Dataset Information

Pharmacokinetic Modeling of Morphine's Effect on Plasma Concentrations of Ticagrelor and Its Metabolite in Healthy Volunteers.

ABSTRACT: This study aimed to build a mathematical model describing the pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) in a stable setting with concomitant administration of morphine. The model consists of a set of four differential equations prepared upon the available knowledge regarding the biological processes in the pharmacokinetics of ticagrelor. The set of equations was solved numerically using the Runge-Kutta method. The data were obtained in a double-blind, randomized, placebo-controlled, crossover trial. Twenty-four healthy volunteers received a 180-mg ticagrelor loading dose together with either 5-mg morphine or placebo. Blood samples were analyzed with liquid chromatography-tandem mass spectrometry to assess plasma concentrations of ticagrelor and AR-C124910XX before ticagrelor loading dose and after that 1, 2, 3, 4, and 6 h. The model allowed us to reproduce the experimental results accurately and led us to conclusions consistent with clinical observations that morphine delays the time of maximum drug concentration and that the morphine effect occurs due to decreased gastrointestinal motility. Based on the model, we were able to predict the effect of drug dose on receptor blocking efficacy.

SUBMITTER: Buszko K

PROVIDER: S-EPMC8264498 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Pharmacokinetic Modeling of Morphine's Effect on Plasma Concentrations of Ticagrelor and Its Metabolite in Healthy Volunteers.

Buszko Katarzyna K Kubica Krystian K Hobl Eva-Luise EL Adamski Piotr P Wnuk Kacper K Jilma Bernd B Kubica Jacek J

Frontiers in physiology 20210624

This study aimed to build a mathematical model describing the pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) in a stable setting with concomitant administration of morphine. The model consists of a set of four differential equations prepared upon the available knowledge regarding the biological processes in the pharmacokinetics of ticagrelor. The set of equations was solved numerically using the Runge-Kutta method. The data were obtained in a double-blind, randomized, pl ...[more]

PMID: 34248659

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Project description: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 (C max/W; p < 0.001) and a shorter half-life (T 1/2; 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 T 1/2 (p < 0.001) and time to reach the maximum plasma concentration (T max; 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 C max/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (V d/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher C max/W (p < 0.001) and AUC/W (p < 0.01), shorter T max (p < 0.001), and lower CL/F (p < 0.001) and V d/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 C max/W and AUC/W and lower CL/F and V d/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.

Project description:BackgroundSeveral opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin.MethodsIn this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes.ResultsRifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters.ConclusionsRifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.

Dataset Information

Pharmacokinetic Modeling of Morphine's Effect on Plasma Concentrations of Ticagrelor and Its Metabolite in Healthy Volunteers.

Publications

Pharmacokinetic Modeling of Morphine's Effect on Plasma Concentrations of Ticagrelor and Its Metabolite in Healthy Volunteers.

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