NEOPLASIAS BENIGNAS Y MALIGNAS Y NO ESPECIFICADAS

T-PC and T-AM are equipotent; since T-AM is present in plasma at a

concentration that is a third of that of the parent compound, the majority of the antiplatelet effect seen is due to the activity of the T-PC (Husted,

Emanuelsson et al. 2006). For the remainder of the thesis, all LC-MS/MS information regarding ticagrelor will relate to T-PC. The subsequent sections demonstrate that although the final plasma concentrations are lower than those quoted in the literature, the trend in terms of T-PC:T-AM production are also observed in our STEMI and NSTEMI groups. In addition, our data supports the rationale to quote T-PC plasma concentrations only, as outlined below.

Plasma concentrations of T-PC and T-AM, indicate that levels in the region of 549 ng/ml after 3.1 hours and 135ng/ml after 3.7 hours respectively in patients with SCAD can be achieved following the administration of a 180mg loading dose (Wallentin 2009). At the time at which the ticagrelor patient group was recruited to the current study, there were no data relating to plasma

concentrations of T-PC or T-AM in the context of STEMI against which the observed LC-MS/MS data could be benchmarked. However, since

completion of this study, a paper has been published in which the plasma concentrations of ticagrelor are investigated in STEMI patients. This study was designed to provide a pharmacokinetic and pharmacodynamic

comparison of crushed vs integral tablets in STEMI patients (Alexopoulos, Barampoutis et al. 2015). The T-PC and T-AM plasma concentrations reported by Alexopoulos et al (2015) at 1 hour were 70ng/ml and 4.3ng/ml

This is not too dissimilar to the T-PC and T-AM results from this study, which in comparison demonstrate plasma concentrations of 47ng/ml and 14.3 ng/ml at 1 hour.

This study data therefore is in line with recently reported pharmacodynamic data, which indicates, reduced plasma concentrations of intact ticagrelor tablets in STEMI patients, which is most likely secondary to delayed gastric absorption and the co-administration of morphine (Alexopoulos, Barampoutis et al. 2015, Kubica, Adamski et al. 2015). Although this study was not

adequately powered to determine the significance of the effect of morphine on the efficacy of ticagrelor, there is a growing body of evidence with

pharmacodynamic data derived from both healthy volunteers and those who present following a STEMI, which indicates that this a drug-drug interaction that is of potential clinical significance (Kubica, Adamski et al. 2015, Parodi, Bellandi et al. 2015).

7.7.3.1 Ticagrelor-Parent Compound (T-PC)

Since, ticagrelor undergoes rapid and complete gastrointestinal absorption following oral ingestion, we would expect the STEMI plasma concentrations to more closely resemble the NSTEMI.

In the STEMI group, the plasma concentrations at 20, 60 and 240 minutes are all less than 100ng/ml, comparatively, in the NSTEMI group, the plasma concentrations are numerically greater, but there is no statistical difference observed at each time point when comparing the two groups.

The amount of T-PC detected in plasma over time increased significantly; the plasma concentration at 240 minutes compared to 20 minutes was statistically

significantly greater in both groups (p = 0.004). However, when assessing the effect of STEMI of plasma concentrations/gastrointestinal absorption, our data indicates no significant difference between the two groups (p = 0.715)

7.7.3.2 Ticagrelor-Active Metabolite (T-AM)

As for theT-PC results, a statistically significant difference was not seen in the plasma concentration of T-AM between the STEMI and NSTEMI groups at each sample collection time point.

However, in terms of the plasma concentration over time, a highly statistically significant increase in T-AM was seen at 240 minutes compared to 20

minutes (p = 0.000). When comparing the effect of STEMI against NSTEMI on the degree of T-AM present over time, we did not see a statistically significant difference between the two groups (p = 0.089).

7.7.3.3 Correlation between T-PC and T-AM

A Pearson’s correlation was undertaken to determine the strength of the relationship between the plasma concentration of T-PC and T-AM. A positive correlation was observed between the plasma concentrations of T-PC and T- AM in each disease state and at each time point that was of statistical

significance (table 33).

On examining the relationship between the pharmacokinetic and

pharmadynamic profiles generated following the administration of a ticagrelor 180mg loading dose, the data in table 35, indicates a very high negative correlation between the degree of platelet inhibition as assessed by VerifyNow and the plasma concentration of T-PC, that is of high statistical

as the plasma concentration of T-PC increases, the antiplaletet effect of ticagrelor increases and the degree of inhibition of platelet reactivity and aggregation increases as evidenced by the reduction in PRU over time.

Table 36. Pharmacokinetic/Pharmacodynamic trend of ticagrelor over time STEMI NSTEMI VerifyNow PRU   VASP-P %PRI   LC-MS/MS plasma concentration (ng/ml)   7.8 Conclusion

The reported pharmacodynamic data from this study indicates that even ticagrelor is subject to HRPR; there is a sufficient enough delay between the oral ingestion of ticagrelor and the onset of its therapeutic antiplatelet effect that reduces its efficacy in patients who present with a STEMI. Since

ticagrelor is directly acting, it does not rely on metabolic activation in order to execute its antiplatelet effect, however, in STEMI gastrointestinal absorption is impaired sufficiently enough to reduce the amount ticagrelor available to act as a P2Y12 inhibitor.

So, despite ticagrelor being directly acting, in the context of STEMI it does not achieve adequate or sufficient levels of platelet inhibition at the time when it is most desirable in STEMI patients; at the time of angioplasty and coronary artery stent implantation.

STEMI is a condition that precipitates heightened platelet reactivity and increased platelet turnover (Alexopoulos, Xanthopoulou et al. 2013). The lag

time between the oral ingestion of ticagrelor and its ability to undergo gastrointestinal absorption and the subsequent onset of action and its antiplatelet effect is sufficiently long enough to allow for the phenomenon of HRPR to take place, as is apparent from our pharmacodynamic VerifyNow and VASP-P data. So despite claims of an improved pharmacodynamic profile with faster onset of action and greater levels of IPA, the observed STEMI data indicates a lack of adequate antiplatelet action for at least 2 hours following administration. This data is supported by other pharmacodynamic studies whose results were published as this study was in progress; these data also indicate reduced antiplatelet efficacy in the immediate period post loading indicating that at least 2 to 4 hours is required to achieve adequate levels of platelet inhibition (Alexopoulos, Xanthopoulou et al. 2012, Parodi, Valenti et al. 2013).

In summary, the observed ticagrelor data demonstrates that the degree and time course of platelet inhibition observed reduces over time in both our STEMI and NSTEMI groups (based on VerifyNow and VASP-P

pharmacodynamic results). Depsite being directly acting, ticagrelor does not provide adequate levels of platelet inhibition at the time of angioplasty and coronary artery stent implantation. From which we can conclude that the delay in gastric emptying and subsequent reduction in GI absorption adversely impacts on the speed of onset and clinical efficacy of ticagrelor. When compared to NSTEMI, the disease state of STEMI does adversely affect the degree of platelet inhibition observed following the administration of a ticagrelor loading dose. NSTEMI patients are not subject to the same

physiological changes or the co-adminstration of opioids as are STEMI patients, these differences most likely account for the improved

Chapter 8 - A Pharmacodynamic Comparison of all Three