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Antimicrobial Agents and Chemotherapy, February 2005, p. 643-649, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.643-649.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Clinical Pharmacokinetics of Nelfinavir and Its Metabolite M8 in Human Immunodeficiency Virus (HIV)-Positive and HIV-Hepatitis C Virus-Coinfected Subjects

Mario Regazzi,1* Renato Maserati,2 Paola Villani,1 Maria Cusato,1 Patrizia Zucchi,2 Elena Briganti,3 Rinaldo Roda,4 Luca Sacchelli,5 Francesca Gatti,6 Palma Delle Foglie,7 Giulia Nardini,8 Paolo Fabris,9 Fernanda Mori,10 Paula Castelli,11 and Lucia Testa12

Department of Pharmacology,1 Clinic of Infectious Diseases, IRCCS Policlinico San Matteo, Pavia,2 Santa Maria Delle Croci Hospital, Ravenna,3 Sant'Anna Hospital, Ferrara,4 Maggiore Hospital, Parma,5 Maggiore Hospital, Verona,6 Santa Chiara Hospital, Trento,7 Modena University, Modena,8 San Bartolo Hospital, Vicenza,9 Infermi Hospital, Rimini,10 General Provincial Hospital, Macerata,11 Santa Maria Nuova Hospital, Reggio Emilia, Italy,12

Received 1 May 2004/ Returned for modification 14 July 2004/ Accepted 20 October 2004

In order to evaluate the potential risk of nelfinavir (NFV) accumulation in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients with liver disease, we investigated the concentrations of NFV and M8, the active metabolite of NFV, in plasma HIV-positive (HIV+) patients coinfected with HCV. A total of 119 HIV+ subjects were included in our study: 67 HIV+ patients, 32 HIV+ and HCV-positive (HCV+) patients without cirrhosis, and 20 HIV+ and HCV+ patients with cirrhosis. Most of the enrolled patients (chronically treated) were taking NFV at the standard dosage of 1,250 mg twice a day. To assay plasma NFV and M8 concentrations, patients underwent serial plasma samplings during the dosing interval at steady state. Plasma NFV and M8 concentrations were measured simultaneously by a high-performance liquid chromatography method with UV detection. The HIV+ and HCV+ patients with and without cirrhosis had significantly lower NFV oral clearances than the HIV+ and HCV-negative individuals (28 and 58% lower, respectively; P < 0.05), which translated into higher areas under the concentration-time curves for cirrhotic and noncirrhotic patients. The NFV absorption rate was significantly lower in cirrhotic patients, resulting in a longer time to the maximum concentration in serum. The mean ratios of the M8 concentration/NFV concentration were significantly lower (P < 0.05) in HIV+ and HCV+ subjects with cirrhosis (0.06 ± 0.074) than in the subjects in the other two groups. The mean ratios for M8 and NFV were not statistically different between HIV+ and HCV-negative patients (0.16 ± 0.13) and HIV+ and HCV+ patients without cirrhosis (0.24 ± 0.17), but the interpatient variability was high. Our results indicate that the pharmacokinetics of NFV and M8 are altered in HIV+ and HCV+ patients, especially those with liver cirrhosis. Therefore, there may be a role for therapeutic drug monitoring in individualizing the NFV dosage in HIV-HCV-coinfected patients.

* Corresponding author. Mailing address: Clinical Pharmacokinetic Unit, Department of Pharmacology, IRCCS Policlinico San Matteo, Piazzale Golgi 1, 27100 Pavia, Italy. Phone: 390382503471. Fax: 390382422701. E-mail: regazzim{at}smatteo.pv.it.

Antimicrobial Agents and Chemotherapy, February 2005, p. 643-649, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.643-649.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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