In vitro and in vivo induction of cytochrome p450: a survey of the current practices and recommendations: a pharmaceutical research and manufacturers of america perspective.

Cytochrome P450 (P450) induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drug-drug interactions due to P450 induction. There is a desire from the pharmaceutical industry and regulatory agencies to harmonize assay methodologies, data interpretation, and the design of clinical drug-drug interaction studies. In this article, a team of 10 scientists from nine Pharmaceutical Research and Manufacturers of America (PhRMA) member companies conducted an anonymous survey among PhRMA companies to query current practices with regards to the conduct of in vitro induction assays, data interpretation, and clinical induction study practices. The results of the survey are presented in this article, along with reviews of current methodologies of in vitro assays and in vivo studies, including modeling efforts in this area. A consensus recommendation regarding common practices for the conduct of P450 induction studies is included.

Pharmacokinetic/pharmacodynamic relationships for otamixaban, a direct factor Xa inhibitor, in healthy subjects.

Direct pharmacokinetic/pharmacodynamic relationships for otamixaban were investigated after rising doses in healthy subjects using mixed-effect modeling. Activated partial thromboplastin time, prothrombin time, dilute prothrombin time, and Russell's viper venom-induced clotting time (RVVT) related linearly, whereas Heptest clotting time (HCT) followed a sigmoidal E(max) model. The pharmacokinetic/pharmacodynamic response (slope) and their corresponding interindividual variability (seconds per ng/mL, [% coefficient of variation]) were 0.263 (29%) for Russell's viper venom-induced clotting time, 0.117 (10%) for dilute prothrombin time, 0.058 (19%) for activated partial thromboplastin time, and 0.021 (11%) for prothrombin time. For Heptest clotting time, the parameter estimates with their corresponding interindividual variability (% coefficient of variation) were 71 ng/mL (30%) for EC(50), 186 seconds (64%) for E(max), and 17 seconds (16%) for E(0). The model predicted otamixaban plasma concentrations to double the clotting times that were close to those observed. These pharmacokinetic/pharmacodynamic relationships, together with the predictable pharmacokinetics, allowed the anticoagulant effect at given doses of otamixaban to be foreseen in healthy subjects.

Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor.

This manuscript reports the assessment of pharmacodynamic (PD) markers of anti-coagulation in the first-in-man study with the novel direct Factor Xa (FXa) inhibitor, otamixaban, with a brief description of safety and pharmacokinetic (PK) findings. The study comprised ten consecutive parallel groups of healthy male subjects (6 active, 2 placebo per group). Eight groups received escalating intravenous doses of otamixaban as 6-hour infusions (1.7 to 183 microg/kg/h) and two groups received a bolus dose (30 or 120 microg/kg) with a 6-hour infusion (60 or 140 microg/ kg/h, respectively). PD markers included anti-FXa activity and clotting time measurements, i.e. activated Thromboplastin Time (aPTT), Prothrombin Time (PT), Heptest Clotting Time (HCT), and Russell's Viper Venom-induced clotting Time (RVVT). In addition, Endogenous Thrombin Potential (ETP) was assessed in the bolus-plus-infusion dose groups. Otamixaban was well tolerated. Otamixaban plasma concentrations increased with escalating dose, were maximal at the end-of-infusion (C(eoi)), and decreased rapidly as the infusion was stopped. Anti-FXa activity coincided with otamixaban plasma concentrations and clotting time measurements followed the same pattern. Maximal changes from baseline at C(eoi) were 1.9 +/- 0.2 for aPTT, 2.0 +/- 0.2 for PT, 5.1 +/- 0.6 for HCT, and 4.5 +/- 1.2 for RVVT. Otamixaban inhibited thrombin generation (24% decrease in ETP) and a delay in thrombin generation was noticed in vitro at high concentrations.

Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand.

The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.

Optimization of the beta-aminoester class of factor Xa inhibitors. Part 1: P(4) and side-chain modifications for improved in vitro potency.

A systematic modification of the C(3) side-chain of the beta-aminoester class of factor Xa inhibitors and a survey of P(4) variations is described. These changes have resulted in the identification of sub-nanomolar inhibitors with improved selectivity versus related proteases. Coagulation parameters (i.e., APTT doubling concentrations) are also improved.

Optimization of the beta-aminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent In vivo anticoagulant activity.

Further optimization of the beta-aminoester class of factor Xa (fXa) inhibitors is described culminating in the identification of 9c (FXV673), a potent and selective factor Xa inhibitor with excellent in vivo anticoagulant activity. An X-ray structure of FXV673 bound to human fXa is also presented. Based on its selectivity, potent in vivo activity and favorable pre-clinical safety profile, FXV673 was selected for further development and is currently undergoing clinical trials.

Benzimidazoles and isosteric compounds as potent and selective factor Xa inhibitors.

Benzimidazoles and their isosteric compounds as factor Xa inhibitors are discussed.