malabry, France, 3Inserm, SC 10, Villejuif, France, 4Hôpital Pitié-Salpétrière, Infectious Diseases, Paris, France, 5Hôpital Bicêtre, AP/HP, University Paris-Sud, Infectious Diseases, Kremlin Bicêtre, France, 6Hôpital Saint Louis, AP/HP, Université Paris Diderot, Infectious Diseases, Paris, France, 7Hotel-Dieu, Hepatogastroenterology, Lyon, France