Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-3281

Safety, Tolerability, and Pharmacokinetics after Single and Multiple Doses of MK-3281 in Healthy Subjects

EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin

D.M. Brainard,1 D. H. Wright,1 K. Sneddon,2 C.E. Cummings,2 P. Sun,1 J. Valentine,3 M.S. Anderson,1 S. Warrington,4 B. Sanderson,5 J.A. Chodakewitz,1 J.A. Wagner1 1Merck & Co., Inc., Whitehouse Station, NJ; 2Merck, Sharp & Dohme Ltd, Hoddesdon, England; 3Merck & Co., Inc., Whitehouse Station, NJ, - current address Bristol Myers Squibb, Princeton, NJ;4Hammersmith Medicines Research, London, England; and 5Chiltern (Early Phase) Limited, Dundee, Scotland

AUTHOR SUMMARY

Single Dose Pharmacokinetics
MMean AUC· 0-∞, Cmax and C12hr values appear to increase dose proportionally through 200 mg and less than dose proportionally at doses greater than 200 mg. PPeak plasma concentrations at ~3.0 hours. TTerminal half-life of ~16.5 hours. HHigh-fat meal has no clinically meaningful effect on pharmacokinetic parameters.

Multiple Dose Pharmacokinetics
DDay 10/Day 1 geometric mean accumulation ratios of AUC 0-12hr: 2.3 to 3.6, Cmax: 1.7 to 2.8.
AAUC 0-12hr, Cmax and C12hr appear to increase less than dose proportionally. SSteady state was achieved after 4-5 days regardless of dose.

Safety
Single doses of MK-3281 up to 2250 mg and multiple doses of MK-3281 up to 800 mg b.i.d. over 10 days were generally well tolerated.

AUTHOR CONCLUSIONS
MMK-3281 is generally well tolerated when administered as single and multiple doses.

MMK-3281 exhibits plasma pharmacokinetics which permit twice daily dosing.

This profile permits further clinical evaluation of MK-3281 including in Hepatitis C infected patients.

ABSTRACT

Background: MK-3281 is a novel non-nucleoside hepatitis C virus (HCV) polymerase inhibitor. MK-3281 has potent and selective in vitro activity against the genotype 1 hepatitis C virus (genotype 1b replicon assay, EC90 = 241 nM in 50% human serum). Pharmacokinetic (PK) and safety data were collected after single-dose (SD) and multiple-dose (MD) administration in healthy subjects.

Methods:
Single Dose: Alternating panel, multiple period, dose escalation study in 16 healthy males who received 25 to 2250 mg single doses of MK-3281 or placebo in the fed or fasted state.

Multiple Dose: Serial-panel study in 32 healthy males who received 100 to 800 mg MK-3281 or placebo q12 hr for 10 days.

Safety evaluations were performed throughout the studies. Plasma samples for MK-3281 concentration determination and pharmacokinetics were collected.

Results:
There were no serious adverse experiences (AEs) reported and no discontinuations due to adverse experiences.

Single Dose: Following oral administration, MK-3281 increased in plasma with median Tmax values of 2.5 - 3.5 hours. Thereafter, concentrations declined in a biphasic manner with mean terminal t· ~14.3 - 18.6 hours. Administration of 800 mg with a high-fat meal had no clinically meaningful effect on the pharmacokinetic parameters. Mean AUC0-∞, Cmax and C12hr values appeared to increase in a dose proportional fashion through 200 mg and in a less than dose proportional manner at doses greater than 200 mg.

Multiple Dose: Steady state was achieved after 4-5 days. Accumulation over the 10-day period occurred in all subjects for AUC0-12hr (geometric mean ratio (GMR) 2.3-3.6), Cmax (GMR 1.7-2.8) and C12hr (GMR 2.5 - 2.7). In general, AUC0-12hr, Cmax and C12hr appeared to increase less than dose proportionally on Day 1 and on Day 10. The apparent terminal half-life on Day 10 following multiple twice daily doses in the present study (e.g., ~17 hours) was consistent with values from the single dose study.

Conclusions: MK-3281 is generally well tolerated and exhibits a pharmacokinetic profile supportive of twice daily dosing.

BACKGROUND MK-3281

MK-3281 is a selective non-nucleoside inhibitor of HCV polymerase.

MK-3281 is a selective non-nucleoside inhibitor of HCV NS5B polymerase.

Potent in vitro activity against HCV genotypes 1 and 3. In cell-based genotype 1b replicon assay, the EC50 and EC90 in 50% human serum are 120 and 241 nM, respectively.

Approximate one log reduction in activity against viral isolates belonging to genotype 2.

Studies in HCV-infected humanized mice and chimpanzees have demonstrated preclinical in vivo efficacy of MK-3281.

MK-3281 is being developed as an antiviral drug for the treatment of chronic infection with HCV genotypes 1.

STUDY OBJECTIVES

Single Dose

Evaluate the safety and tolerability of single rising oral doses of MK-3281 in healthy young male volunteers.

Evaluate plasma PK profile of single doses of MK-3281 in the fasted state and following a high-fat meal. (e.g., AUC0-∞, Cmax, C12hr, Tmax, apparent t1/2).

Multiple Dose
Evaluate the safety and tolerability of MK-3281 orally administered twice-daily for a 10 day period in healthy young male volunteers.

Evaluate plasma PK profile of multiple doses of MK-· 3281 (e.g., AUC0-12hr, Cmax, C12hr, Tmax, apparent t1/2 and accumulation ratios).

STUDY DESIGN

Single Dose
- Double-blind, randomised, placebo-controlled, alternating panel, multiple-period, single rising dose study in 16 healthy male volunteers.
- 2 panels (A & B), 8 subjects per panel (6 active, 2 placebo), alternating rising single oral doses ofMK-3281/placebo over 5 periods.
- Identical assignment of MK-3281/placebo for panel B periods 2 and 4.
- Clinical safety evaluation (AEs, vital signs, ECG, laboratory safety) throughout the study.
- Plasma and urine samples for PK throughout the study.

Multiple Dose
- Double-blind, randomised, placebo-controlled, serial panel multiple rising dose study in 32 healthy male volunteers.
- 4 successive panels (A, B, C & D), 8 subjects per panel (6 active, 2 placebo).
- MK-3821 or placebo given b.i.d. (q12 hours) for 10 consecutive days (AM & PM) with AM dosing only on day 10.
- Clinical safety evaluation (AEs, vital signs, ECG, laboratory safety) throughout the study.
- Plasma and urine samples for PK throughout the study

Safety & Tolerability - Blinded Assessment

Single Dose
- 11 subjects reported 23 AEs, 10 considered drug related by the Investigator.
- Most common drug related AE: headache.

Multiple Dose
26 subjects reported 64 AEs, 8 considered drug related by the Investigator.

Most common drug related AEs: elevated ALT, muscle spasm.

Integrated Summary (Single and Multiple Dose)
- All AEs resolved, no subjects discontinued due to an AE, no serious AEs.
- No apparent relationship between dose of MK-3281 and frequency or intensity of any AE.
- No consistent, clinically relevant, treatment- or dose-related effects of MK-3281 on ECGs, vital signs or laboratory safety tests.

Single Dose Pharmacokinetics