Effect of age on the pharmacokinetics and pharmacodynamics of prasugrel during multiple dosing: an open-label, single-sequence, clinical trial.
BACKGROUND
A substantial portion of patients at risk for acute coronary syndrome (ACS) are >65 years old. Prasugrel is a novel antiplatelet agent approved for the treatment of ACS patients undergoing percutaneous coronary intervention, and will be used in this population.


OBJECTIVE
This study assessed the effect of age >or=65 years on the pharmacokinetics (PK) and pharmacodynamics (PD) of the active metabolite (R-138727) of prasugrel in healthy subjects taking aspirin (acetylsalicylic acid).


METHODS
This was an open-label, single-sequence trial conducted in a single clinical research centre in the UK. A total of 17 subjects aged 65-80 years and 15 subjects aged 20-39 years received a prasugrel 5-mg once-daily maintenance dose for 10 days followed by 10-mg once daily maintenance doses for 10 days. All subjects also received aspirin 75 mg daily. Serial blood samples were collected pre-dose and at various times post-dose for measurement of the active metabolite of prasugrel in plasma on days 10 and 20, following the last 5- and 10-mg prasugrel dose, respectively. PK parameters of the active metabolite of prasugrel included area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUC(last)), maximum plasma concentration (C(max)) and time to C(max) (t(max)). Maximal platelet aggregation (MPA), assessed by light transmission aggregometry using adenosine diphosphate (ADP) 20 micromol/L, was assessed at baseline and on day 10 (5-mg maintenance dose) and day 20 (10-mg maintenance dose). Bleeding times (BTs) were determined on days -5, 1, 10, 11, 20 and 21 using a modified Ivy technique.


RESULTS
AUC(last) did not differ significantly between age groups. The steady-state trough MPA to ADP 20 micromol/L during 10-mg maintenance dosing was 30.6% and 26.6% in elderly and young subjects, respectively. Mean MPA was consistently higher in elderly subjects compared with young subjects; however, differences were generally less than ten percentage points. BTs did not differ between the two populations during 5-mg maintenance dosing; however, during 10-mg maintenance dosing, BTs were up to 67% longer in young compared with elderly subjects. A higher frequency of minor bleeding during 10-mg maintenance dosing was observed in elderly subjects compared with young subjects.


CONCLUSIONS
These data indicate that prasugrel PK and MPA were similar in healthy subjects regardless of age. Compared with younger subjects, elderly subjects had shorter BTs but a greater frequency of mild bleeding-related adverse events.
Small
David S
DS
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. dsmall@lilly.com
Wrishko
Rebecca E
RE
Ernest
C Steven
CS
Ni
Lan
L
Winters
Kenneth J
KJ
Farid
Nagy A
NA
Li
Ying G
YG
Salazar
Daniel E
DE
Payne
Christopher D
CD
D000244:Adenosine Diphosphate; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D001241:Aspirin / Q000494:pharmacology; D001760:Bleeding Time; D015992:Body Mass Index; D016001:Confidence Intervals; D004359:Drug Therapy, Combination; D005215:Fasting; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D010879:Piperazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics*; D058919:Purinergic P2 Receptor Antagonists; D018709:Statistics, Nonparametric; D013608:Tablets, Enteric-Coated; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D058919:Purinergic P2 Receptor Antagonists; C510685:R-138727; D013608:Tablets, Enteric-Coated; D013876:Thiophenes; D000244:Adenosine Diphosphate; D000068799:Prasugrel Hydrochloride; D001241:Aspirin