Pietro Laddomada1,2, Alessandro Di Deo1,2, Oscar Della Pasqua1,2
1Clinical Pharmacology & Therapeutics Group, University College London, 2Consiglio Nazionale delle Ricerche (CNR)
Introduction Cangrelor is a direct and reversible P2Y12 receptor antagonist that inhibits platelet activation and aggregation, currently approved for intravenous administration in adults undergoing percutaneous coronary intervention. Cangrelor exhibits a rapid onset of effect, achieving peak platelet inhibition immediately after administration. It also shows rapid offset, allowing rapid recovery of platelet aggregation (<1 hour) due to its reversible binding (1). This rapid onset-offset makes it particularly advantageous in high-risk surgical settings where rapid restoration of platelet activity is necessary to minimize bleeding risk. The intraoperative use of cangrelor has led to a reduction in thromboembolic events (TE) compared to standard anticoagulation protocols (2, 3), and comparable outcomes have been observed where cangrelor has been used off-label in paediatric settings (4, 5). However, despite its successful use in clinical settings, there are limited data on the determinants of interindividual variability in the pharmacokinetics and pharmacodynamics of cangrelor in the paediatric population. Objectives The aim of this investigation was to characterise the pharmacokinetic-pharmacodynamic (PKPD) relationship along with age and weight-related changes in the disposition properties of cangrelor in children. Insight into the underlying PKPD relationship is expected to provide the basis for extrapolating efficacy from adults and defining the dose rationale for infants and children. Methods After a systematic review of the available literature on the pharmacokinetics (PK) and the PKPD of cangrelor, data from a Phase I study in healthy adults have been used to model the pharmacokinetics of cangrelor and derive metrics of exposure. This was followed by the evaluation of the platelet aggregation inhibition effect. Modelling and subsequent simulation steps were implemented based on a non-linear mixed effects approach, as implemented in NONMEM v.7.5. In brief, the approach relies on the assumption that the PK can be allometrically scaled from adults to children and infants. In addition, the effect of ontogeny in dephosphorylation was explored through a Michaelis-Menten function, as it appears that there is a more than proportional dose-exposure relationship in neonates (6). An Emax and an indirect response model were used to describe in a semi-mechanistic manner the relatively rapid onset and offset of the effect of cangrelor on platelet aggregation, as assessed by aggregometry in in vitro protocols, in healthy subjects and adult and neonatal patients (7). Model diagnostics (i.e., visual predictive checks, goodness-of-fit, decrease in log-likelihood) were used for model selection and evaluation. Comparison of hierarchical models was based on the likelihood ratio test and standard error of the parameter estimates. Eventually, covariate model building was implemented using a forward inclusion-backward elimination procedure. Following model evaluation and evidence of adequate predictive performance, the final model has been used to simulate individual concentration vs. time profiles in a paediatric population, testing different dosing regimens (1h IV infusion of 0.1 µg/kg/min up to 2.0 µg/kg/min), taking into account the exposure range associated with currently approved doses in adults and baseline platelets across the different age groups (i.e., 100- 150 ×10?/L in neonates, vs 136–473×10?/L, regardless of gender, under 15 years of age); Results A one-compartment pharmacokinetic model successfully described the exposure profiles reported in adults receiving a) 15 µg/kg bolus + 2 µg/kg/min infusion for 1 hour, b) 30 µg/kg bolus + 4 µg/kg/min. Predicted secondary PK parameters have been extrapolated in neonates and compared with the available published results (6). For the 0.25 µg/kg/min and 0.5 µg/kg/min dosing group, the predicted AUC0-t was 12.2 (6.9-21.2) and 48.2 (29.2-82.2) ng*h/mL, respectively, showing acceptable accordance with previous published results. Predicted Cmax was 12.3 (7-21.4) ng/mL and 48.7 (29.5-82.9) ng/mL, respectively. The use of an Emax model did not accurately describe the offset of the inhibitory effect despite the reversible binding of cangrelor to its receptor. Therefore, an indirect response model was required to account for the somewhat slower return of platelet aggregation to baseline levels. A weight-banded regimen is proposed for infants and older children, taking into account platelet counts at baseline. Differences in cangrelor potency observed in vitro and in clinical studies appear to be driven by experimental conditions (e.g., P2Y12 reaction units by VerifyNow, and concentration of ADP maximal platelet aggregation (MPA) by light transmittance aggregometry). Conclusion This study represents an initial attempt to integrate PK and PKPD data from various sources to establish the dose rationale for a treatment with high clinical value in operative settings in infants and paediatric patients. In contrast to other antiplatelet aggregation inhibitors for which metabolic processes occur exclusively through hepatic and/or renal processes, the use of allometric principles, including metabolic saturation, were sufficient to describe changes in cangrelor disposition. Moreover, variations in aggregation signalling induced by different ADP concentrations in an experimental setting do not allow for accurate extrapolation of the physiological response to trauma in patients, irrespective of age or gender. Whilst it can be assumed that the PKPD relationship of cangrelor is comparable in adults and paediatric patients, our analysis provides an initial step towards dosing recommendations that take into account age-related differences in platelet counts in infants and children.
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Reference: PAGE 33 (2025) Abstr 11520 [www.page-meeting.org/?abstract=11520]
Poster: Drug/Disease Modelling - Other Topics