Anne Paccaly

Pharmacokinetics of otamixaban, a direct factor Xa inhibitor, in healthy male subjects: pharmacokinetic model development for phase 2/3 simulation of exposure.

The pharmacokinetics of otamixaban was investigated in healthy male subjects over a wide range of intravenous doses, with duration of administration varying between 1‐minute infusions (bolus dose) and 24‐hour infusions, using noncompartmental and multicompartmental methods. A global compartmental analysis (2 and 3 compartments) generated a single set of pharmacokinetic parameters, regardless of infusion rate and duration, and took into account the 30% decrease in clearance and volume of distribution observed over the dose range. The 2‐compartment model was retained to predict bolus plus 3‐hour‐infusion doses of otamixaban for future phase 2/3 studies. Otamixaban exhibited in healthy subjects several interesting pharmacokinetic features in view of its potential therapeutic use in coronary thrombosis: a rapid plasma distribution and elimination, a well‐described dose‐exposure relationship, a low intersubject variability in plasma exposure, and a mixed renal and biliary excretion with constant renal clearance.

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 Russells 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.

Direct and rapid inhibition of factor Xa by otamixaban: A pharmacokinetic and pharmacodynamic investigation in patients with coronary artery disease

New anticoagulants that combine effective anticoagulation with low bleeding rates are still sought after. We investigated the safety, pharmacokinetics, and pharmacodynamics of otamixaban, a direct factor Xa inhibitor, in patients with stable coronary artery disease.

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 Russells viper venom—induced clotting time (RVVT) related linearly, whereas Heptest clotting time (HCT) followed a sigmoidal Emax model. The pharmacokinetic/pharmacodynamic response (slope) and their corresponding interindividual variability (seconds per ng/mL, [% coefficient of variation]) were 0.263 (29%) for Russells 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 EC50, 186 seconds (64%) for Emax, and 17 seconds (16%) for E0. 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.

Prospective dose prediction for FXa inhibitor otamixaban (OTAM) using PK/PD simulations accounting for non‐dose proportional plasma exposure

OTAM is a direct and selective FXa inhibitor under development for treatment of Acute Coronary Syndrome (ACS). This work describes PK/PD modeling and simulations to predict doses for dose‐ranging Phase II study with target Ceoi of 75 to 600 ng/mL (MTD).

AB0184 Disease-Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis

Background Elevated IL-6 levels occur in rheumatoid arthritis (RA) and can lead to modulation of cytochrome P450 (CYP) enzyme activity and changes in drug levels (CYP substrates) compared with individuals without RA. Conversely, blockade of IL-6 signaling by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. Hence, IL-6 is expected to inhibit CYP3A4 activity, while IL-6 inhibitors, such as sarilumab, are expected to restore elevated simvastatin (a CYP3A4 substrate) concentrations in patients with RA back to those observed in healthy individuals. Objectives This study (NCT02017639) evaluated the pharmacokinetic profile of simvastatin, a CYP3A4 substrate, before and after a single dose of sarilumab, an investigational anti–IL-6R monoclonal antibody, in patients with active RA to assess disease-drug interaction of sarilumab on simvastatin. Methods Nineteen adult patients with moderate-to-severe RA with CRP >6.0 mg/L at baseline received simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. A series of plasma samples were collected over 24 hours and analyzed for concentrations of simvastatin and its major metabolite, β-hydroxy-simvastatin acid, using a validated LC-MS/MS method. Pharmacokinetic parameters of plasma simvastatin and β-hydroxy-simvastatin acid were calculated using noncompartmental analysis. The geometric mean ratios (with vs without sarilumab) and 90% CIs for peak plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUC0–∞) were calculated. C-reactive protein was also analyzed. Results The majority of patients were female (78.9%) and Caucasian (63.2%). All patients had moderate-to-severe disease activity per study inclusion criteria with a mean CRP (± SD) of 22.1±24.4 mg/L. Administration of a single dose of sarilumab along with simvastatin to patients with RA resulted in reduced exposure to simvastatin by 45% and to β-hydroxy-simvastatin acid by 36% compared with simvastatin alone. Mean effect ratios (90% CI) for simvastatin Cmax and AUC0-∞ were 54.1% (42.2%>69.4%) and 54.7% (47.2%>63.3%), respectively (Table). There were no changes in time to Cmax (tmax) or half-life (t1/2) for either simvastatin or β-hydroxy-simvastatin acid following sarilumab exposure (Table). Levels of CRP decreased from 22.1±24.4 mg/L at baseline to reach a nadir of 1.9±0.9 mg/L at 1 wk after sarilumab administration and remained low thereafter. Consistent with the anticipated effects of IL-6 inhibition and the known safety profile of sarilumab, the most frequently reported TEAE across all study treatments was neutropenia, followed by increased alanine aminotransferase level. Conclusions Sarilumab reverses IL-6–mediated suppression of CYP3A4 activity in patients with active RA. The observed reduction of simvastatin exposure is consistent with similar studies conducted with tocilizumab and sirukumab, in agreement with IL-6–mediated disease-drug interaction effect. Acknowledgement This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Editorial assistance was provided by Andrea Eckhart, PhD, MedThink SciCom, and funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest E. Lee Consultant for: Pfizer, N. Daskalakis Shareholder of: Sanofi, Employee of: Sanofi, C. Xu Shareholder of: Sanofi, Employee of: Sanofi, A. Paccaly Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, B. Miller Shareholder of: Sanofi, Employee of: Sanofi, R. Fleischmann Grant/research support from: has received research grants from AbbVie, Amgen, Ardea, AstraZeneca, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Pfizer, Roche, Sanofi, and UCB, Consultant for: has received consulting fees from AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Eli Lilly, Pfizer, Roche, and UCB, I. Bodrug: None declared, A. Kivitz Shareholder of: has received research grants from and holds stock in Sanofi and Regeneron Pharmaceuticals, Inc., Grant/research support from: has received research grants from and holds stock in Sanofi and Regeneron Pharmaceuticals, Inc.