Roche trials database

Protocol number:

BP17921

Title of Study:

Effect of moderate liver impairment on the pharmacokinetics of saquinavir after administration of saquinavir/ritonavir 1000/100mg BID in HIV patients

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

saquinavir [Invirase]

Generic name:

saquinavir

Therapeutic area:

• HIV Infections

Clinical study summary:

This multicenter, open-label, non-randomized, parallel-group study was designed to evaluate the effect of moderate liver impairment on the pharmacokinetics after administration of saquinavir [Invirase] in HIV patients. The study compared patients with HIV who had either moderate liver disease (defined by Child-Pugh score of B) or with no evidence of liver disease. Each enrolled HIV patient with moderate liver disease (Group 2) was matched on the basis of age (± 10 years), gender, weight (± 20%), and tobacco use to a HIV patient with no known liver disease (Group 1). Study treatment with SQV/RTV 1000/100 mg BID was administered for 14 days.

Study center(s):

8 centers in Canada and the United States

Phase of development:

I

Objectives:

The primary objective was to assess the effect of moderate liver impairment on the pharmacokinetics (PK) of saquinavir (SQV) at steady state following saquinavir/ritonavir (SQV/RTV) 1000/100 mg twice-a-day (BID) in HIV (human immunodeficiency virus) patients.

The secondary objectives were as follows: to assess the effect of moderate liver impairment on the PK of RTV at steady state following SQV/RTV 1000/100 mg BID in HIV patients; to evaluate SQV and RTV drug exposure for HIV patients co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and raised liver enzymes at baseline; to investigate the safety and tolerability of SQV combined with RTV in HIV patients with moderate liver impairment following SQV/RTV 1000/100 mg BID.

Methodology:

In this multicenter, open-label, non-randomized, parallel-group study evaluating sequinavir [Invirase], HIV patients with moderate liver impairment and with no known liver disease were administered sequinavir/ritonavir 1000/100 mg twice daily for 14 days. During the study, all patients received concomitant treatment with 2 or 3 nucleoside reverse transcriptase inhibitors, the choice of which was made by the treating physician. All other anti-viral therapies for HIV were discontinued prior to the start of study drug treatment.

Number of patients (planned/analyzed):

16 patients enrolled and treated

Diagnosis and main criteria for inclusion:

Adult male and female patients, 18-65 years of age with HIV infection; normal liver function, or moderate liver disease (Child-Pugh score B); antiretroviral therapy naive and eligible to take antiretroviral treatment as per treatment guidelines, or treatment experienced for at least 4 weeks prior to first dosing.

Test product, dose and mode of administration or test procedure:

SQV/RTV 1000/100 mg, administered every 12±1 hours, on Days 1 to 14; SQV/RTV 1000/100 mg in morning of Day 14 approximately 30 minutes after standardized high-fat breakfast.

Duration of treatment:

14 days

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

 

Efficay: N/A

Pharmacodynamics: HIV-1 RNA viral load (based on Roche Amplicor® HIV Monitor Test) and CD4 cell count determined at screening, predose on Days 8 and 14, and at follow-up.

Pharmacokinetics: The following PK parameters were calculated for analysis of SQV and RTV from plasma samples obtained on Day 14: area under the plasma concentration-time curve from 0 to 12 hours post-dose (AUC_0-12) and maximum observed plasma concentration (C_max).

Safety: Adverse events (AEs), clinical laboratory tests, vital sign measurements, 12-lead ECGs, and physical examinations.

Statistical methods:

All PK parameters were presented in individual data listings and summary tables of descriptive statistics including arithmetic means, standard deviations (SD), coefficients of variation (CV), and ranges. An analysis of covariance (ANCOVA) model that included terms for liver disease, gender, tobacco use, body weight, site and subject (random) was applied to logarithmically-transformed AUC_0-12 and C_max values for SQV and RTV. A second analysis was conducted that included a fixed effect for group in addition to a random effect for “pair” reflecting the patient matching. Ratios of geometric least-squares means (GMR) for Group 2 (moderate liver disease) versus Group 1 (no known liver disease) and associated 2 sided 90% confidence intervals (CIs) were derived from the ANCOVA models.

Summary (efficacy, safety, other results):

Efficacy: N/A

Pharmacodynamics: Relative to screening values, CD4 cell counts were generally stable or slightly increased while on treatment and at follow-up for all but 1 patient. Similarly, HIV-1 RNA viral loads were generally unchanged or lower at follow-up relative to screening values. Observations were similar for patients in Groups 1 and 2.

Pharmacokinetics: There were no meaningful differences in PK profile for SQV or RTV following 14 days of administration with SQV/RTV 1000/100 mg BID between HIV patients with moderate liver disease and those with no known liver disease. Peak plasma concentrations of SQV and RTV were reached at approximately 5h and 4h post-dose, respectively, in both patient groups. The mean ± SD of SQV AUC_0-12 on Day 14 in Group 2 (HIV patients with moderate liver disease; 24332 ± 24700 ng·hr/mL) was similar to that in Group 1 (matched HIV patients with no known liver disease; 28518 ± 20157 ng·hr/mL), with high variability (%CV of 101.5% for Group 2 and 70.7% for Group 1). Similarly, the mean ± SD of RTV AUC_0-12 on Day 14 was similar for Group 2 (9930 ± 5243 ng·hr/mL) and Group 1 (10985 ± 1723 ng·hr/mL). Mean ± SD C_max values on Day 14 in Groups 1 and 2 were 4300 ± 2940 and 3610 ± 3000 ng/mL, respectively, for SQV and 1500 ± 294 and 1460 ± 690 ng/mL, respectively, for RTV.

Based on the GMR (Group 2 to Group 1), the PK exposure to both SQV and RTV was modestly reduced in HIV patients with moderate liver disease (see table below).

First Analysis Model (Protocol-Specified)			Second Analysis Model (Random Pair)
Analyte	GMR (Group 2/Group 1), %		GMR (Group 2/Group 1), %
SQV	AUC0-12	65.6 [26.8, 160.3]	AUC0-12	69.3 [33.5, 143.2]
	Cmax	71.6 [31.1, 164.4]	Cmax	73.9 [40.8, 133.6]
RTV	AUC0-12	76.4 [50.5, 115.6]	AUC0-12	81.8 [57.4, 116.4]
	Cmax	84.4 [55.2, 129.1]	Cmax	88.6 [61.9, 126.7]

There was no difference in protein binding (as evidenced by fraction unbound) of SQV or RTV between Groups 1 and 2 at low and high concentrations.

Safety: Treatment with SQV/RTV 1000/100 mg BID for 14 days was generally well tolerated by HIV patients with moderate liver disease. While the number of reported AEs was higher in Group 2 (21 AEs in 5/9 patients) than in Group 1 (6 AEs in 3/7 patients), no patient in either group discontinued study treatment due to an AE and there were no marked laboratory abnormalities. There was a single serious adverse event (SAE; upper gastrointestinal hemorrhage) that occurred 17 days after the last dose of SQV/RTV in a patient in Group 2; this SAE was assessed by the Investigator as related to esophageal varices and not related to study treatment.

The safety laboratory findings among patients in Group 2 were within the ranges expected for a population with hepatic impairment. No patient in Group 2 had a worsening of liver function during the study. No clinically relevant changes in vital signs or ECGs were observed in either group.

Conclusions:

Moderate liver impairment had no consistent effect on the pharmacokinetics of SQV or RTV.

On average, the PK exposure in patients with moderate hepatic disease was reduced by approximately 35% for SQV and 25% for RTV.

PK exposure seen for SQV in both groups of patients was generally within the range reported from a number of studies in healthy volunteers and HIV infected patients at the same dose.

Review of the safety data did not indicate any special safety concerns regarding the administration of RTV-boosted SQV to HIV patients with moderate liver disease.

No dose adjustment is warranted for SQV in HIV patients with moderate liver disease in view of the wide exposure boundary, safety profile of SQV, and modest effect seen in this study.

Date of report:

01.11.2009

Click here for the protocol registry listing of this trial.