Chemical formula: C₂₉H₃₃FN₂O₄ Molecular mass: 492.582 g/mol PubChem compound: 10077130
Vorapaxar is a selective and reversible inhibitor of the PAR-1 receptors on platelets that are activated by thrombin.
Vorapaxar inhibits thrombin-induced platelet aggregation in in vitro studies. In addition, vorapaxar inhibits thrombin receptor agonist peptide (TRAP)-induced platelet aggregation without affecting coagulation parameters. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as adenosine diphosphate (ADP), collagen or a thromboxane mimetic.
At a dose of 2.5 mg of vorapaxar sulfate (equivalent to 2.08 mg vorapaxar) daily, vorapaxar consistently achieves ≥80% inhibition of TRAP-induced platelet aggregation within one week of initiation of treatment. The duration of platelet inhibition is dose and concentration dependent. Inhibition of TRAP-induced platelet aggregation at a level of ≥80% may last for 2 to 4 weeks after discontinuation of daily doses of vorapaxar sulfate 2.5 mg. The duration of these pharmacodynamic effects is consistent with the drug’s elimination half-life.
Consistent with its selective molecular target (PAR-1), vorapaxar has no effect on ADP-induced platelet aggregation in healthy subjects and patient populations.
In healthy volunteer studies, no changes in platelet P-selectin and soluble CD40 ligand (sCD40L) expression or coagulation test parameters (TT, PT, aPTT, ACT, ECT) occurred after single or multiple dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L and hs-CRP concentrations were observed in patients treated with vorapaxar in the Phase ⅔ clinical trials.
The effect of vorapaxar on the QTc interval was evaluated in a thorough QT study and in other studies. Vorapaxar had no effect on the QTc interval at single doses up to 120 mg.
After oral administration of a single vorapaxar sulfate 2.5 mg dose, vorapaxar is rapidly absorbed and peak concentrations occur at a median tmax of 1 hour (range: 1 to 2) under fasted conditions. The mean absolute bioavailability of vorapaxar from the 2.5 mg dose of vorapaxar sulfate is 100%.
Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small (21%) decrease in Cmax and delayed tmax (45 minutes). Vorapaxar may be taken with or without food. Co-administration of an aluminium hydroxide/magnesium carbonate antacid or proton pump inhibitor (pantoprazole) did not affect vorapaxar AUC with only small decreases in Cmax. Therefore, vorapaxar may be administered without regard to co-administration of agents that increase gastric pH (antacid or proton pump inhibitor).
The mean volume of distribution of vorapaxar is approximately 424 litres. Vorapaxar and the major circulating active metabolite, M20, are extensively bound (≥99%) to human plasma proteins. Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells.
Vorapaxar is eliminated by metabolism, with CYP3A4 and CYP2J2 responsible for formation of M20, its major active circulating metabolite, and M19, the predominant metabolite identified in excreta. The systemic exposure of M20 is ~20% of the exposure to vorapaxar.
The primary route of elimination is through the faeces, with approximately 91.5% of radiolabeled dose predicted to be recovered in the faeces compared to 8.5% in the urine. Vorapaxar is eliminated primarily in the form of metabolites, with no vorapaxar detected in urine. The apparent terminal half-life for vorapaxar is 187 hours (range 115-317 hours) and is similar for the active metabolite.
Vorapaxar exposure increases in an approximately dose-proportional manner following single doses of 1 to 40 mg and multiple doses of 0.5 to 2.5 mg of vorapaxar sulfate. The systemic pharmacokinetics of vorapaxar are linear with accumulation (6-fold) predictable from single- to multiple-dose data. Steady-state is achieved by 21 days following once-daily dosing.
The effects of renal (end-stage renal disease undergoing haemodialysis) and hepatic impairment on the pharmacokinetics of vorapaxar were evaluated in specific pharmacokinetic studies and are summarized below.
Pharmacokinetics of vorapaxar are similar between patients with end-stage renal disease (ESRD) undergoing haemodialysis and healthy subjects. Based on population pharmacokinetic analysis using data from healthy subjects and patients with atherosclerotic disease, vorapaxar mean AUC is estimated to be higher in patients with mild (17%) and moderate (34%) renal impairment compared to those with normal renal function; these differences are not considered to be clinically relevant. No dose adjustment is necessary for patients with renal impairment, including subjects with ESRD. There is limited therapeutic experience in patients with severe renal impairment or end stage renal disease. Therefore, vorapaxar should be used with caution in such patients.
Pharmacokinetics of vorapaxar are similar between patients with mild (Child Pugh, 5 to 6 points) to moderate (Child Pugh, 7 to 9 points) hepatic impairment and healthy patients. Reduced hepatic function is a risk factor for bleeding and should be considered before initiating vorapaxar. No dose adjustment is required for patients with mild hepatic impairment. Vorapaxar should be used with caution in patients with moderate hepatic impairment. Vorapaxar is contraindicated in patients with severe hepatic impairment (Child Pugh, 10 to 15 points). Age, gender, weight and race were included as factors assessed in the population pharmacokinetic model to evaluate vorapaxar pharmacokinetics in healthy subjects and patients:
Pharmacokinetics of vorapaxar are similar between elderly, including those ≥75 years of age, and younger patients. No dose adjustment is necessary.
The mean estimated vorapaxar Cmax and AUC were 30% and 32% higher, respectively, in females compared to males. These differences are not considered to be clinically relevant and no dose adjustment is necessary.
The mean estimated vorapaxar Cmax and AUC were 35% and 33% higher, respectively, in patients with a body weight of <60 kg compared to those weighing 60-100 kg. By comparison, vorapaxar exposure (AUC and Cmax) is estimated to be 19-21% lower in patients with a body weight of >100 kg compared to those weighing 60-100 kg. In general, a body weight <60 kg is a risk factor for bleeding. Vorapaxar should be used with caution in patients with a body weight <60 kg.
The mean estimated vorapaxar Cmax and AUC were 24% and 22% higher in Asian patients compared to that of Caucasians. Vorapaxar exposure (AUC and Cmax) in patients of African descent is estimated to be 17-19% lower compared to that of Caucasians. These differences are not considered to be clinically relevant and no dose adjustment is necessary.
In vitro metabolism studies demonstrate that vorapaxar is unlikely to cause clinically significant inhibition of human CYP1A2, CYP2B6, CYP3A, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. No clinically meaningful inhibition of CYP2B6, CYP3A, CYP2C19, or CYP2D6 by M20 is expected. In addition, no clinically meaningful inhibition of OATP1B1, OATP1B3, BCRP, OAT1, OAT3, and OCT2 by vorapaxar or M20 is anticipated. Based upon in vitro data, chronic administration of vorapaxar is unlikely to induce the metabolism of drugs metabolized by major CYP isoforms.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, and fertility.
In repeat dose oral toxicity studies in rodents and monkeys, the principal treatment-related findings were urinary bladder and ureter hyperplasia in mice, hepatic vascular thrombi, lymphoid necrosis and retinal vacuolation in rats and phospholipidosis in all species. Phospholipidosis occurs at acceptable human to animal safety margins and was reversible. The clinical significance of this finding is currently unknown.
No defects were observed in embryo-foetal developmental studies in rats and rabbits at exposures sufficiently in excess of human exposure at the recommended human dose (RHD). Pre and postnatal studies in rats only showed some inconsistent developmental effects at exposures sufficiently in excess of human exposure at the RHD of 2.08 mg vorapaxar. The overall no effect level for the pre- and postnatal development effects was 5 mg/kg/day (6.8-times [female animals] the human steady-state exposure at 2.5 mg/day).
Vorapaxar had no effects on fertility of male and female rats at exposures sufficiently in excess of human exposure at the RHD.
Vorapaxar was not mutagenic or genotoxic in a battery of in vitro and in vivo studies.
Vorapaxar did not increase bleeding time in non-human primates when administered alone at 1 mg/kg. Bleeding time was prolonged slightly with administration of acetylsalicylic acid alone or in combination with vorapaxar. Acetylsalicylic acid, vorapaxar, and clopidogrel in combination produced significant prolongation of bleeding time. Transfusion of human platelet rich plasma normalised bleeding times with partial recovery of ex vivo platelet aggregation induced with arachidonic acid, but not induced with ADP or TRAP. Platelet poor plasma had no effect on bleeding times or platelet aggregation.
No vorapaxar-related tumours were observed in 2-year rat and mouse studies at oral doses up to 30 mg/kg/day in rats and 15 mg/kg/day in mice (8.9 and 30 times the recommended therapeutic exposures in humans based on plasma exposure to vorapaxar for rats and mice, respectively).
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