JAC Advance Access published online on September 5, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn383
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Original research |
A pilot study on the efficacy, pharmacokinetics and safety of atazanavir in patients with end-stage liver disease
1 Department of Internal Medicine and Medical Specialties, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy 2 Department of Infectious Diseases, University of Turin, Turin, Italy 3 Department of General Surgery, Liver and Multivisceral Transplant Centre, University of Modena and Reggio Emilia, Modena, Italy 4 Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy 5 Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Modena, Italy
Received 9 April 2008; returned 16 June 2008; revised 13 August 2008; accepted 16 August 2008
* Correspondence address. Department of Internal Medicine and Medical Specialties, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy. Tel: +39-059-422-5318; Fax: +39-059-422-3710; E-mail: g.guaraldi{at}unimore.it
Objectives: Antiretroviral combinations including atazanavir are currently not recommended in HIV-infected patients with end-stage liver disease (ESLD). The objective of our study was to evaluate efficacy, pharmacokinetics and safety of unboosted atazanavir in HIV-infected patients with ESLD screened for orthotopic liver transplantation (OLTx).
Patients and methods: Single-arm, 24 week pilot study. Atazanavir-naive patients undergoing highly active antiretroviral therapy were switched to atazanavir 400 mg/day plus two non-thymidine nucleoside reverse transcriptase inhibitors.
Results: Fifteen patients (10 males and 5 females) were included. In the study period, 2 patients were transplanted and 10 completed 24 weeks of atazanavir treatment. Median area under the concentration–time curve at week 4 was 19 211 ng·h/mL (IQR = 8959–27 500). At week 24, median atazanavir trough concentrations (Ctrough) per patient calculated across the study were above the minimum effective concentration (MEC = 100 ng/mL) in 8 of 10 subjects. Atazanavir Ctrough time-point values were always above the MEC in five patients. The other three subjects experienced only one determination below the MEC, with median atazanavir Ctrough levels across the study being above the MEC in two of them. At 8 of 11 time-points when atazanavir and proton pump inhibitors (PPIs) were co-administered and at 16 of 19 time-points in which patients had a concomitant tenofovir association, atazanavir Ctrough was above the MEC.
Conclusions: Unboosted atazanavir showed a favourable pharmacokinetic profile and was able to maintain or gain immuno-virological eligibility for OLTx in all patients. Limited biochemical toxicities (including unconjugated hyperbilirubinaemia) and allowance of concomitant administration of tenofovir and PPIs were observed.
Key Words: HIV , therapeutic drug monitoring , unboosted protease inhibitors , liver insufficiency , drug–drug interactions