Biological Matrix-Dependent Pharmacokinetic and Pharmacodynamic Parameters of a Novel Platelet Glycoprotein Iib/Iiia Receptor Antagonist, Xu063, in Beagle Dogs

Kapil, Ram P.; Emm, Thomas; Mousa, Shaker A.; Padovani, P.; Quon, Check Y.; Lam, Gilbert N.

doi:10.1016/s0049-3848(97)00065-0

Cited by 5 publications

(5 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, the type of biological matrix used for quantitation of drug concentrations at therapeutic levels could play a major role in the estimation of pharmacokinetic and pharmacodynamic parameters. 34 Results demonstrated that XV459 exhibited nonlinear, dose-dependent pharmacokinetics in beagle dogs. The nonlinearity in pharmacokinetics suggested that prediction of plasma concentrations of XV459 after a certain dose and time will be difficult.…”

Section: Mousa Et Al Antithrombotic Efficacy Of Dmp754 (Roxifiban) Anmentioning

confidence: 95%

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Mousa

Kapil

1999

ATVB

Self Cite

View full text Add to dashboard Cite

Abstract-Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. DMP754 (roxifiban), a prodrug of XV459, is a recently discovered, potent antiplatelet agent with high affinity and specificity for platelet GPIIb/IIIa receptors that blocks platelet aggregate formation regardless of the agonist (IC 50 ϭ0.030 to 0.05 mol/L) or anticoagulant used for blood collection. DMP754 rapidly converts to its active free-acid form, XV459, which has a comparable high affinity for both resting and activated platelets (K d ϭ1 to 2 nmol/L) and a relatively slow rate of dissociation from resting platelets. The present study was undertaken to determine intravenous and oral antithrombotic efficacies of DMP754 and XV459 and to compare them with those of other antiplatelet and anticoagulant agents in canine models of arterial thrombosis. In these models, thrombosis was induced either electrolytically (200-A anodal current) in the carotid artery or mechanically by external clamping of the femoral artery along with stenosis, which resulted in either total occlusive thrombus formation or cyclic flow reduction, respectively. DMP754 and XV459 were given either intravenously (0.1 mg/kg bolus) or orally (0.1 to 0.4 mg/kg). Additionally, the antithrombotic efficacies of DMP754, aspirin, heparin, and ticlopidine in the canine carotid artery electrolytic injury model were compared. DMP754 demonstrated oral bioavailability of 20.8% in dogs after administration at different doses and prevented cyclic flow reduction (ED 90 -100 ϭϽ0.1 mg/kg IV or PO). Additionally, both DMP754 and XV459 (0.1 mg/kg IV or 0.3 to 0.4 mg/kg PO) demonstrated maximal antithrombotic efficacy in preventing electrically induced carotid and coronary artery thrombosis and significant antithrombotic efficacy (PϽ0.001) at relatively low doses in different settings of arterial thrombosis in the canine model. DMP754 resulted in a significant reduction in thrombus mass and sustained arterial blood flow with 100% prevention of occlusive and nonocclusive thrombosis. In contrast, administration of aspirin (10 mg/kg PO for 2 days), heparin (10 IU/kg IV bolus followed by 90 IU/kg IV infusion over 3 hours), or ticlopidine (300 mg/kg PO for 3 days) before initiation of arterial thrombosis did not reduce the incidence of electrolytic injury-induced occlusive arterial thrombosis. These studies demonstrated a distinct antithrombotic efficacy of DMP754 as compared with existing strategies and suggest potential intravenous and oral antithrombotic uses of DMP754 in the prevention and treatment of thromboembolic disorders. (Arterioscler Thromb Vasc Biol. 1999;19:2535-2541.)

show abstract

Section: Mousa Et Al Antithrombotic Efficacy Of Dmp754 (Roxifiban) Anmentioning

confidence: 95%

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Mousa

Kapil

1999

ATVB

Self Cite

View full text Add to dashboard Cite

show abstract

“…Unactivated platelets were prepared by treatment with PGE1, 10 mg/mL (Sigma Chemical Co.). XP280 K d values were determined by direct competition between XP280 and labelled tracer GP IIb/IIIa ligands, 3 H-SA202 (NEN, Boston, MA; K d = 1.4 nM for activated guinea pig platelets and 2.13 nM for inactivated platelets) and 3 H-DMP728 (NEN, Boston, MA; K d = 11.4 nM for activated guinea pig platelets and 54.0 nM for unactivated platelets).…”

Section: K D Determination By Direct Binding Competition With Radiolamentioning

confidence: 99%

“…The citrate tubes were gently inverted by hand for 30 s to disperse the citrate anticoagulant. The choice of citrate as an anticoagulant for this phase of the study was necessary because of the interference of EDTA with the platelet aggregometry results [4].…”

Section: Study Design and Conductmentioning

confidence: 99%

See 1 more Smart Citation

Disposition and exposure of the fibrinogen receptor antagonist XV459 on αIIBβ3 binding sites in the guinea pig

Barrett

Kapil

et al. 1999

Biopharm. Drug Dispos.

Self Cite

View full text Add to dashboard Cite

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and 3H‐SA202, the trifluroacetic acid salt, to male guinea pigs. A liquid chromatography‐mass spectrometry (LC‐MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0.1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 μg/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 ng/mL was obtained at the 2.0 μg/kg dose. Pooling individual concentration–time data yielded a systemic clearance of 1.42 mL/min/kg, Vss of 0.24 L/kg, and a terminal half‐life of 2.8 h in the guinea pig at the 0.5 μg/kg dose. The 2.0 μg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non‐plasma GP IIb/IIIa binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitro studies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists. Copyright © 1999 John Wiley & Sons, Ltd.

show abstract

“…However, when the total concentration of XV459 exceeds the binding capacity of the platelets, the resulting increase in the unbound fraction allows "excess" drug to be quickly cleared from the plasma. 5 Hence, XV459 exhibits pharmacodynamically mediated pharmacokinetics.…”

mentioning

confidence: 99%

Integrated Pharmacokinetic/Pharmacodynamic Model of XV459, a Potent and Specific GPIIb/IIIa Inhibitor, in Healthy Male Volunteers

Fossler

Ebling

et al. 2002

The Journal of Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Roxifiban is an oral prodrug of XV459, a potent and specific inhibitor of the glycoprotein (GP) IIb/IIIa receptor previously under investigation for the treatment of peripheral arterial disease and acute coronary care syndrome. The objective of the present analysis was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that would be used to guide dose selection in Phase 2. This was a randomized, sequential, rising multiple-dose study in 41 healthy male volunteers given doses of 0.5 to 1.25 mg daily for 7 to 10 days. Total XV459 was measured in plasma by a sensitive and specific LC/MS/MS method. The percent inhibition of platelet aggregation (%IPA) was evaluated in citrated plasma in response to 10 microM ADP using the initial slope of the response. The resulting PK data were fit to a two-compartment model with first-order absorption and saturable oral absorption. The pharmacodynamics was modeled using a direct sigmoidal Emax model. Modeling was performed using NONMEM V. Intersubject variability was moderate in both PK and PD (15.3%-18.5%), except for V2/F (64.8%). Residual variability was low at 11.8%. Platelet count influenced both CL/F and EC50. Age and weight did not explain any additional variability in either PK or PD. The model was shown to produce realistic data when used for simulation. Overall, the results suggest that XV459 concentrations in the range of 10 to 20 ng/ml will yield %IPA values in the range of 40% to 80% inhibition. Because of the pharmacodynamically mediated PK of XV459 (due to platelet binding), the EC50 and CL/F are negatively correlated, limiting the utility of plasma concentration monitoring.

show abstract

Biological Matrix-Dependent Pharmacokinetic and Pharmacodynamic Parameters of a Novel Platelet Glycoprotein Iib/Iiia Receptor Antagonist, Xu063, in Beagle Dogs

Cited by 5 publications

References 10 publications

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459

Disposition and exposure of the fibrinogen receptor antagonist XV459 on αIIBβ3 binding sites in the guinea pig

Integrated Pharmacokinetic/Pharmacodynamic Model of XV459, a Potent and Specific GPIIb/IIIa Inhibitor, in Healthy Male Volunteers

Contact Info

Product

Resources

About