Pharmacodynamics and pharmacokinetics of single doses of prasugrel 30 mg and clopidogrel 300 mg in healthy Chinese and white volunteers: an open-label trial.
BACKGROUND
Prasugrel is an oral antiplatelet agent approved for the reduction of atherothrombotic cardiovascular events in patients presenting with acute coronary syndrome and undergoing percutaneous coronary intervention. Although the approved loading dose is 60 mg, earlier studies of prasugrel suggested that active-metabolite exposure and pharmacodynamic response may be higher in Asian subjects than in white subjects.


OBJECTIVE
This study compared the pharmacodynamic response to a single 30-mg dose of prasugrel in healthy Chinese and white subjects and the response to a single 30-mg dose of prasugrel and a single 300-mg dose of clopidogrel in healthy Chinese subjects. The pharmacokinetics and tolerability of both drugs were also assessed.


METHODS
This was an open-label, single-dose study conducted in Singapore. Chinese subjects were randomly allocated to receive prasugrel 30 mg or clopidogrel 300 mg; after a 14-day washout period, they received the alternative drug. White subjects received only prasugrel 30 mg. Blood samples for pharmaco-dynamic assessments were collected before dosing and at 0.5, 1, 2, 4, and 24 hours after dosing. Three methods were used to measure inhibition of platelet aggregation (IPA)-traditional light transmission aggregometry (LTA), the Verify Now P2Y12 (VN-P2Y12) assay, and a vasodilator-stimulated phosphoprotein (VASP) phosphorylation flow cytometry assay-and their results were compared. Blood samples for pharmacokinetic assessments were collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours after dosing. Concentrations of the active metabolite of prasugrel were measured using a validated LC-MS/MS method.


RESULTS
The study enrolled 18 Chinese subjects and 14 white subjects. Chinese subjects had a mean (SD) age of 31 (10) years and a mean body weight of 65.2 (8.9) kg; 83% were male. The corresponding values for white subjects were 30 (10) years, 77.2 (12.4) kg, and 86%. Thirty of the 32 enrolled subjects completed the study. Two Chinese men were withdrawn from the study, one due to a low platelet-rich plasma count after receipt of prasugrel 30 mg and the other due to mild, intermittent rectal bleeding after bowel movements that began approximately 2 days after receipt of clopidogrel 300 mg. The mean IPA with prasugrel was significantly higher in Chinese than in white subjects at 0.5, 1, and 2 hours after dosing (P < 0.05), but not at 4 or 24 hours. In Chinese subjects, mean maximal IPA (87%) occurred 1 hour after prasugrel dosing; in white subjects, mean maximal IPA (78%) occurred 2 hours after prasugrel dosing. In Chinese subjects, the mean IPA was significantly higher at all time points after administration of prasugrel 30 mg than after administration of clopidogrel 300 mg (P <0.001). After administration of Clopidogrel 300 mg in Chinese subjects, mean maximal IPA (58%) occurred at 4 hours. The VN-P2Y12 and VASP phosphorylation assays yielded results comparable to those obtained by LTA. Mean exposure to prasugrel's active metabolite was higher in Chinese than in white subjects (geometric least squares mean ratio for AUC(0-t) = 1.47 (90% CI, 1.24-1.73). Both drugs were well tolerated.


CONCLUSIONS
In this study, platelet inhibition was significantly higher in Chinese than in white subjects up to 2 hours after a single 30-mg dose of prasugrel. Platelet inhibition was significantly higher in Chinese subjects at all time points after a 30-mg dose of prasugrel than after a 300-mg dose of clopidogrel. Both treatments were generally well tolerated.
Small
David S
DS
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. dsmall@lilly.com
Payne
Christopher D
CD
Kothare
Prajakti
P
Yuen
Eunice
E
Natanegara
Fanni
F
Teng Loh
Mei
M
Jakubowski
Joseph A
JA
Richard Lachno
D
D
Li
Ying G
YG
Winters
Kenneth J
KJ
Farid
Nagy A
NA
Ni
Lan
L
Salazar
Daniel E
DE
Tomlin
Molly
M
Kelly
Ronan
R
D000284:Administration, Oral; D000328:Adult; D044466:Asian People; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D002681:China / Q000208:ethnology; D000077144:Clopidogrel; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D010750:Phosphoproteins / Q000097:blood; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D000068799:Prasugrel Hydrochloride; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000097:blood; D058925:Receptors, Purinergic P2Y12; D012846:Singapore / Q000453:epidemiology; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D044465:White People; D055815:Young Adult; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine