title: Pharmacokinetic interactions between cyclosporine and protease inhibitors in HIV+ subjects.
abstract: With advances in antiretroviral therapy, many HIV+ individuals are living longer lives and some are developing end-stage renal and/or hepatic disease requiring transplantation. These patients require concomitant use of immunosuppressants (e.g., cyclosporine [CsA]) and antiretrovirals (e.g., protease inhibitors [PIs]), which exhibit narrow therapeutic windows and are substrates and inhibitors of cytochrome P450 3A enzymes and the cellular transporter P-glycoprotein. In this pilot study, HIV+ subjects on either oral nelfinavir (NFV) or indinavir (IND) with nondetectable viral loads and normal renal and hepatic function had 12 hour pharmacokinetic (PK) studies on 3 separate days: PIs alone, PIs+intravenous CsA, and PIs+oral CsA to determine the extent of PK interactions between these medications. PIs and CsA concentrations were measured by LC/MS in plasma and whole blood, respectively. Nine subjects (n=7 on NFV, n=2 on IND) completed the study. Only the results of those subjects taking NFV are reported. Oral co-administration of CsA increased NFV T(max) from 2.6+/-0.9 to 3.2+/-0.8 h (p<0.05), and AUC(0-infinity) from 27.9+/-15.2 to 43.2+/-27.1 mg(*)h/mL (p=0.06). Intravenous CsA did not appreciably alter oral pharmacokinetics of NFV. Both CsA and NFV PK parameters exhibited a high degree of intersubject variability, underscoring the need for routine therapeutic drug monitoring of both CsA and PIs in HIV+ subjects undergoing transplantation.
authors.affiliation: Department of Medicine, General Clinical Research Center, University of California, San Francisco 94143, USA. frassett@gcrc.ucsf.edu
authors.forename: Lynda
authors.initials: L
authors.lastname: Frassetto
authors.forename: Thien
authors.initials: T
authors.lastname: Thai
authors.forename: Anjana M
authors.initials: AM
authors.lastname: Aggarwal
authors.forename: Patricia
authors.initials: P
authors.lastname: Bucher
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jacobsen
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Floren