Interactions Between Different P2Y12 Antagonists

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Currently, attention is focused on the therapeutic use of P2Y12 receptor antagonists in patients with cardiovascular pathologies, especially during and following coronary interventions. Such drugs inhibit platelet aggregation brought about by adenosine diphosphate (ADP), which plays a central role in platelet function.1 ADP activates platelets via two specific receptors on the platelet surface, known as the P2Y1 and P2Y12 receptors.2,3 By blocking the effect of ADP at P2Y12 receptors, antagonists that act at this receptor markedly inhibit platelet aggregation and other aspects of platelet function and help to prevent thrombus formation.4 Currently, clopidogrel is the most widely used P2Y12 antagonist, but this may change as other P2Y12 antagonists are developed and become available for clinical use. Clopidogrel is a thienopyridine prodrug that needs to be converted into the active metabolite that is responsible for the inhibitory effects of the drug on platelet function.5,6

Prasugrel is a new P2Y12 antagonist that is also a thienopyridine prodrug and has enhanced potency compared with clopidogrel as a consequence of more efficient conversion to its own active metabolite,7–9 and may prove to be an important competitor within this class of drugs that inhibit platelet function irreversibly. Once the active metabolites of both clopidogrel and prasugrel are produced they form a covalent disulfide bond between their reactive thiol group and a cysteine in the extracellular part of the P2Y12 receptor, and in this way provide irreversible platelet inhibition.6,10 There is also considerable interest in reversible P2Y12 antagonists, one being cangrelor, which is a potent agent that acts directly at the P2Y12 receptor and is being developed as an agent for intravenous use.11 It differs from clopidogrel and prasugrel in two important ways. First, the onset of action of this drug is very rapid: it achieves its maximum inhibitory effect within 15 minutes after the infusion is initiated, whereas with the prodrugs a certain time is needed for their metabolites to be produced and to be effective. Second, the drug has a short half-life and completely disappears within 15 minutes after the termination of infusion,12 after which platelet function returns to normal. Another potential drug is AZD6140, which is also a potent, direct-acting and reversible P2Y12 antagonist, but with a longer half-life compared with cangrelor – approximately 12 hours. Unlike cangrelor, AZD6140 is being developed for oral administration and has a fairly rapid onset of action, with maximal inhibition of platelet function achieved within two to four hours following a single administration.13

If and when these various drugs become available, there will be situations when there is the need to terminate the use of one drug in a certain patient and replace it with another. The particular situation that comes to mind is following intravenous administration of cangrelor during percutaneous coronary intervention (PCI), when clopidogrel or prasugrel may be prescribed for long-term maintenance antiplatelet therapy. Therefore, the question is: will any difficulties be encountered in effecting this transfer from one drug to another? To answer this question we need to understand how different P2Y12 antagonists work. A direct-acting agent such as cangrelor or AZD6140 enters the bloodstream following administration and acts directly at P2Y12 receptors on the platelet surface. This prevents any ADP present in the vicinity of the platelet from occupying the receptor and inducing a functional response. The degree of occupation of the receptor by the antagonist depends on the concentration of the drug present in the blood plasma, and as this falls (e.g. when infusion of the drug is terminated or no further drug is administered) receptor occupation also falls. As receptor occupation falls, the platelets regain their ability to respond to ADP.

An indirect-acting agent such as clopidogrel or prasugrel has to be converted into an active metabolite before it can act as a P2Y12 antagonist and reduce platelet function. Following administration of both clopidogrel and prasugrel, the active metabolite is generated gradually and reaches maximum concentration after approximately two hours. Thereafter, the concentration of the metabolite decreases quite rapidly, within three hours for clopidogrel and around six hours for prasugrel.14 Although the metabolite is present in blood only relatively transiently, it interacts irreversibly with the P2Y12 receptor, thus producing a long-term effect. Therefore, unlike the direct-acting, reversible antagonists, the inhibitory effects of clopidogrel and prasugrel on platelet function do not disappear once the active metabolite is no longer present in the blood plasma.

So, what happens if different types of drugs are present in the circulation at the same time? Imagine a situation where cangrelor is still present on P2Y12 receptors at the time that clopidogrel or prasugrel is administered and their active metabolites start to be produced. Theoretically, one of two scenarios may arise: the active metabolite may still interact with the receptor replacing the direct-acting antagonist, or the active metabolite may be unable to interact with the receptor because the presence of the other antagonist prevents it from doing so.

The first scenario would result in continuation of inhibition of platelet function when the direct-acting antagonist is no longer administered since the active metabolite of clopidogrel or prasugrel will have bound to the P2Y12 receptor irreversibly and achieved continued inhibition. However, the second scenario could result in a period during which there is little or no inhibition of platelet function when the direct-acting antagonist is no longer administered.

So far, there have been only two studies that have addressed the possible influence of cangrelor on the ability of thienopyridine to interact with the P2Y12 receptor and inhibit platelet function; there have been no such studies using AZD6140. The first was a study by Steinhubl et al. in which cangrelor and clopidogrel were administered singly and in combination to healthy volunteers.15 In this study, administration of cangrelor alone or clopidogrel alone provided inhibition of platelet function that was of short and long duration, respectively. However, when cangrelor infusion was initiated simultaneously with the administration of clopidogrel and then infusion of cangrelor was terminated, the sustained platelet inhibition anticipated for clopidogrel did not occur, and platelet function recovered rapidly. Clearly, the indication is that the presence of cangrelor does influence the ability of clopidogrel to provide sustained inhibition of platelet function.

The second study was performed entirely in vitro at the University of Nottingham.16 This study was designed to directly explore the possibilities of interactions between different drugs. The study involved the addition of cangrelor and/or the active metabolite of clopidogrel or prasugrel to whole blood, followed by the measurement of platelet activation in response to ADP. Both clopidogrel and prasugrel are prodrugs, thus they are inactive in vitro. The active metabolites of these drugs were manufactured by Daiichi Sankyo & Lilly specifically for the purpose of in vitro investigations. Expression of P-selectin was chosen as the measure of platelet activation, which was one of the measures used by Steinhubl et al.,15 and was particularly appropriate for the experimental design that we employed. In fact, according to our own experience, measurement of P-selectin expression induced by different agonists and combinations of agonists is proving to be a robust approach to assessing platelet function and responsiveness to antiplatelet drugs in a number of clinical scenarios (paper in preparation).

The method used in our in vitro study involved the rapid removal of the antagonists by diluting the blood samples and then measurement of residual platelet activation induced by ADP. We found that cangrelor, the active metabolite of clopidogrel or the active metabolite of prasugrel used alone markedly inhibited P-selectin expression induced by ADP, and that the effect of cangrelor was reversible following antagonist removal. In contrast, as expected, the effects of the clopidogrel and prasugrel metabolites were sustained following agonist removal. However, pre-incubation of blood with cangrelor prior to the addition of one of the clopidogrel- or prasugrel-active metabolites reduced the ability of metabolites to irreversibly antagonise P2Y12, as evidenced by the recovery of platelet function following dilution of the blood. On the other hand, irreversible inhibition was maintained when blood was pre-incubated with either of the metabolites prior to cangrelor. The combination of cangrelor and clopidogrel active metabolite is demonstrated in Figure 1. Similar results were obtained with cangrelor and prasugrel-active metabolite (not shown). We maintain that these data provide clear evidence that cangrelor can limit the ability of both clopidogrel and prasugrel to inhibit platelet function. It remains to be seen whether a similar scenario will arise when the possibility of interactions between another direct-acting P2Y12 antagonist (e.g. AZD6140) and either clopidogrel or prasugrel are considered. It may not necessarily follow that other direct-acting antagonists will interact with clopidogrel or prasugrel metabolites in the same way as cangrelor, and each situation needs to be looked at separately. Even the possibility of an interaction between the reversible short-lasting cangrelor and the reversible AZD6140 should be studied as these antagonists could also be prescribed sequentially in certain clinical situations.

In conclusion, interactions between different reversible and irreversible P2Y12 antagonists do occur according to the results of recently performed in vivo15 and in vitro16 studies, and the consequences of such interactions need to be assessed. A particular situation that requires consideration is the transition from intravenous therapy with cangrelor to oral therapy with clopidogrel or prasugrel. Ideally, the physician will aim to ensure continuation of P2Y12 blockade during the changeover; however, clearly this could easily go wrong. For example, if oral therapy was initiated early so that cangrelor was still present in a high concentration at the time at which the active metabolite of clopidogrel or prasugrel appeared in the blood, irreversible blockade of P2Y12 would not occur.

Both the cangrelor and the metabolite would subsequently be removed and platelet function would return to normal. The situation would only be rescued if a second dose of an oral drug was administered at a later time. On the other hand, if there was a time gap between cangrelor being discontinued and oral therapy being initiated, again, there would be a period when a P2Y12 blockade was not being achieved. Perhaps a means of overcoming this unwanted situation of reduced P2Y12 blockade would be regular administration (for example half-hourly) of doses of oral drug during and immediately after the termination of cangrelor infusion. Further clinical investigations will need to be performed to establish the optimum procedures needed to effect transfer from intravenous P2Y12 blockade to that achieved following oral therapy.

In view of these perceived difficulties, perhaps the timing of the transfer from one drug to another in relation to the clinical procedure should be a focus of attention. Would one really want to take the risk of withdrawing effective P2Y12 blockade immediately after an acute coronary intervention? Would it be more sensible to wait until the acute and particularly dangerous period during which thrombus formation may occur has passed? It may be prudent to delay the transfer from intravenous to oral treatment until after the critical period during which it is considered that P2Y12 blockade is deemed to be providing most clinical benefit.


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