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Antimicrobial Agents and Chemotherapy, October 2009, p. 4147-4152, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00460-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic Assessment of Nevirapine and Metabolites in Human Immunodeficiency Virus Type 1-Infected Patients with Hepatic Fibrosis {triangledown}

Anna Maria Cammett,* Thomas R. MacGregor, Jan M. Wruck, Franco Felizarta, Patrick Miailhes, Josep Mallolas, and Peter J. Piliero

Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut

Received 7 April 2009/ Returned for modification 22 June 2009/ Accepted 12 July 2009

Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for ≥6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.

* Corresponding author. Mailing address: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877. Phone: (203) 798-4961. Fax: (203) 837-4961. E-mail: annamaria.cammett{at}boehringer-ingelheim.com

{triangledown} Published ahead of print on 20 July 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4147-4152, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00460-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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