Letter by Caruthers and Dorsch Regarding Article, “Dosing of Clopidogrel for Platelet Inhibition in Infants and Young Children: Primary Results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) Trial”
To the Editor:
We appreciate and were excited to read the article by Li et al,1 which evaluated the pharmacodynamics of clopidogrel in children to determine the dose of clopidogrel necessary to achieve a mean 30% to 50% inhibition of 5-μmol/L ADP-induced platelet aggregation. We have concerns, however, about the authors’ conclusion that a uniform clopidogrel dose of 0.2 mg · kg−1 · d−1 in children between 0 and 24 months of age produces levels of inhibition similar to those observed in adults receiving the standard clopidogrel dose of 75 mg/d.
The pharmacokinetic profile of clopidogrel is complex and has yet to be completely elucidated. However, clopidogrel is a known prodrug that undergoes activation by cytochrome P450, namely CYP3A4, to produce its antiplatelet effects.2–4 The activity of CYP3A4 is highly variable in the first year of life. Lacroix and colleagues5 reported CYP3A4 activity to be 8% of that seen in adults in the first 24 hours of life, 13% on days 1 to 7, 29% on days 8 to 28, 34% during the second and third month of life, 43% during months 3 through 12, and 108% of adult activity between the ages of 1 and 15 years.
In the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial, patients were stratified on the basis of age into 2 groups; this methodology, however, does not take into account developmental and pharmacokinetic differences present in the neonatal period and throughout infancy. Similarly, it raises the question of whether the method of patient stratification impacted the variability observed in the data presented in their Figure 2. Clinical experience with clopidogrel has shown a need for higher doses of clopidogrel to achieve 30% to 50% inhibition of 5-μmol/L ADP-induced platelet aggregation in the early years of life. The presentation of subset data, based on age, would be helpful in interpreting and understanding the variability in the data and its impact on the surrogate end points of inhibition of maximum extent and rate of platelet aggregation. It also seems reasonable to start with a dose based on this subset data and then check periodic platelet aggregation based on simple point-of-care tests to confirm the 30% to 50% inhibition.
Dr Dorsch is on the Speakers Bureau for Bristol-Myers Squib/Sanofi Pharmaceuticals Partnership. Dr Caruthers reports no conflict of interest.
Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP, Sanders SP, Sidi D, Bonnet D, Ewert P, Jennings LK, Michelson AD; the PICOLO Investigators. Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial. Circulation. 2008; 117: 553–559.
Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos. 2003; 31: 53–59.
Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DGM, Guyer KE, Tait AR, Bates ER. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004; 109: 166–171.
Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Cavallari U, Trabetti E, Sabate M, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Pignatti PF, Macaya C. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Aterioscler Thromb Vasc Biol. 2006; 26: 1895–1900.