title: Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets.
abstract: Rifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C(0)) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC(0-12)), C(0), C(12), maximum concentration of drug in serum (C(max)), or half-life (t(1/2)) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Decloedt
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Concepta
authors.initials: C
authors.lastname: Merry
authors.forename: Catherine
authors.initials: C
authors.lastname: Orrell
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D061466:Lopinavir; D008297:Male; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*; D013607:Tablets / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D011744:Pyrimidinones; D013607:Tablets; D061466:Lopinavir; D019438:Ritonavir; D012293:Rifampin