Pharmacokinetics and platelet aggregation inhibitory effects of a novel intravenous formulation of clopidogrel in humans

Abstract

1. PM103 is an intravenous formulation of clopidogrel being developed as an alternative to oral clopidogrel to provide for dosing flexibility in the emergent clinical setting. The present first-in-human study assessed the pharmacokinetic and pharmacodynamic effects of PM103 and its safety in 144 healthy human subjects. 2. The present was a randomized open-label parallel-group trial. Single intravenous doses of PM103 (0.1, 1.0, 10, 30, 100 or 300 mg) were administered to each group (n = 24 subjects per group). Platelet aggregation was assessed at baseline and then 15 and 30 min and 2, 5 and 24 h after drug administration. Determination of plasma concentrations of clopidogrel, clopidogrel carboxylic acid metabolite and the clopidogrel thiol metabolite were assessed at baseline and at 1, 5, 10, 20 and 30 min and 1, 2, 3, 4, 6, 8, 12 and 24 h after drug administration. 3. PM103 produced a rapid, persistent and dose-related inhibition of platelet aggregation. The onset of the ant platelet effect paralleled the appearance in plasma of the clopidogrel thiol active metabolite. PM103 was well tolerated and no subjects discontinued treatment because of adverse events. 4. These data suggest that PM103 may be a suitable alternative to oral clopidogrel for patients in whom the desired clinical management would include administration of clopidogrel after coronary angiography but prior to percutaneous coronary intervention.

Significant Improvement of Antithrombotic Responses to Clopidogrel by Use of a Novel Conjugate as Revealed in an Arterial Model of Thrombosis

“…Tuffal et al (2011) reported that the plasma concentration of the active metabolite in healthy human subjects receiving an oral dose of 300 mg clopidogrel reached a C max of 38 ng/ml. A C max of 91 ng/ml was reported in human subjects after a 300-mg intravenous dose of clopidogrel (Cushing et al, 2012). Using a relatively comparable dose of 10 mg/kg, we observed that ClopNPT reached a C max of 1242 ng/ml at 5 minutes in C57BL/6 mice, which represents a 35-fold increase in C max and an approximately 10-fold decrease in the time to maximal plasma concentration compared with the values obtained for rats.…”

Antiplatelet therapy: new pharmacological agents and changing paradigms

“…An intravenous formulation of clopidogrel (PM103) is at an early stage of clinical development to serve as an alternative to oral clopidogrel and provide for dosing flexibility in the emergent clinical setting . Dedicated pharmacokinetic and pharmacodynamic studies are warranted to define the bioequivalence between oral and intravenous formulations of clopidogrel.…”

Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug–Drug Interaction Between Clopidogrel and Dasabuvir

“…For clopidogrel, all model‐building steps and parameters were the same as those published by Tornio et al ., with the following modifications: Approximately 30% of total clearance was assigned to formation of clopidogrel acyl‐β‐D‐glucuronide metabolite via UGT2B7. About 60% of the remaining clearance was assigned to hepatic and intestinal metabolism via human liver S9 (HLS9 Cl int 3000 μL/min/mg‐microsomal protein, HIS9 ms Cl int 450 μL/min/mg‐microsomal protein). UGT2B7 CL int estimated (1,000 μL/min/pmol), f u,mic (0.1) to enable formation‐limited metabolite kinetics matching the observed PK profile of the glucuronide metabolite, and to capture dynamic changes of the glucuronide concentrations over time during DDI simulations. Additional systemic clearance of 15 L/h was estimated to match the reported intravenous clearance of about 110 L/h …”