title: Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients.
abstract: Solid organ transplantation in HIV-infected individuals requires concomitant use of immunosuppressants and antiretrovirals that may cause significant drug interactions. Here we report on a peculiar pharmacokinetic interaction between tacrolimus and protease inhibitors (PIs) which occurred in four HIV-infected liver transplant patients who had to shift PI therapy from nelfinavir to fosamprenavir as a consequence of regulatory restrictions. After the switch, tacrolimus trough blood concentrations significantly dropped in all patients (mean +/- SD 6.9 +/- 2.6 versus 3.2 +/- 2.0 ng/ml before and after the switch, respectively; P=0.01), so that a marked dosage increase was needed (0.29 +/- 0.14 versus 0.88 +/- 0.48 mg/day, 1-3 days before and 3 weeks after the switch, respectively; P=0.046) to attain the desired target (8.7 +/- 2.3 ng/ml). Consistently, marked changes of the concentration/dose ratio of tacrolimus were observed in all cases (27.2 +/- 9.7 ng/ml per mg/kg/day versus 9.7 +/- 4.0 ng/ml per mg/kg/day before and after the switch, respectively; P<0.001). Our findings suggest that fosamprenavir may be less potent than nelfinavir in inhibiting tacrolimus clearance and support the need for higher tacrolimus dosage to avoid insufficient immunosuppression in HIV-infected liver transplant patients when switching from nelfinavir to fosamprenavir or even when directly starting antiretroviral therapy with fosamprenavir.
authors.affiliation: Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Udine, Italy. pea.federico@aoud.sanita.fvg.it
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
authors.forename: Marcello
authors.initials: M
authors.lastname: Tavio
authors.forename: Federica
authors.initials: F
authors.lastname: Pavan
authors.forename: Angela
authors.initials: A
authors.lastname: Londero
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bresadola
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Adani
authors.forename: Mario
authors.initials: M
authors.lastname: Furlanut
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Viale
mesh_terms: D000328:Adult; D002219:Carbamates / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000008:administration & dosage*; D010755:Organophosphates / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D007166:Immunosuppressive Agents; D010755:Organophosphates; D013449:Sulfonamides; D019888:Nelfinavir; D016559:Tacrolimus; C426859:fosamprenavir