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

Barrett, Jeffrey S.; Yu, Jun; Kapil, Ram P.; Padovani, P.; Brown, Frederick J.; Ebling, William F.; Corjay, Martha H.; Reilly, Thomas M.; Bozarth, Jeffrey M.; Mousa, Shaker A.; Pieniaszek, Henry J.

doi:10.1002/(sici)1099-081x(199909)20:6<309::aid-bdd190>3.0.co;2-7

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…Narjes et al18 evaluated the use of inhibition of ex vivo platelet aggregation as surrogate for PD activity of glycoprotein IIb/IIIa receptor antagonists. Barrett et al 19 identified the guinea pig as the most appropriate rodent species to investigate the PK/PD of glycoprotein IIb/IIIa inhibitors due to PD similarities with humans in drug/receptor binding.…”

Section: Pk/pd During Preclinical Drug Evaluationmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Studies in Drug Product Development

Meibohm

Derendorf

2002

Journal of Pharmaceutical Sciences

155

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Section: Pk/pd During Preclinical Drug Evaluationmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Studies in Drug Product Development

Meibohm

Derendorf

2002

Journal of Pharmaceutical Sciences

155

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“…An example is the proportion of hemoglobin molecules modified to have a high oxygen-binding affinity (%MOD) used in early phase evaluation of tucaresol-a drug designed to prevent hemoglobin S (HbS) polymerization, subsequent hemolysis and painful crises in sickle cell anemia (39). Erythrocyte concentration of deoxygenated HbS determines the extent of HbS polymerization.…”

Section: Biomarkers In Early (Exploratory) Phase Clinical Developmentmentioning

confidence: 99%

“…The study provided the first strong evidence for advancing cholesterol measurements from biomarker to surrogate endpoint status by demonstrating that the relative risk of death for patients receiving simvastatin compared with placebo-treated patients was 0.70 (95% confidence interval: 0.58-0.85, p = 0.003). By selecting the dose of 20 mg/day as the minimal dose for satisfactory effect rather than the maximally tolerated dose, the all-too-common pitfall of registering a starting dose that was subsequently found to be excessive was avoided (39).…”

Section: Surrogate Endpointmentioning

confidence: 99%

A Rational Approach to Drug Development: The Exploratory Phase

Ette

Garg

Jayaraj

2004

Clinical Research and Regulatory Affairs

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Drug development is a complex process, and added to it is the sophisticated new technologies and approaches to drug design, of which rational drug design is the epitome. A low success rate for investigational new drugs calls for improvement in drug discovery and development processes. Implementing knowledge driven drug development strategies founded on informative, powerful, and robust studies would greatly improve the drug discovery and development processes. Knowledge driven drug discovery and development that emphasizes a learn-confirm-learn paradigm is proposed as the rational basis for drug development. Although clinical drug development is usually divided into Phases I, II, III, and IV; it should rather be defined by those studies necessary to obtain data to answer the fundamental development decision questions: ''Is the new molecular entity tolerated and at what dose range?'' and ''Does it show efficacy for intended use within the tolerated dose range?'' In setting out to answer these questions during drug development, we propose that the learn-confirm-learn paradigm of drug development provides the most appropriate answers to these questions and hence a rational and optimal drug development process (DDP). The exploratory phase of drug development provides the Clinical Research and Regulatory Affairs Downloaded from informahealthcare.com by Kainan University on 04/08/15For personal use only.answer to the first question, and answers the second question in part through a welldesigned proof of concept study.

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“…It provides prolonged antiplatelet effects in dogs and guinea pigs. [19][20][21] The objective of this study was to determine the safety, tolerability, pharmacokinetics, and time course of pharmacologic response following administration of single and multiple escalating oral doses of roxifiban to healthy young (ages 18-46 years) and older (ages 47-75 years) adult populations. We also studied these parameters in subjects exposed to aspirin prior to roxifiban administration versus subjects naive to antiplatelet therapy.…”

mentioning

confidence: 99%

Safety, Tolerability, Pharmacokinetics, and Time Course of Pharmacologic Response of the Active Metabolite of Roxifiban, XV459, a Glycoprotein IIb/IIIa Antagonist, following Oral Administration in Healthy Volunteers

Pieniaszek

Ebling

et al. 2002

The Journal of Clinical Pharma

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Roxifiban is an esterprodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five-part double-blind, placebo-controlled study. Healthy male volunteers (ages 18-46 years) received 7 (0.75-1.5 mg; n = 20) and 10 (0.75-1.0 mg; n = 8) multiple, oral, qd doses of roxifiban or placebo (n = 5). Healthy older male and female volunteers (ages 47-75 years) received roxifiban qd doses (0.5-0.75 mg; n = 8) or placebo (n = 3) for 7 days. Healthy male subjects (ages 18-46 years; n = 16) received a 1.5 or 1.0 mg loading dose either with or without pretreatment of 325 mg aspirin once daily for 3 days followed by single daily doses of 1.0 mg roxifiban for 6 days. Measurable plasma concentrations of XV459 appeared rapidly and were sustained throughout the dosing interval of 24 hours. The pharmacokinetics of XV459 were nonlinear. Systemic exposure of XV459 plateaued at the 1-mg dose level; plasma concentrations approached steady state in 4 to 6 days for doses greater than 1.0 mg. The time course of pharmacologic response as measured by the inhibition of platelet aggregation in response to an ex vivo 10 microM adenosine 5'-diphosphate (ADP) agonist correlated closely to the plasma concentration of XV459. Potent inhibition of ADP-induced platelet aggregation (IPA) persisted over the entire dosing interval. A clear dose response was achieved with roxifiban doses of 0.5 and 1.0 mg. For doses greater than 1.0 mg, a dose-proportional increase in IPA was not observed. Both the pharmacokinetics and pharmacologic response of XV459 exhibited low intraindividual variability (coefficient of variation [CV] < 15%) and higher interindividual variability (CV < 30%). Pretreatment with aspirin and/or a loading dose of 1.5 mg roxifiban had no significant effect on the pharmacokinetics and pharmacologic response of XV459. A dose-related increase in template bleeding time was observed at 1.25- and 1.5-mg doses of roxifiban, as compared to placebo. However, these bleeding time increases in the 1.25- and 1.5-mg dose groups were not significantly different from those at the lower dose groups. Overall, once-daily oral administration of roxifiban was fairly well tolerated and provided sustained systemic drug exposure and pharmacologic response over the entire administration interval.

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

Cited by 6 publications

References 25 publications

Pharmacokinetic/Pharmacodynamic Studies in Drug Product Development

Pharmacokinetic/Pharmacodynamic Studies in Drug Product Development

A Rational Approach to Drug Development: The Exploratory Phase

Safety, Tolerability, Pharmacokinetics, and Time Course of Pharmacologic Response of the Active Metabolite of Roxifiban, XV459, a Glycoprotein IIb/IIIa Antagonist, following Oral Administration in Healthy Volunteers

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