Purpose: CTS-1027, a novel matrix metalloproteinase inhibitor, is being investigated for the treatment of hepatitis C virus and other liver diseases. The objective of this study was to determine the pharmacokinetics of CTS-1027 and its metabolites, CTS‑1027-2 and CTS‑1027-6, following once and twice daily oral dosing in healthy volunteers.

Methods: This was an open-label, multiple‑dose, ascending frequency, tolerability and pharmacokinetic Study. Eight subjects received CTS‑1027 oral 30 mg QD on Days 1 and 2, 15 mg BID on Days 3 and 4, and a 15 mg dose on the morning of Day 5. Plasma samples were analyzed for CTS-1027 and its metabolites using a validated HPLC‑MS/MS assay and the PK was determined by standard model independent methods based on the plasma concentration‑time.

Results: CTS‑1027 was rapidly absorbed and its Tmax was comparable for QD and BID dosing (~1.50 hours post-dose). Following CTS‑1027 at 30 mg QD , Days 1 and 2 Cmax and AUC(0-12) were similar (686 ± 150 and 651 ± 179 ng/mL and 4010 ± 1090 and 3220  ±  910  ng·h/mL, respectively). Following 15 mg BID on Day 3, Cmax 1 of 376 ± 63.9 was similar to Cmax 2 of 358 ± 89.1 ng/mL and both were comparable to Day 5 Cmax of 398 ± 91.1 ng/mL for 15 mg single dose. AUC(0-12) on Days 2 and 5 were similar. The dose-normalized Cmax and AUC(0-12) were similar for all Days. CTS‑1027 elimination for QD and BID dosing was comparable (T1/2 ~ 5 hours). The Cmax and AUC(0-12) values of CTS‑1027-2 ranged from 7.03% to 61.1% of the parent compound and CTS‑1027-6 values ranged from 12.5% to 217%. Metabolites T1/2 was longer than the parent compound.

Conclusions: CTS‑1027, CTS‑1027-2 and CTS‑1027-6 exhibited favorable PK in humans. CTS‑1027 was rapidly absorbed and did not accumulate during the study. The T1/2 of ~ 5 hours and dose-normalized PK parameters support that CTS‑1027 achieved the steady-state within two days and that predose values on Days 2 and 3 may represent reasonable estimates of that steady-state. The metabolites have apparently reached the steady state on Day 5.

Pharmacokinetics of CTS-1027, a Novel Matrix Metalloproteinase (MMP) Inhibitor, and its Main Metabolites Following Once and Twice Daily Oral Dosing of CTS-1027 in Healthy Volunteers Ahmed A. Kousba1, MiRa C. Huyghe2, Anthony W. Fox2, Mario Marquez3, Patricia C. Contreras2

1MicroConstants, Inc., San Diego, CA 92121; 2Conatus Pharmaceuticals, Inc. San Diego, CA 92121; 3MDS, Inc., Tempe, AZ, 85283

ABSTRACT

OBJECTIVE

INTRODUCTION

MATERIALS & METHODS

RESULTS & DISCUSSION

CONCLUSION

REFERENCES

To compare the pharmacokinetics of CTS-1027 and its metabolites, CTS‑1027-2 and CTS‑1027-6 during QD and BID oral dosing in healthy volunteers.

Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury including hepatitis C virus (HCV) (Elkington et al., 2005; Roderfeld et al., 2007). Liver disease and HCV represent major worldwide health problems.

CTS-1027, a novel selective MMP inhibitor developed by Conatus Pharmaceuticals, demonstrates potency and strong efficacy in multiple models of liver disease (Kahraman et al., 2009).

CTS-1027 is currently being investigated in a Phase II clinical trail for potential treatment of liver disease associated with HCV infection.

STUDY A Healthy Volunteer, Open-Label, Multiple‑Dose, Ascending Frequency, Tolerability and Pharmacokinetic Study of Oral CTS-1027 Administered Once and Twice Daily.

DOSE Eight subjects received CTS‑1027 as QD oral 30 mg dose on Days 1 and 2, 15 mg BID on Days 3 and 4, and a QD 15 mg dose on the morning of Day 5.

ANALYTICAL METHOD The plasma was analyzed for CTS-1027, CTS‑1027-2 and CTS‑1027-6 using a validated HPLC-MS/MS assay (See Abstract # 1180 for details).

PK ANALYSIS Cmax, Tmax, terminal half-life (T1/2) and AUC(0-12) were determined by standard model independent methods (Gibaldi and Perrier, 1982) from the concentration‑time data of each subject using WinNonlin Professional 4.1 (Pharsight Corp., Mountain View, CA).

CTS‑1027 For both QD and BID dosing, CTS‑1027 was absorbed rapidly (median Tmax ~ 1.5 h) and had similar Cmax, T1/2 and AUC(0-12) on Days 1 and 2 (30 mg) and on Days 3 and 5 (15 mg).

The dose-normalized Cmax and AUC(0-12) were equal for all days.

CTS‑1027 was apparently approaching a steady state on study Day 2 and exhibited no accumulation following repeated dosing.

CTS‑1027-2 and CTS‑1027-6 Both metabolites were rapidly produced in plasma and their Cmax and AUC(0-12) increased over study days with the highest exposure observed on Day 5.

Cmax values for CTS‑1027-2 and CTS‑1027-6 ranged from 7.03% to 31.2% and 12.5% to 108% of the parent compound values, respectively. AUC(0-12) ranged from 11.8% to 61.1% and 10.8% to 217%, respectively. Exposure of CTS‑1027-6 was ~ 4x > CTS‑1027-2.

Both metabolites concentrations were apparently approaching steady state on study Day 5.

CTS‑1027-6 CTS‑1027-2

aParameter estimates for Day 3 first and (second) dose; bTmax value is expressed as a median; cT1/2 is expressed as a harmonic mean;dAUC(0-12) Day 2, 3 or 5/ AUC(0-12) Day 1; e%(Cmax CTS‑1027-6 or CTS‑1027-2/Cmax CTS‑1027); f%(AUC(0-12) CTS‑1027-6 or

CTS‑1027-2/(AUC(0-12) CTS‑1027; ND - Not Determined

CTS‑1027B

Mean PK Parameters of CTS‑1027 and its Metabolites in Human Subjects Following QD and BID Oral Administration of CTS‑1027

Mean PK Parameters of CTS‑1027 and its Metabolites in Human Subjects Following QD and BID Oral Administration of CTS‑1027

CTS‑1027-2 CTS‑1027-6

CTS‑1027

Mean Cmax and AUC(0-12) of CTS‑1027 and its Metabolites in Human Subjects Following QD and BID Oral Administration of CTS‑1027

CTS‑1027-6

CTS‑1027 Cmax AUC(0-12)

CTS‑1027-2

CTS‑1027 and its metabolites CTS‑1027-2 CTS‑1027-6 exhibited favorable PK in humans.

CTS‑1027 was absorbed rapidly, its PK for QD and BID dosing was comparable, did not accumulate due to repeated dosing and reached a steady-state within two days.

CTS‑1027-2 and CTS‑1027-6 were readily measurable in plasma with CTS‑1027-6 ~ 4x > CTS‑1027-2 and both metabolites have apparently reached a steady state at end of the study.

Elkington PT, O’Kane CM, Friedland JS. (2005). The paradox of matrix metalloproteinases in infectious disease. Clin Exp Immunol; 142: 12–20.

Gibaldi, M. and Perrier, D. (1982). Pharmacokinetics, Second Edition, Marcel Dekker, Inc., New York.

Kahraman A., Bronk S., Cazanave S., Werneburg N., Mott J., Contreras P., and Gores G. (2009). Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouse Hepatology Research 2009; 39: 805–813.

Roderfeld M, Hemmann S, Roeb E. (2007). Mechanisms of fibrinolysis in chronic liver injury (with special emphasis on MMPs and TIMPs). Z Gastroenterol; 45: 25–33.

AAPS Los Angeles, CA Nov. 2009