Pharmacokinetics (PK) and Pharmacodynamics (PD) of a New Direct Thrombin Inhibitor (DPOC-4088) After Single Oral Doses of Two Prolonged Release Formulations in Healthy Male Subjects,

DPOC-4088 is an orally active, potent, rapidly binding, reversible direct thrombin inhibitor (DTI) being developed as a once-a-day alternative to warfarin for primary prevention of venous thromboembolism.

This Phase I study was designed to: (1) compare plasma concentration-ratios (C_max/C_{12 hr} and C_max/C_{24 hr}) and other standard PK parameters (T_max, AUC_0-∞, T_{1/2 terminal}) following single oral dosing with 100 mg and 200 mg DPOC-4088 tablets in two prolonged release formulations (16 and 20 hr); (2) determine the extent of thrombin inhibition of these formulations as measured by activated partial thromboplastin time [aPTT], ecarin clotting time [ECT], thrombin time [TT] and prothrombin time [PT] (reported as the international normalized ratio [INR]); and (3) assess the safety of DPOC-4088 in healthy male volunteers.

Randomized, open-label, 4-period crossover design. Subjects were dosed in 4 periods after an overnight fast and had blood drawn for PK/PD determinations immediately prior to dosing and at specified time intervals for 48 hrs post-dosing. Each dosing period was separated by a ≥5-day washout.

Twelve subjects aged 21 to 45 (mean 32.9 ± 8.55) years were enrolled and completed all 4 dosing periods. Increases in C_max and AUC were dose proportional for both formulations, with the 20 hr-release formulation exhibiting slightly lower C_max, and C_max/C_{12 hr} and C_max/C_{24 hr} ratios for a given dose compared to the 16 hr formulation (Table). Median t_max was 3–4 hrs. Geometric means of T_{1/2 terminal} ranged from 4.0 to 5.8 hrs. Compared to pre-dose values, increases in all PD clotting parameters (aPTT, ECT, TT, and INR) closely followed the shape of the PK profile, were dose-dependent, and exhibited no lag time in response, suggesting a direct effect of DPOC-4088. Changes in aPTT, ECT, TT, and INR were correlated with peak DPOC-4088 concentrations. At 24 hrs post-dose, mean aPTT remained 12–15% above the pre-dose aPTT after 100 mg DPOC-4088 and 21–24% above pre-dose after 200 mg. The mean 24 hr ECT remained 21–23% and 35–36% above the pre-dose ECT for the 100 and 200 mg doses, respectively. Mean TT returned to within 1–15% of pre-dosing TT by 48 hrs. After single doses of 100 or 200 mg DPOC-4088, mean peak INRs were reached at 4 hrs for both the 100 mg (1.15–1.17) and 200 mg (1.28–1.30) formulations, returning to pre-dose INRs by 48 hrs. DPOC-4088 at both doses and release formulations was well-tolerated. Adverse events (AEs) occurred in 9/12 subjects; most were grade 1, unrelated or unlikely to be related to DPOC-4088, and resolved within hours without sequelae (headache, oropharyngeal pain, nausea, cervical lymphadenopathy, neck pain, fatigue). Among the AEs considered at least possibly related to DPOC-4088 administration, only grade 1 epistaxis (n=1) and blood in stools (n=1) were potentially linked to the PD activity of DPOC-4088.

Following administration of single oral doses of DPOC-4088, a new once-daily DTI, dose proportionality was observed in the PK parameters for two prolonged release formulations. Evidence of anticoagulation efficacy by direct thrombin inhibition was reflected in key PD clotting parameters. The PD parameters were well-correlated with DPOC-4088 plasma concentrations and other PK parameters. At 100 and 200 mg doses, DPOC-4088 was safe and well-tolerated. Given the slightly lower C_max/C_{24 hr} and corresponding peak/trough PD ratios, the 20 hr release tablet is the preferred candidate formulation for further testing of DPOC-4088 in multiple-dose studies and for continued clinical development of DPOC-4088 for prevention of venous thromboembolism.

PK/PD Parameters of Two Doses and Two Prolonged Release Formulations of DPOC-4088

Van Bortel:Diakron, GSK, JNJ, Merck, Menarini, Novartis, Nycomed, Recordati, Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hettema:Kinesis Pharma, BV: Employment. Spaans:Kinesis Pharma, BV: Employment. Ramakrishnan:Orchid Healthcare: Employment. Elumalai:Orchid Healthcare: Employment. Jayanthi:Orchid Healthcare: Employment. Allard:Diakron Pharmaceuticals: Employment.