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1.
J Cardiovasc Pharmacol ; 65(6): 611-9, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25714598

ABSTRACT

Inclacumab, a novel monoclonal antibody against P-selectin in development for the treatment and prevention of atherosclerotic cardiovascular diseases, was administered in an ascending single-dose study as intravenous infusion to evaluate safety, pharmacokinetics, and pharmacodynamics. Fifty-six healthy subjects were enrolled in this randomized, double-blind placebo-controlled study. Each dose level (0.03-20 mg/kg) was investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo). Platelet-leukocyte aggregates, free/total soluble P-selectin concentration ratio, drug concentrations, bleeding time, platelet aggregation, antibody formation, and routine laboratory parameters were measured frequently until 32 weeks. Pharmacokinetic profiles were indicative of target-mediated drug disposition. Platelet-leukocyte aggregate inhibition and soluble P-selectin occupancy showed dose dependency and were strongly correlated to inclacumab plasma concentrations, with IC50 of 740 and 4600 ng/mL, respectively. Inclacumab was well tolerated by the majority of subjects and did neither affect bleeding time nor platelet aggregation. These findings allowed the investigation of the potential beneficial therapeutic use of inclacumab in patient study.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Cardiovascular Agents/administration & dosage , P-Selectin/antagonists & inhibitors , Adult , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/pharmacokinetics , Bleeding Time , Cardiovascular Agents/adverse effects , Cardiovascular Agents/blood , Cardiovascular Agents/pharmacokinetics , Double-Blind Method , England , Female , Healthy Volunteers , Hemorrhage/chemically induced , Humans , Infusions, Intravenous , Male , Middle Aged , P-Selectin/immunology , Platelet Aggregation/drug effects , Predictive Value of Tests , Risk Assessment , Young Adult
2.
J Cardiovasc Pharmacol ; 65(4): 386-92, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25602360

ABSTRACT

Inclacumab is a novel monoclonal antibody directed against P-selectin in development for the prevention and treatment of atherosclerotic cardiovascular diseases. It is likely to be used concomitantly with heparin in patients undergoing percutaneous coronary intervention. Coadministration of both drugs may potentially increase the bleeding risk associated with heparin. This crossover study evaluated the potential pharmacodynamic interaction between inclacumab and unfractionated heparin in 18 healthy smokers. Owing to the long elimination of inclacumab (half-life of approximately 18 days), a 2-period, one-sequence study design was used. Subjects received an intravenous bolus injection of unfractionated heparin (5000 IU) on days 1 and 8 and an intravenous infusion of inclacumab (20 mg/kg) on day 8. Blood samples were collected on days 1 and 8 for pharmacodynamic effects of unfractionated heparin (anti-FXa and anti-FIIa activities, activated partial thromboplastin time and tissue factor pathway inhibitor) and over 6 months for pharmacokinetics of inclacumab. Sixteen subjects were eligible for pharmacodynamic analysis. Inclacumab had no clinically significant pharmacodynamic interaction with unfractionated heparin. With the exception of the minor but statistically significant increase of the maximum effect [Emax] of anti-FIIa activity, pharmacodynamic parameters (areas under the effect curve [AUElast] and Emax of anti-FXa) were almost similar on days 1 and 8. The 90% confidence intervals of geometric mean ratios of day 8 to day 1 for AUElast and Emax were however all contained within bioequivalence boundaries. The data demonstrate that the anticoagulant effect of unfractionated heparin was not affected by the administration of inclacumab.


Subject(s)
Antibodies, Monoclonal , Blood Coagulation/drug effects , Heparin , P-Selectin/antagonists & inhibitors , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/pharmacology , Anticoagulants/administration & dosage , Anticoagulants/pharmacokinetics , Cardiovascular Agents/administration & dosage , Cardiovascular Agents/pharmacokinetics , Cross-Over Studies , Drug Interactions , Female , Healthy Volunteers , Heparin/administration & dosage , Heparin/pharmacokinetics , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/methods , Treatment Outcome
3.
Int J Clin Pharmacol Ther ; 50(8): 566-72, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22735461

ABSTRACT

AIMS: To explore the effect of food intake on the relative bioavailability of R1663 and on its pharmacodynamic effects (prothrombin time (PT) and activated partial thromboplastin time (aPTT)) after a single oral dose of 200 mg. METHODS: This was a prospective, open-label, randomized, two-way crossover study. Eight healthy male volunteers received R1663 on two occasions, after a high fat/high calorie breakfast and after an overnight fast of 10 h, with a 7-day washout between doses. Blood was sampled up to 48 h for the pharmacokinetic and pharmacodynamic evaluation of R1663. Pharmacokinetic parameters (area under the plasma concentration-time curve from Time 0 extrapolated to infinity (AUC(0-∞)) and maximal concentration (C(max)) as well as pharmacodynamic parameters (area under the effect curve over 48 h (AUE(0-48)) and maximal effect (E(max)) were determined on both occasions. Geometric mean ratios fed/ fasted (GMR) and 90% confidence intervals (CI) were calculated for AUC(0-∞) and C(max) of R1663 and AUE(0-48) and E(max) of PT and aPTT. RESULTS: Following food intake, C(max) was reduced by 10% with CI extended outside the bioequivalence range (GMR, 0.90; CI 0.72 - 1.13). R1663 t(max) was delayed in the fed state (4 h) as compared to the fasted state (1 h). There was no significant food effect on R1663 AUC(0-∞) (GMR, 1.09; CI 0.97 - 1.24). Although the Emax of PT showed statistically significant reduction with food, the 90% CIs for Emax and AUE(0-48) of PT and aPTT were all contained within the bioequivalence range (0.80 - 1.25). CONCLUSIONS: These findings will allow the administration of R1663 without regard to food in the upcoming trials.


Subject(s)
Factor Xa Inhibitors , Food-Drug Interactions , Pyridones/pharmacology , Pyridones/pharmacokinetics , Pyrrolidines/pharmacology , Pyrrolidines/pharmacokinetics , Adult , Area Under Curve , Biological Availability , Cross-Over Studies , Diet, High-Fat , Energy Intake , Fasting , Humans , Male , Partial Thromboplastin Time/statistics & numerical data , Prothrombin Time/statistics & numerical data , Pyridones/adverse effects , Pyrrolidines/adverse effects
4.
Expert Opin Drug Saf ; 11(4): 581-96, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22616935

ABSTRACT

INTRODUCTION: The kidneys are vulnerable to injury due to their high filtration capacity and high metabolic activity, and most drugs, especially hydrophilic drugs and their metabolites, are eliminated largely by kidneys in urine, thus increasing the risk of drug-induced nephrotoxicity (DIN). DIN accounts for 18 - 27% of community- and hospital-acquired episodes of acute kidney injury (AKI) and is a serious concern during development of novel therapeutic drugs. AREAS COVERED: This review provides an overview of definitions, classification, risk factors, complications, and outcomes of DIN. In addition, it gives a practical source of information when dealing with nephrotoxicity issues during drug development and provides guidance on renal safety risk evaluation for clinical studies. Lastly, current research focus in the search for novel biomarkers of DIN is also provided. EXPERT OPINION: To enable early detection of DIN and to ensure patients' safety through appropriate risk minimization and mitigation strategies, future research should focus on identification and validation of novel predictive biomarkers of kidney injury and development of DIN-specific classification and staging system. This could help in reducing the current high rate of attrition during drug development, and reduce marketing and post-marketing withdrawals of nephrotoxic drugs.


Subject(s)
Drug Discovery , Kidney Diseases/chemically induced , Risk Management , Acute Kidney Injury/chemically induced , Chronic Disease , Humans , Kidney Diseases/diagnosis , Risk Factors
5.
Thromb Haemost ; 108(1): 54-64, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22552265

ABSTRACT

This study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3-5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC50 = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.


Subject(s)
Factor Xa Inhibitors , Pyridones/administration & dosage , Pyridones/pharmacokinetics , Pyrrolidines/administration & dosage , Pyrrolidines/pharmacokinetics , Adolescent , Adult , Age Factors , Aged , Blood Coagulation Tests , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Pyridones/adverse effects , Pyrrolidines/adverse effects , Sex Factors , Young Adult
6.
J Clin Pharmacol ; 52(4): 499-510, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21566199

ABSTRACT

This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.


Subject(s)
Anticoagulants/pharmacology , Factor Xa Inhibitors , Pyridones/pharmacology , Pyrrolidines/pharmacology , Thrombin/antagonists & inhibitors , Administration, Oral , Adolescent , Adult , Anticoagulants/adverse effects , Anticoagulants/pharmacokinetics , Cross-Over Studies , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Male , Middle Aged , Partial Thromboplastin Time , Prothrombin Time , Pyridones/adverse effects , Pyridones/pharmacokinetics , Pyrrolidines/adverse effects , Pyrrolidines/pharmacokinetics , Single-Blind Method , Time Factors , Young Adult
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