Indian Heart Journal. 2008 Nov-Dec; 60(6): 543-7
The use of clopidogrel presents another interesting challenge with respect to the variability in drug response.
Clopidogrel is a a platelet inhibitor, acting through irreversible binding to the P2Y12 purinergic receptor on the platelet membrane; though it is not clopidogrel itself that binds, but the active metabolite. The PK of clopidogrel itself is quite complex. Upon oral administration about 90% of clopidogrel is removed through the action of circulating and hepatic esterases to inactive metabolites. Only about 10-15% gets activated by CYP2C19 and CYP3A4 to the final metabolite that binds to the P2Y12 receptor. As the receptor inactivation is irreversible, the recovery of function is dependent on fresh platelet regeneration from megakaryocytes.
The way clopidogrel produces its action is therefore fraught with all kinds of problems which clearly contributes to the observed variability in therapeutic response. These are potential sources of variability:
a) high first pass and low active metabolite bioavailability
b) variability of CYP3A4 and CYP2C19 activities due to pharmacogenetics and food/drug interactions
c) irreversible binding to receptor
d) temporal delay in onset, as well as in recovery of platelet function
e] variability in rate of platelet recovery.
This extent of variability really points to a crying need for dosages of clopidogrel to be optimized according to some clinical measure of drug response. Unlike the situation with warfarin however, there isn't a universally accepted way of monitoring plate function. Nevertheless, platelet function test is shaping up to become a standard bedside test for this very reason. A recent review by Williams et al (Thromb Haemost 2010; 103: 29–33) is worth a read.
Drug level testing would clearly not be useful as it is not clopidogrel itself but the metabolite that is active. Furthermore the irreversible binding to the platelet purinergic receptor would not allow concentrations of the active metabolite to be useful in predicting the level of platelet inhibition.
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Hi Prof Lee,
ReplyDeleteI was wondering if we should expect a similar variability in response to prasugrel (also an ADP-antagonist)? From what I understand, it is also a pro-drug metabolized by CYP2C19, but via a one-pass mechanism, as opposed to a two-pass mechanism as in clopidogrel.
From the clinical data currently available, it seems that the drug is efficacious irrespective of a patient's CYP2C19 genotype. Is it too early to generalize that this is truly the case?
There was a recent comment on this issue:
ReplyDeleteCytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes
Mega JL, Close SL, Wiviott SD, et al
Circulation. 2009;119:2553-2560
The CYP2C19 polymorphism accounts for only one of the variability factors for clopidogrel, but not all. It is unclear what the non-CYP2C19 factors are but may include variability associated with P2Y12 receptor expression and function, platelet regeneration rates etc.
This emphasizes the need to move away from fixed doses of platelet inhibitors to targeting a specific level of platelet inhibition. The aggregometer technolgies are developing and are being validated and in future I hope this will reduce variability of the clinical target response. One caveat is that the aggregometer may provide and indication of aggregability, but I believe the main effect of inhibiting P2Y12 may be more an inhibition of the stabilization of the aggregate, an event not as easily measured.
Hi Prof Lee, I'm from Malaysia and would really appreciate it if you could let me know if there are any blood tests available in Singapore to check the body's reactivity to Clopidogrel? Thanks so much for your help in advance!
ReplyDelete'fraid not. Nothing in routine use..
ReplyDelete