title: Clinical pharmacokinetics of nelfinavir and its metabolite M8 in human immunodeficiency virus (HIV)-positive and HIV-hepatitis C virus-coinfected subjects.
abstract: 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.
authors.affiliation: Clinical Pharmacokinetic Unit, Department of Pharmacology, IRCCS Policlinico San Matteo, Piazzale Golgi 1, 27100 Pavia, Italy. regazzim@smatteo.pv.it
authors.forename: Mario
authors.initials: M
authors.lastname: Regazzi
authors.forename: Renato
authors.initials: R
authors.lastname: Maserati
authors.forename: Paola
authors.initials: P
authors.lastname: Villani
authors.forename: Maria
authors.initials: M
authors.lastname: Cusato
authors.forename: Patrizia
authors.initials: P
authors.lastname: Zucchi
authors.forename: Elena
authors.initials: E
authors.lastname: Briganti
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Roda
authors.forename: Luca
authors.initials: L
authors.lastname: Sacchelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Gatti
authors.forename: Palma
authors.initials: P
authors.lastname: Delle Foglie
authors.forename: Giulia
authors.initials: G
authors.lastname: Nardini
authors.forename: Paolo
authors.initials: P
authors.lastname: Fabris
authors.forename: Fernanda
authors.initials: F
authors.lastname: Mori
authors.forename: Paula
authors.initials: P
authors.lastname: Castelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Testa
mesh_terms: D000293:Adolescent; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006679:HIV Seropositivity; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000097:blood / Q000493:pharmacokinetics*; D011786:Quality Control; D013056:Spectrophotometry, Ultraviolet
chemical_list: D017320:HIV Protease Inhibitors; D019888:Nelfinavir