Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects

Liu, Shuaibing; Xue, Liang; Shi, Xiaoguang; Sun, Zhenchang; Zhu, Zhenfeng; Zhang, Xiaojian; Tian, Xin

doi:10.1007/s00228-018-2427-3

Cited by 13 publications

(8 citation statements)

References 20 publications

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“…Data from a clinical trial further corroborated the finding that the CYP3A4*22 allele impaired the elimination and increased the exposure of ticagrelor in healthy Finnish volunteers of Caucasian ethnicity (Holmberg et al, 2019). Furthermore, the CYP3A4*1G allele also increased the clearance of its active metabolite, AR-C124910XX, and had no effect on the PK of ticagrelor in healthy Chinese volunteers (Liu et al, 2018). Moreover, genetic variants of SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), and CYP3A5*3 (rs776746) were also reported to have no relevance in the PK of ticagrelor in healthy Chinese volunteers (Li et al, 2017a).…”

Section: Introductionsupporting

confidence: 52%

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

et al. 2022

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Background: Ticagrelor belongs to a new class of P2Y12 receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX.Methods: The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography–tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing.Results: Female participants had a higher maximum plasma concentration/weight ratio (Cmax/W; p < 0.001) and a shorter half-life (T1/2; p < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/W; p < 0.001), and longer T1/2 (p < 0.001) and time to reach the maximum plasma concentration (Tmax; p < 0.001), as well as a lower apparent drug clearance (CL/F; p < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher Cmax/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (Vd/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher Cmax/W (p < 0.001) and AUC/W (p < 0.01), shorter Tmax (p < 0.001), and lower CL/F (p < 0.001) and Vd/F (p < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the CYP4F2 rs2074900 A/A carriers were associated with higher Cmax/W and AUC/W and lower CL/F and Vd/F than the CYP4F2 rs2074900 A/G and G/G carriers.Conclusion: This study is the first to show that the CYP4F2 rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.

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Section: Introductionsupporting

confidence: 52%

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

et al. 2022

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“…The EC50 for TAM is much lower at 98.5 nmol/L. The model presented here is different from others in literature 14,18 where the relationship is either modeled as a sum of TICA and TAM or just TICA alone. The model presented here fits the placebo data (subjects who received TICA plus a placebo) well, suggesting that the model here performs as well as those used elsewhere.…”

Section: Discussionmentioning

confidence: 62%

Population pharmacokinetic–pharmacodynamic modeling of PB2452, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers

Kathman

Wheeler

Bhatt

et al. 2021

CPT Pharmacom & Syst Pharma

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PB2452, a neutralizing monoclonal antibody fragment that binds the antiplatelet drug ticagrelor with high affinity, is being developed as a ticagrelor reversal agent.To identify a clinically useful intravenous (i.v.) reversal regimen, a semimechanistic exposure-response model was developed during the PB2452 first-in-human phase I study. From a randomized, double-blind, placebo-controlled, single-dose trial to evaluate the safety, efficacy, and pharmacokinetics (PKs) of PB2452 in 61 healthy volunteers pretreated with ticagrelor, sequential dose cohort data were used to build and refine an exposure-response model that combined population PK models for ticagrelor (TICA), ticagrelor active metabolite (TAM), and PB2452, and related their binding relationships to the PK of uncomplexed TICA and TAM which is predictive of platelet inhibition. Platelet function was assessed by multiple assays. The model was developed using Bayesian methods in NONMEM.Human PK and pharmacodynamic data from sequential dose cohorts were used to initially define and then refine model parameters. Model simulations indicated that an initial i.v. bolus of PB2452, followed by a high-rate infusion, and then a slower-rate infusion would provide immediate and sustained reversal of the antiplatelet effects of ticagrelor. Based on model predictions, a 6 g i.v. bolus followed by 6 g infused over 4 h and then 6 g over 12 h was identified and tested in study subjects and shown to provide complete reversal within 5 min of infusion onset that was sustained for 20-24 h. The model is predictive of the reversal profile of PB2452 and will inform future trials of PB2452. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Ticagrelor (TICA) is a direct acting, reversibly binding, oral P2Y 12 receptor antagonist. PB2452 (bentracimab), a neutralizing monoclonal antibody fragment that binds the antiplatelet drug TICA with high affinity, is being developed as a TICA reversal agent.

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“…Because ticagrelor is a substrate of P‐glycoprotein (P‐gp), the levels of which are higher in men than in women, it is speculated that the effect of ticagrelor on metabolite clearance may be related to sex differences. Few factors influence the PKs of ticagrelor, and the most common ones that have been reported are gender and age as significant covariates in PopPK models of ticagrelor and AR‐C124910XX 17,27 . Among them, the PopPK model of ticagrelor developed by Li et al 28 .…”

Section: Discussionmentioning

confidence: 99%

“…15,16 Liu et al reported that the serum levels of ticagrelor correlate with the bleeding risk in Chinese patients. 17 Thus, adjusting the ticagrelor dose in Chinese patients with ACS might be a potential way to reduce the risk of bleeding in these patients.…”

Section: Articlementioning

confidence: 99%

Model‐Informed Dosing Regimen of Ticagrelor in Chinese Patients With Acute Coronary Syndrome

Liu,

Kuang,

Hai

et al. 2023

Clin Pharma and Therapeutics

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The exposure to ticagrelor (BRILINTA) is higher in the East Asian population compared with the White population, thus, East Asians have an increased risk of bleeding. We developed a population pharmacokinetic (PopPK) model of ticagrelor based on a randomized 3 × 3 crossover study in healthy subjects. The area under the concentration‐time curve (AUC) of Chinese patients with acute coronary syndrome was simulated based on this model. Following this, eight machine learning (ML) methods were used to construct bleeding risk models. Variables included in the final bleeding risk model were age, hypertension, body weight, AUC, drinking status, calcium channel blockers, antidiabetic medications, β‐blockers, peripheral vascular disease, diabetes, transient ischemic attack, sex, and proton pump inhibitor. In terms of F1 scores and area under the curve of receiver operating characteristic curve (ROC‐AUC), the Random Forest model performed best among all models, with an F1 score of 0.73 and ROC‐AUC of 0.81. Moreover, the PopPK model and ML algorithm were used to bridge the real‐world data to build a bleeding risk prediction model based on drug exposure and clinical information. Using this model, a ticagrelor regimen that is associated with a lower risk of bleeding in individuals can be obtained. This model should be further validated prospectively in clinical settings.

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Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects

Cited by 13 publications

References 20 publications

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers

Population pharmacokinetic–pharmacodynamic modeling of PB2452, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers

Model‐Informed Dosing Regimen of Ticagrelor in Chinese Patients With Acute Coronary Syndrome

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