Safety, Tolerability, and Pharmacokinetic Data Following Single- and Multiple-Dose Administration of MK-7009

59th Annual Meeting of the American Association
for the Study of Liver Diseases
(AASLD)
Oct 31-Nov 1 2008
San Francisco, CA Back

Safety, Tolerability, and Pharmacokinetic Data Following Single- and Multiple-Dose Administration of MK-7009, a Hepatitis C Virus Non-structural 3/4a Protease Inhibitor, to Healthy Male Subjects (1910)

Reported by Jules Levin
AASLD Nov 4 2008

Duncan Hamish Wright, Jutta Miller, Ilse Verlinden, Caroline Cilissen, John Valentine, Peng Sun, Marina De Smet, Jan de Hoon, Marleen Depré, Luc Cavens, Jeffrey Chodakewitz, John Wagner
Whitehouse Station, NJ; Antwerp, Brussels and Leuven, Belgium

Copyright 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All Rights Reserved.

Author Summary & Conclusion

Pharmacokinetics

SD
-- Plasma AUC0-∞ and Cmax values increase greater than dose proportionally.
-- Short apparent terminal half-life in plasma, averaging ~ 4-5 hours.
-- High-fat meal has no overall effect on plasma PK.
-- Renal excretion of unchanged drug plays a minimal role in the elimination of MK-7009 in man.

MD
-- Geometric mean accumulation ratios (GMR) of AUC0-12hr exposure (Day 14 vs. Day 1): ~1.66.
-- AUC0-12hr and Cmax both appear to increase greater than dose proportionally.
-- Steady state PK rapidly achieved by second b.i.d. dose in all panels.

Safety
-- Single doses of MK-7009 ≦1300 mg and multiple doses of MK-7009 ≦800 mg q.d. over 14 days were generally well tolerated.
-- AEs: mild to moderate in intensity; all resolved spontaneously.

Author Conclusions

MK-7009 is generally safe and well-tolerated when administered at single and multiple doses that correlate with plasma pharmacokinetics, which are multiples over the in vitro measured EC50s and the extrapolated EC90s derived from these data.

MK-7009 exhibits plasma pharmacokinetics which permit once or twice daily dosing.

This profile permits further clinical evaluation of MK-7009, including in HCV-infected patients.

ABSTRACT

Background:
MK-7009 is a rapidly reversible non-covalent competitive inhibitor of the nonstructural 3/4A protease of the hepatitis C virus.

It exhibits good inhibitory potency against genotypes 1 and 2 (replicon EC50 values = 17 and 7 nM for genotypes 1b and 2a, in the presence of 50% human serum and 10% fetal calf serum, respectively).

Initial studies were conducted to evaluate the safety, tolerability and pharmacokinetics following single-dose (SD) and multiple-dose (MD) administration of MK-7009 to healthy male subjects.

Methods:
SD: 16 healthy males received single doses of 10-825 mg MK-7009/placebo in the fasted state, with 80 mg single doses of MK-7009/placebo also evaluated in the fed state, in an alternating panel, multiple period, dose escalation study.

Single doses of 1000-1300 mg MK-7009/placebo were evaluated in the fasted state in a separate group of 16 healthy males.

MD: 40 healthy males received multiple doses of 100-800 mg MK-7009/ placebo for 14 days (once daily doses on days 1 and 14, twice daily doses on days 2-13) in a serial-panel study.

Clinical safety evaluations were performed throughout each study. Plasma and urine samples for MK-7009 pharmacokinetic data were collected.

Results:

There were no serious adverse experiences (AEs) reported, nor were there any discontinuations due to AEs.

Additionally, there were no dose-dependent patterns with respect to the frequency or the intensity of the AEs observed after SD and MD administration of MK-7009.

SD: Following oral administration, AUC0-∞ and Cmax values increased greater than dose proportionally. The apparent terminal half-life averaged ~ 4-5 h. SD administration of 80 mg of MK-7009 with a high-fat meal did not have a meaningful effect on plasma pharmacokinetics of MK-7009. Data suggest that renal excretion of unchanged drug plays a minimal role in the elimination of MK-7009 in man.

MD: Accumulation occurred over the 14-day period in all subjects, as evidenced by geometric mean ratios (Day 14/Day 1) for AUC0-12hr (1.5-1.8), Cmax (1.4-1.9) and C12hr (1.2-1.9). The apparent terminal half-lives stayed constant (~3.8-5.1 hours), regardless of dose, and were consistent with previously identified values collected after SD administration.

Conclusions:

MK-7009 is generally safe and well-tolerated, and exhibits plasma pharmacokinetics which permit once or twice daily dosing. This profile permits further clinical evaluation of MK-7009, including in HCV-infected patients.

Background - MK-7009

In vitro
-- Rapidly reversible non-covalent competitive inhibitor of hepatitis C virus (HCV) NS3/4A protease.
-- Sub-nM inhibitor of GT1a and 1b proteases, low nM potency against GT2a and 2b and potent activity in cell-based HCV replicon assay (GT1b & GT2a EC50s = 17 & 7 nM with 50% human serum & 10% fetal calf serum, respectively).

In vivo
-- Good plasma PK across preclinical species.
-- Liver concentrations maintained at a significant multiple of the cell-based replicon activity over 12-24 h following moderate oral doses (5-10 mg/kg) of MK-7009.
-- Dosing of MK-7009 (5 mg/kg, b.i.d) to a protease inhibitor naive GT1b chronically HCV-infected chimpanzee resulted in a highly significant 4.4 log10 drop in plasma viral load.

Based on this overall profile, MK-7009 was selected for clinical development.

Premise

SD
-- Evaluate safety and tolerability of single-rising oral doses of MK-7009 in healthy young male volunteers.
-- Obtain preliminary plasma PK (e.g., area under the plasma concentration versus time curve [(AUC0-∞)], maximum concentration of drug in the plasma [Cmax], plasma concentrations at 12 hours postdose [C12hr], time to reach Cmax [Tmax], and apparent terminal half-life[t1/2] of MK-7009 in the fasted state and following a standard high-fat meal.
-- Obtain preliminary data on urinary excretion of intact drug following administration of single oral doses of MK-7009.

MD
-- Evaluate safety and tolerability of MK-7009 administered for a 14 day period. -- Assess single-dose and steady-state plasma PK of MK-7009 (e.g., area under the plasma concentration versus time curve [AUC0-12hr, AUC0-24hr, and AUC0-∞ as appropriate on Day 1, and AUC0-12hr on Day 14], Cmax, trough concentration of drug in the plasma [Ctrough; C12hr after b.i.d. dosing], Tmax, T1/2 and accumulation ratio).

Methods
Study Design - Protocol 001 (PN001)
· Double-blind, placebo-controlled, alternating-panel, multiple-period, single-rising dose study in 16 healthy male volunteers.
· 2 panels (Panels A & B), 8 subjects (6 active/2 placebo), alternating rising single oral doses of MK-7009/placebo over 5 Periods.
· Panel A: 10, 40, 160, 350, and 825 mg MK-7009 or placebo.
· Panel B: 20, 80, 240, and 550 mg MK-7009 or placebo.
· Period 5, Panel B: 80 mg MK-7009 or placebo (identical assignment to that of Period 2 ) following a high-fat meal.
· Clinical safety evaluation (AEs, VS, ECG, laboratory safety) throughout the study.
· Plasma & urine samples for PK collected throughout the study.

Study Design - Protocol 002 (PN002) · Double-blind, randomized, placebo-controlled, staggered incremental dose study in 48 healthy male volunteers.
· 6 successive panels (Panels A, B, C, D, E and F), 8 subjects (6 active/2 placebo).
· Panels A, B, C & F (100, 200, 400 and 800 mg of MK-7009 or placebo): q.d. on Day 1 & Day 14, b.i.d. doses over 12 day MD period (Days 2-13).
· Panel D: 1200 mg SD MK-7009 or placebo, 7 day washout, 600 mg q.d. MK-7009 or placebo on Day 1 & Day 14, b.i.d. doses over 12 day MD period (Days 2-13).
· Panel E: 1000 mg SD MK-7009 or placebo, 7 day washout, 1300 mg SD MK 7009 or placebo, 7 day washout, 1300 mg SD MK-7009 or placebo.
· Clinical safety (AEs, VS, ECG, laboratory safety) evaluated and plasma & urine
samples for PK collected throughout the study.

No notable differences observed between treatment groups or between subjects who received active treatment versus placebo.

Safety & Tolerability - Blinded Assessment

PN001
PN001: 15 subjects reported 73 adverse experiences (AEs), 23 determined to be drug-related by the investigator.

Most common drug-related AE: headache.

PN002
PN001: 43 subjects reported 111 AEs, 70 drug-related.

Most common drug-related AEs: loose stools, headache, & stomach discomfort.

PN001 & PN002
All AEs resolved, no subjects discontinued due to an AE, no serious AEs.

No apparent relationship between dose of MK-7009 and frequency or intensity of any AE.

No consistent, clinically relevant, treatment- or dose-related effects of MK-7009 on ECGs, VS (blood pressure/heart rate) or laboratory safety tests.