NATAP: TPV/r PK IN Hepatic Impairment

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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

Reported by Jules Levin

IAS-Rio July 2005

Poster TuPe3.1B07

C ,1 R van Heeswijk,1 M Bilodeau,2 B Kovacs,3 J Sabo,3 T MacGregor,3 J Wruck,3 M Elgadi,4 D Neubacher,3 S McCallister3

1. The Ottawa Hospital, Ottawa, ONT, Canada; 2. Montreal, QC, Canada; 3. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 4. Boehringer Ingelheim Canada, Ltd., Burlington, ONT, Canada.

ABSTRACT

BACKGROUND: 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 AUC0-∞, Cmax, and Cp12h 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 AUC0-∞ 1.35 (0.47-3.90), Cmax 0.69 (0.25- 1.91), and Cp12h 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.

RESULTS: NO DIFFERENCE IN SINGLE-DOSE PK OF TPV IN

SUBJECTS WITH MILD HEPATIC INSUFFICIENCY

Following a single-dose of TPV/r there was no significant difference in systemic exposure to TPV between subjects with mild hepatic insufficiency and matched controls.

RESULTS: STEADY-STATE PK OF TPV IN SUBJECTS WITH MILD HEPATIC

INSUFFICIENCY

After 7 days of TPV/r twice daily, there was no significant difference in systemic exposure to TPV between subjects with mild hepatic impairment and matched controls.

RESULTS: SINGLE-DOSE PK OF TPV IN SUBJECTS WITH MODERATE

HEPATIC INSUFFICIENCY

Following a single-dose of TPV/r there was no significant difference in systemic exposure to TPV among subjects with moderate hepatic insufficiency and their matched controls.

RESULTS: ADVERSE EVENTS

All subjects completed the trial at the planned TPV/r dosage

All AEs were mild or moderate in intensity; none were severe

GI AEs were the most frequent (20/24, 83.3%)

- AEs that were more common in the hepatically impaired group than controls were abdominal pain (5/12, 41.7% vs 2/12, 16.7%), nausea (6/12, 50.0% vs 1/12, 8.3%), and flatulence (6/12, 50.0% vs 0/12)

AEs of moderate intensity were more frequent in the hepatically impaired group (8/12, 66.7%) than the control group (1/12, 8.3%)

RESULTS: LABORATORY ANALYSIS

Majority of changes were Grade 1 elevations of ALT/AST, which were greatest in subjects with mild hepatic impairment

Two subjects (one with mild and one with moderate hepatic impairment) experienced transient DAIDS Grade 3-4 GGT and total bilirubin, respectively

- Both subjects completed the trial

AUTHOR'S SUMMARY

Systemic concentrations of TPV were comparable in healthy subjects and subjects with mild impairment in hepatic function following single and multiple doses of TPV/r:

- TPV/r 500 mg/200 mg can be safely administered without dose adjustment to HIV+ patients with mild hepatic impairment

The influence of moderate hepatic impairment on TPV PK warrants further study:

- The use of TPV/r in HIV+ patients with moderately impaired liver function needs to be considered on an individual basis with close patient monitoring

No adverse events of concern were seen in Child-Pugh A subjects given single or multiple doses of TPV/r, or in Child-Pugh B subjects given single-dose TPV/r

INTRODUCTION

Tipranavir (TPV) is a potent non-peptidic protease inhibitor (NPPI) that has a resistance profile distinct from currently available protease inhibitors (PIs). It retains a broad in vitro antiviral activity against a wide range of patient-derived HIV isolates resistant to peptidic PIs.1,2 The companion phase 3 trials, RESIST-1 and RESIST-2, demonstrated that TPV/r was superior to a comparator PI at 24 weeks in efficacy, with an adverse event profile similar in rate and type.3,4 Based on their results, TPV was recently cleared for marketing by US FDA.

TPV plasma levels are boosted by the addition of low-dose ritonavir (RTV),5 a PI that is used to enhance the therapeutic plasma levels of other PIs by inhibiting the cytochrome P450 isoenzyme 3A4 (CYP3A4).6 In HIV-1-infected subjects treated with TPV/r, some subjects have developed elevations in hepatic transaminases and triglycerides.3,4

The optimal dose combination of TPV/r for PI-experienced HIV+ patients has been determined to be 500 mg/200 mg bid. The objective of this phase I open-label study was to understand the single-dose PK of TPV/r in subjects with Child- Pugh A and Child-Pugh B hepatic insufficiency and the steady-state PK of TPV/r in

subjects with mild hepatic insufficiency. Because the primary route of TPV/r metabolism is through hepatic enzyme systems, PK data are required to determine appropriate dosing of TPV/r for HIV+ patients with mild or moderate hepatic insufficiency.

STUDY DESIGN

Phase I, open-label study in HIV-negative males and females with mild to moderate hepatic insufficiency:

- Controls matched for race, gender, age (±3 years), weight (±3 kg), and smoking history

Entry Criteria

- Diagnostically established hepatic disease that was either mild (maximum ever Child-Pugh score ≤6, Class A) or moderate (maximum ever Child-Pugh score 7-9 for less than 5 years, Class or matched healthy subjects

- Willingness and ability to abstain from alcohol and other restricted substances (coffee, tea, garlic supplements, chocolate, cola, energy drinks, grapefruit juice, St. 's Wort, etc), and to refrain from vigorous exercise

- Child-Pugh A subjects with positive hepatitis B or hepatitis C serology were not excluded from the study

Healthy controls had laboratory values less than or equal to Grade 1, based on the ACTG Grading Scale.

For Child-Pugh A subjects and matched controls:

- All subjects received a single dose of TPV/r 500 mg/200 mg on day 1, followed by twice-daily dosing for 5 days and a single dose on day 7

- Intensive PK sampling took place on days 1 and 7, and trough sampling on days 2 to 6. PK samples following the last dose were collected at 24, 48, 72, 96, and 120 hours after dosing

For Child-Pugh B subjects and matched controls:

- Subjects received a single dose of TPV/r 500 mg/200 mg

- PK sampling took place on day 1, with additional samples collected at 24, 48, 72, 96, and 120 hours after dosing

- These subjects did not receive multiple doses of TPV/r

Primary intensive PK parameters for all subjects were AUC0-∞ single dose (plus AUC0-12 and AUC0-∞ steady state for mild subjects), Cmax, and Cp12h

BASELINE DEMOGRAPHICS

REFERENCES

1. Back NK, van Wijk A, Remmerswaal D, et al. AIDS. 2000;14:101-102.

2. Larder BA, Hertogs K, Bloor S, et al. AIDS. 2000;14:1943-1948.

3. Hicks C, for the RESIST-1 study team. Presented at: 44th ICAAC; October 30-November 2, 2004; Washington, DC. Abstract H-1137a.

4. Cahn P, and the RESIST-2 study team. Presented at: 7th International Congress on Drug Therapy in HIV Infection; November 14-18, 2004; Glasgow, Scotland. Abstract PL14.3.

5. MacGregor TR, Sabo JP, Norris SH, P, Galitz L, McCallister S. HIV Clin Trials. 2004;5(6):311-382.

6. CL, van Heeswijk RPG, Gallicano K, Cameron DW. Clin Infect Dis. 2003;36: 1585-1592.