Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults

Abstract

Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel’s dose–concentration–response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel’s bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.

Identifying clinically relevant sources of variability: The clopidogrel challenge

“…The model integrated information on in vitro enzyme kinetic data, blood flow, as well as genetic and nongenetic covariates, in particular CYP2C19 polymorphisms, into a single, unifying approach. Once developed, the model was externally qualified using a subset of 138 healthy adults from the PAPI study who were not used for model development ( Figure ) . The observed and model predicted MPA for the CYP2C19 EMs, IMs, and PMs from PAPI evaluation dataset are in close agreement ( Figure ).…”

“…CLOP's absorption from the gut (A 1 ) to the liver (A 2 ) following oral drug administration was described by a transit compartment model ( Figure ) ( Supplementary Information ) . The fraction of the oral dose absorbed from the gut entering the liver ( F a ) was fixed to 0.5 for the 75 mg CLOP dose based on the urinary metabolite and fecal recovery 14C‐labeled data…”

“…The developed pop‐PK/PD model was used to characterize CLOP and CLOP‐AM plasma concentrations and MPA measurements from 486 healthy Amish subjects in the PGXB2B and PAPI studies. The study details have been previously described in detail …”

“…1 Genetic polymorphisms in CYP enzymes and/or CYPmediated drug-drug interactions (DDIs) have received particular attention for their association with between-subject variability in response to CLOP treatment. 1,2,[11][12][13] CYP2C19 loss-of-function (LOF) polymorphisms (*2 or *3), age, obesity, high pretreatment platelet reactivity, diabetes mellitus, smoking, DDIs with proton pump inhibitors (PPIs), calcium channel blockers (CCBs), and angiotensin converting enzyme inhibitors (ACE inhibitors) have been identified as potential covariates mediating interindividual differences in response to CLOP treatment. 2,14 There is a considerable body of evidence that links CYP2C19 LOF polymorphisms to an increased risk of adverse ischemic events, especially stent thrombosis in high-risk patients undergoing PCI and receiving dual antiplatelet therapy.…”

“…First, we developed a mechanism-based model that considers CLOP's absorption from the gut following oral administration, its two-step bioactivation via five different CYP enzymes as well as its breakdown via CES1 in the liver, and CLOP-AM's irreversible binding to P2Y 12 receptors on the surface of platelets ( Figure 1). 11,13 In contrast to most published pop-PK/PD analyses, we did not estimate all of the structural model parameters but rather used an in vitro-in vivo correlation (IVIVC) approach, to compute the intrinsic clearance values for each of the five CYP enzymes involved in CLOP's bioactivation ( Table 2). 8 We accounted for the effect of CYP2C19 LOF polymorphism by decreasing CYP2C19 activity for carriers of one LOF allele by 50% and for carriers of two LOF alleles by 100%.…”