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Thromb Haemost 1998; 79(01): 169-176
DOI: 10.1055/s-0037-1614238
Review Article
Schattauer GmbH

Pharmacokinetics, Pharmacodynamics and Tolerability of a Potent, Non-peptidic, GP IIb/IIIa Receptor Antagonist following Multiple Oral Administrations of a Prodrug Form

Canio J. Refino
1   From the Departments of Cardiovascular Research, Cardiovascular Research
,
Nishit B. Modi
2   From the Departments oP Pharmacokinetics, South San Francisco CA, USA
,
Sherron Bullens
1   From the Departments of Cardiovascular Research, Cardiovascular Research
,
Cheryl Pater
1   From the Departments of Cardiovascular Research, Cardiovascular Research
,
Michael T. Lipari
1   From the Departments of Cardiovascular Research, Cardiovascular Research
,
Kirk Robarge
3   From the Departments of Bio Organic Chemistry, South San Francisco CA, USA
,
Brent Blackburn
3   From the Departments of Bio Organic Chemistry, South San Francisco CA, USA
,
Maureen Beresini
4   From the Departments of BioAnalytical Technology, Genentech Inc. South San Francisco CA, USA
,
Thomas Weller
5   From the Departments of Pharma Division, Preclinical Research, F. Hoffmann-La Roche LTD, Basel, Switzerland
,
Beat Steiner
5   From the Departments of Pharma Division, Preclinical Research, F. Hoffmann-La Roche LTD, Basel, Switzerland
,
Stuart Bunting
1   From the Departments of Cardiovascular Research, Cardiovascular Research
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Publikationsverlauf

Received 21. Januar 1997

Accepted after revision 14. August 1997

Publikationsdatum:
08. Dezember 2017 (online)

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Summary

Ro 44-3888 is a potent and selective antagonist of GP IIb/IIIa. Following IV administration to rhesus monkeys, the (mean ± SD.) clear ance, volume of distribution and terminal half-life of Ro 44-3888 were 4.4 ± 1.8 ml/min/kg, 0.8 ± 0.4 l/kg and 2.5 ± 0.8 h respectively. Oral administration of Ro 48-3657 (1 mg/kg), a doubly protected prodrug form, produced peak concentrations of Ro 44-3888 (152 ± 51 ng/ml), 4.2 ± 2.2 h after dosing. Terminal half-life and estimated bioavailabil ity were 5.1 ± 1.6 h and 33 ± 6% respectively. No effect on blood pressure, heart rate or platelet counts were seen. Adenosine diphosohate (ADP) induced platelet aggregation (PA) and cutaneous bleeding times (CBT) were determined prior to and after the last of 8 daily oral administrations of Ro 48-3657 (0.25 or 0.5 mg/kg) to eight rhesus monkeys. Peak and trough plasma concentrations were proportional to dose and steady state was achieved after the second administration. Inhibition of PA and prolongation of CBT were concentration dependent. The ex vivo IC50 (82 nM) for ADP-mediated PA correlated with a value (58 nM) determined in vitro. The CBT response curve was displaced to the right of the PA curve. CBT was prolonged to ≥25 min when levels of Ro 44-3888 exceeded 190 nM and PA was >90% inhibited. Therefore, in rhesus monkeys, Ro 48-3657 is reproducibly absorbed and converted to its active form, is well tolerated, and has a concentration-dependent effect on PA and CBT. These properties make Ro 48-3657 an attractive candidate for evaluation in patients at high risk for arterial thrombosis.

 

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