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

• Published in: Journal of clinical pharmacology 2002-12, Vol.42 (12), p.1326-1334
• Main Authors: Fossler, Michael J., Ebling, William F., Ma, Su, Kornhauser, David, Mondick, John, Barrett, Jeffrey S., Garner, Dennis, Quon, Check Y., Pieniaszek Jr, Henry J.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aged; Amidines - blood; Amidines - pharmacokinetics; Amidines - pharmacology; Amino Acids - blood; Area Under Curve; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Dose-Response Relationship, Drug; Double-Blind Method; Half-Life; Humans; Isoxazoles - blood; Isoxazoles - pharmacokinetics; Isoxazoles - pharmacology; Medical sciences; Middle Aged; Models, Biological; Pharmacology. Drug treatments; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Prodrugs - pharmacology
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270002042012003

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 inplasma by a sensitiveand specific LC/MS/MS method. The percent inhibition of platelet aggregation (%IPA) was evaluated in citrated plasma in response to 10 μM 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 sigmoidalEmax 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.