[TuPe3.1B07] The Pharmacokinetics (PK) of Single-dose and Steady-state Tipranavir/Ritonavir (TPV/r) 500 mg/200 mg in Subjects with Mild or Moderate Hepatic Impairment

3rd International AIDS Society Conference on HIV Pathogenesis and Treatment

Rio de Janeiro - July 24 - 27, 2005

THE PHARMACOKINETICS (PK) OF SINGLE-DOSE AND STEADY-STATE TIPRANAVIR/RITONAVIR (TPV/R) 500 MG/200 MG IN SUBJECTS WITH MILD OR MODERATE HEPATIC IMPAIRMENT

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. TuPe3.1B07

Cooper C.¹, van Heeswijk R.¹, Bilodeau M.², Kovacs B.³, Sabo J.⁴, MacGregor T.⁴, Wruck J.⁴, Elgadi M.⁵, Neubacher D.⁴, McCallister S.⁴
¹The Ottawa Hospital, Ottawa, Canada, ²Université de Montréal, Montreal, Canada, ³Boehringer Ingelheim Pharmaceuticals, Ridgefield, United States of America, ⁴Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, United States of America, 5Boehringer Ingelheim Canada, Ltd, Burlington, United States of America

INTRODUCTION: TPV is a non-peptidic PI with potent activity against PI-resistant HIV-1 variants; plasma concentrations are greatly elevated by coadministration with ritonavir. Because the liver metabolizes both TPV and ritonavir, we examined the effects of mild (Child Pugh score A <6; CPA) and moderate hepatic impairment (Child Pugh score B 7–9; CPB) on the PK of TPV/r in HIV-1–negative volunteers.

METHODS: TPV and ritonavir PK were assessed in 9 subjects with CPA following single-dose (24h) and at steady-state (12h; after 7 days of dosing) TPV/r 500 mg/200 mg twice daily. Three subjects with CPB were assessed for single-dose PK (12h) following TPV/r 500 mg/200 mg. Results were compared with healthy controls matched for age, weight, gender, and race. Plasma concentrations of TPV were measured by LC-MS/MS, and non-compartmental methods were used for PK analysis.

RESULTS: For the CPA subjects, single dose geometric mean ratio (GMR and 90% CI) of TPV AUC_0-8, C_max, and Cp_12h relative to healthy controls were 0.89 (0.55–1.45), 0.79 (0.44–1.43), and 1.03 (0.62–1.71), respectively (P>0.48). For steady-state TPV/r, the GMR (90% CI) for these TPV PK parameters were 1.30 (0.88–1.92), 1.14 (0.83–1.56), and 1.84 (0.81–4.20), respectively (P>0.2). For the CPB subjects, the TPV GMR (90% CI) were AUC_0-8 1.35 (0.47–3.90), C_max 0.69 (0.25–1.91), and Cp_12h 1.38 (0.44–4.30) (P>0.4). Two subjects (one with mild and one with moderate hepatic impairment) experienced transient DAIDS Grade III–IV lab abnormalities (GGT and total bilirubin, respectively). Reported AEs were minimal.

CONCLUSIONS: TPV/r 500 mg/200 mg can be safely administered without dose adjustment in subjects with mild hepatic impairment. The influence of moderate hepatic impairment on TPV PK warrants further study and indicates that monitoring of patients with moderately impaired liver function taking TPV/r may be required.

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050724
Basic | TuPe3.1B07 | C Cooper
PK and pharmacodynamics

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