9TH EUROPEAN AIDS CONFERENCE (EACS)
1st EACS RESISTANCE & PHARMACOLOGY WORKSHOP

 October 25 - 29, 2003 Warsaw, Poland

4.1 PK and Pharmacodynamics

 F2/6 - EVALUATION OF THE MULTIPLE-DOSE PHARMACOKINETICS OF LOPINAVIR/RITONAVIR (LPV/R) IN HIV AND HCV CO-INFECTED SUBJECTS WITH MILD OR MODERATE HEPATIC INSUFFICIENCY
Arribas J.1, Pulido F.2, Peng J.Z.3, Kemmis S.3, Li J.-L.3, Lorenzo A.1, Cepeda C.2, Reisch T.3, Moseley J.3, Grebner K.3, Cabanillas J.A.4, Da Silva B.3, Bernstein B.3, Chiu Y.-L.3, Bertz R.3
 
(1) H. La Paz HIV Unit, Madrid, Spain,2 H. 12 de Octubre HIV Unit, Madrid, Spain,3 Abbott Laboratories, Abbott Park, IL, USA,4 Abbott International, Spain
 

Background of Study: Lopinavir (LPV) is primarily eliminated by CYP3A, and ritonavir (RTV) is a potent inhibitor of LPV metabolism. Hepatic insufficiency (HI) may further reduce the clearance of LPV/r.

Objectives: To evaluate LPV pharmacokinetics (PK) when given as LPV/r in subjects with mild or moderate HI.

Methods: 24 HIV+ subjects were receiving LPV/r 400/100 mg BID prior to and during the study: 12 control subjects and 6 each mild or moderate HI subjects. All HI subjects were HCV co-infected. PK sampling over 12 h and protein binding assessments were performed on Study Day 14. Noncompartmental methods were used for PK. 90% confidence intervals (CI) for the bioavailability of HI relative to control were obtained for log-transformed AUC12, Cmax, and Cmin using ANCOVA.

Results: % free LPV was similar between mild (0.89±0.21) and moderate (0.94±0.10) HI groups but higher than that in control group (0.69±0.06, p<0.01). Mild and moderate HI had similar effects on LPV PK. The relative bioavailability (90% CI) of total and free LPV exposure (HI vs. control) can be found in the table.

    Total Lopinavir   
HI Group (vs. Control)  AUC  Cmax  Cmin 
Mild  1.39 (0.98 - 1.96)  1.25 (0.91 - 1.73)  1.67 (1.05 - 2.64) 
Moderate  1.25 (0.89 - 1.76)  1.16 (0.84 - 1.59)  1.80 (1.13 - 2.86) 
Mild + Moderate  1.32 (1.00 - 1.73)  1.20 (0.93 - 1.55)  1.73 (1.20 - 2.50) 
    Free Lopinavir   
  AUC  Cmax  Cmin 
Mild + Moderate  1.71 (1.32 - 2.20)  1.56 (1.24 - 1.96)  2.23 (1.57 - 3.16) 
RTV AUC12 was about 41% higher in mild HI group and 185% higher in moderate HI group than that in control group. The average RTV AUC12 observed in moderate HI subjects was 18% of that after clinical doses of RTV (600 mg BID).

Conclusions: Both mild and moderate HI result in similar effects on LPV concentrations. Total and free LPV AUC12 were approximately 32% and 71% higher, respectively, in HI subjects vs. control.

Presenting Author: Doctor Jose Arribas, Hospital La Paz, Madrid, Spain, Medicina Interna 2. Consultas VIH, Paseo de la Castellana, 261, 28046, Madrid, Spain, Phone: 34 91 727 7099

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