Single and Multiple-Dose Assessments of the Safety and Pharmacokinetics of SCH 900518

Single and Multiple-Dose Assessments of the Safety and Pharmacokinetics of SCH 900518 and Its Effect on the Pharmacokinetics of Midazolam in Healthy Subjects

44th EASL April 23-26 2009 Copenhagen Denmark
Reported by Jules Levin

E. A. Hughes,1 M. A. Treitel,1 S. Gupta,1 C. Xu,1 C. Hu,1 B. Yue,1 A. Sheth,1 M. Corpus,1 D. Marchisin,1 P. Prasad,1 E. O'Mara,1 A. van Vliet,2 J. van Lier21Schering-Plough Research Institute, Kenilworth, New Jersey, USA; 2PRA International, Zuidlaren, Netherlands

Author Conclusions
SCH 900518 was safe and well tolerated as single and multiple doses in healthy adult subjects. No serious, severe, or life-threatening AEs were reported.

SCH 900518 was rapidly absorbed.
-- Dose-related increases in Cmax and AUC occurred over the dose range of 50 mg to 2000 mg.
-- After multiple doses of SCH 900518 at 400 mg tid in the fasted state, mean Cmin values exceeded the EC90 of the compound for HCV, as determined by the replicon assay.

In contrast to administration in fasted subjects, the bioavailability of SCH 900518 increased in subjects fed a high-fat meal.

A crystalline formulation administered as an oral suspension exhibited decreased bioavailability compared with the amorphous oral suspension, whereas microemulsion demonstrated higher bioavailability compared with the amorphous oral suspension of SCH 900518.

No clinically significant change in midazolam level was noted when midazolam was coadministered with SCH 900518.

Abstract
Background: SCH 900518, a novel hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitor, demonstrates potent antiviral activity with an EC90 of 40 nM in the in vitro HCV replicon assay. This study explored the safety and pharmacokinetics (PK) of single and multiple doses of SCH 900518 and its effect on the PK of midazolam (MDZ) in healthy subjects.

Methods: This was a randomized, placebo-controlled, blinded study composed of 8 cohorts of healthy subjects. Cohorts 1 to 6 received single doses of SCH 900518 as an oral amorphous suspension in the fasted state (50, 150, 400, 800, 1500, or 2000 mg). Following a washout period, subjects who received 800 mg also received single 800-mg doses after a high-fat meal, and subjects who received 400 mg also received single 400-mg doses of two different formulations (crystalline and microemulsion) after a high-fat meal. Cohorts 7 and 8 received multiple doses of SCH 900518 in the fasted state (400 mg 3 times a day [tid] x 10 days), as an oral suspension with active pharmaceutical ingredient (API) of 2 different particle sizes, as well as a single 4-mg dose of MDZ before and after SCH 900518. Safety, tolerability, and PK were assessed.

Results: 63 subjects completed the study. Single and multiple doses of SCH 900518 were well tolerated. There were no serious adverse events (SAEs), or clinically significant changes in vital signs, clinical laboratories, or ECG recordings. The majority of AEs were mild or moderate. SCH 900518 was rapidly absorbed following a single oral dose. There was a dose-related increase in Cmax and AUC of SCH 900518.

The bioavailability of SCH 900518 increased when given with a high-fat meal. A crystalline formulation administered as an oral suspension exhibited decreased bioavailability, whereas the microemulsion demonstrated higher bioavailability. Following multiple doses of SCH 900518, there was a minor accumulation of SCH 900518 and no clinically significant change in the MDZ:1-OH-MDZ ratios. Exposures of SCH 900518 were greater using a smaller particle size of API in the oral suspension. Trough concentrations during multiple doses were above the EC90 of the compound, as determined by the HCV replicon assay.

Conclusions: SCH 900518 was safe and well tolerated as single and multiple doses in healthy subjects. Multiple doses of SCH 900518 (400 mg tid) achieved potentially therapeutic exposures as predicted by the in vitro HCV replicon assay.
Note: Abstract has been updated since submission.

Background
· Approximately 40% of patients chronically infected with hepatitis C virus (HCV) genotype 1 do not respond to the current standard of care, pegylated interferon + ribavirin combination.
· Thus, there remains an urgent unmet medical need to offer new therapies that may eradicate HCV infection and prevent the serious sequelae (cirrhosis, hepatocellular carcinoma, decompensation, and transplantation) associated with persistent HCV infection.
· SCH 900518 is a potent, orally administered, novel serine protease inhibitor specifically designed to inhibit the HCV nonstructural protein 3 (NS3) protease.
-- Inhibition of this protease prevents cleavage of the HCV polyprotein into functional viral proteins and thereby inhibits viral replication.

Study End Points
· The primary end point was to evaluate the safety and tolerability of SCH 900518 administered orally to healthy volunteers as single doses of 50, 150, 400, 800, 1500, or 2000 mg or multiple doses of 400 mg tid.
· Secondary end points were to evaluate the effect of SCH 900518 on the PK profile of coadministered MDZ and to determine the PK profile of SCH 900518 administered orally to healthy volunteers as:
- Single doses of 50, 150, 400, 800, 1500, or 2000 mg
- Multiple doses of 400 mg tid
- One 800-mg dose under fed conditions
- One 400-mg dose with the crystalline formulation
--- One 400-mg dose with the microemulsion formulation

Study End Points
· The primary end point was to evaluate the safety and tolerability of SCH 900518 administered orally to healthy volunteers as single doses of 50, 150, 400, 800, 1500, or 2000 mg or multiple doses of 400 mg tid. · Secondary end points were to evaluate the effect of SCH 900518 on the PK profile of coadministered MDZ and to determine the PK profile of SCH 900518 administered orally to healthy volunteers as:
- Single doses of 50, 150, 400, 800, 1500, or 2000 mg
- Multiple doses of 400 mg tid
- One 800-mg dose under fed conditions
- One 400-mg dose with the crystalline formulation
--- One 400-mg dose with the microemulsion formulation

Rising Single Dose
· SCH 900518 was rapidly absorbed and eliminated after oral administration. - Dose-related increases in Cmax and AUC occurred over the dose range of 50 to 2000 mg

Effect of Food
· Oral bioavailability of SCH 900518 as a single oral 800-mg dose increased when SCH 900518 was administered with a high-fat meal compared with when it was administered in a fasted state (Table 2).

Comparison of Formulations
· Compared with the amorphous oral suspension of SCH 900518, a crystalline formulation administered as an oral suspension exhibited decreased bioavailability, whereas a microemulsion formulation demonstrated higher bioavailability (n = 6 for each cohort) (Table 3).

Ratios (%) and 90% CIs are ANOVA models extracting the effect from treatment, sequence, and subject. ANOVA = analysis of variance; AUCtf = area under the curve from time zero to last measurable concentration; CI = confidence interval.a Least squares mean.

Multiple-Dose Study
· After multiple dosing, SCH 900518 (400 mg) was rapidly absorbed. - Median Tmax was 0.50 hours in female and male subjects on days 1 and 10 (Table 4).
- There was a minor accumulation of SCH 900518.
· Exposure after multiple doses was greater when a smaller particle size of SCH 900518 was used in the oral suspension.
- AUC and Cmax values of SCH 900518 in cohort 8 were higher than those in cohort 7 on days 1 and 10 (Figure 3).
· After multiple-dose administration of 400 mg tid, the Cmin values of SCH 900518 were 50.6 ng/mL and 206 ng·h/mL for cohort 7 and cohort 8, respectively.
--- These Cmin concentrations were higher than the EC90 for the suppression of the HCV subgenomic replicon (genotype 1b).

Safety
· Most adverse events (AEs) were mild and were considered unlikely to be related to study drug.
· No severe, serious, or life-threatening AEs developed.
· No clinically significant changes occurred in clinical laboratory parameters, vital signs, or electrocardiograms.

Rising Single Dose
· Twenty-nine (60%) subjects reported at least 1 AE during the study. - AEs reported by subjects who received SCH 900518 were varied and showed no dose-related trends.
· The percentage of subjects reporting AEs and the frequency of the most common AEs were greater for subjects who received placebo.
· The most commonly reported treatment-emergent AE was headache (SCH 900518, n = 4; placebo, n = 3).

Food Effect
· There was no clinically significant difference in the number or severity of AEs among the fasted, fed, and placebo groups.
· Six (75%) subjects experienced at least 1 treatment-emergent AE.
· The most commonly reported treatment-emergent AEs were rhinitis and headache.

Multiple Dose
· Ten subjects in the active treatment group and 4 subjects in the placebo group reported at least 1 treatment-emergent AE.
· The most common AE was abdominal pain (multiple-dose group, n = 2; placebo, n = 3)