CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS PDF

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Define and differentiate between pharmacokinetics and clinical pharmacokinetics . 2. Define pharmacodynamics and relate it to pharma- cokinetics. 3. Describe. Clinical pharmacokinetics is the discipline that describes the absorption . Pharmacodynamics is the study of the relationship between the concentration of a. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Article ( PDF Available) in Clinical Pharmacokinetics 56(8) · January.


Clinical Pharmacokinetics And Pharmacodynamics Pdf

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Article (PDF Available) in Clinical Pharmacokinetics 57(2) · May with pharmacokinetic and pharmacodynamic data as well as. Core Entrustables in Clinical Pharmacology: Pearls for Clinical Practice. The Journal of pharmacokinetics, pharmacodynamics, drug interactions, medical. Publisher's PDF, also known as Version of record. Publication date: .. pharmacokinetics/pharmacodynamics, but no clinically relevant.

A significant difference was observed between fast-acting formulations and standard ibuprofen tablets for both maximum concentration and time taken to reach it. Individual formulations had an effect on PGE2 WAI during the 8 hours following treatment, resulting in significantly lower WAI in standard ibuprofen: ibuprofen arginine Conclusion: Rapid absorption and higher peak concentration were observed in ibuprofen arginine and the solubilized ibuprofen capsule.

Additionally, fast-acting formulations had more predominant inhibitory activity on the COX2 enzyme. Keywords: ibuprofen, different formulation, COX2-inhibitory effects Introduction The severity of pain is influenced by several factors, including the amount of damage and emotional and environmental factors, and pharmacological treatment, interventional techniques, and behavioral therapies are available for pain management.

Finally, it is excreted in the form of a glucuronide-conjugate metabolite through urine. In this clinical study, the pharmacokinetic and pharmacodynamic profiles of three ibuprofen formulations were evaluated at a dose of mg, the usual prescribed dose for an analgesic effect, and the pharmacodynamic effects were compared based on time—COX inhibition relationships.

Participants were enrolled according to the following inclusion criteria: body mass index of The objective and contents were fully explained, and written informed consent was obtained. The 36 participants were randomly assigned to one of six sequences of the three treatments. Participants received the study drugs with mL of water after an overnight fast of 10 hours and were discharged 24 hours following the treatment.

A washout interval of 7 days was required from the last dose of the previous treatment period. Pharmacokinetic and pharmacodynamic assessment Blood samples for pharmacokinetic evaluation were obtained before dosing 0 hour and 0. For pharmacodynamic evaluation of PGE2, blood samples were collected at 0, 0. The plasma specimens were mixed with methanol in the presence of an internal standard ibuprofen-d3. The flow rate was 0.

The calibration curves were linear within the range of 0. PGE2 is synthesized and released into the extracellular space when cells are activated or exogenous free arachidonate is supplied. Both samples and standards were assayed in parallel. This assay typically develops in 1. The time to the maximum concentration observed in plasma Tmax and maximum observed plasma concentration Cmax were directly obtained from the plasma concentration—time profiles. The area under the plasma concentration—time curve AUC0—t after the administration of the study drug was calculated by the linear-up and log-down trapezoidal method.

The observed Tmax was assessed from the PGE2-inhibition time course. There were INR values obtained in the study. Being serious in nature of the heart disease, the compliance of the enrolled patients in the study was relatively low. These CHD patients with AF had been taking warfarin for a long period of time to decrease the risk of thromboembolic complications. The underlying conditions included hypertension Various medications were concomitantly used in the patients due to its complicated property of the disease.

Identification of the effect of CDDP on profiles of PK and PD of warfarin were established on a self-control design, maintaining all concomitant medications except warfarin from beginning to end of trial. The PK behavior of warfarin, S-warfarin and R-warfarin was in accordance with one-compartment model or two-compartment model based on literatures Jiang et al.

The One-compartment models were more optimal and reasonable for warfarin, either S-warfarin or R-warfarin in our study. There had a great variation of Ka with a higher RSE Moreover, there were few reports to evaluate the absorption of warfarin due to its high bioavailability. During 2 years follow-up, many patients still took the combination for a long time, and there were no report about bleeding. However, this was not a randomized clinical trial, some researches would be needed to further demonstrate the clinical efficacy.

CLv and YH wrote the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We wish to thank all those who volunteered to participate in this study. National Center for Biotechnology Information , U. Journal List Front Pharmacol v. Front Pharmacol. Published online Nov Author information Article notes Copyright and License information Disclaimer.

Edited by: Reviewed by: Domenico Criscuolo, Genovax S. Lins, Retired, Antwerpen, Belgium. Yuhong Huang, moc.

This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology. Received Aug 28; Accepted Oct The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.

No use, distribution or reproduction is permitted which does not comply with these terms. Abstract Warfarin is used as anticoagulant and Compound Danshen prescription CDP is able to promote blood circulation. Materials and Methods Patients The study was conducted in four hospitals in Tianjin from November to January Genotyping The information of genes which affect the metabolism of warfarin was obtained by literatures Lin G.

Bioanalysis Plasma warfarin concentrations were determined using a high-performance liquid chromatography tandem mass spectrometry method.

PK Model Development Structural Model After inspection of the PK profiles, a one-compartment model with first-order absorption was adopted as the optimal base model for warfarin, R-warfarin, and S-warfarin. Covariate Models These covariates were first explored graphically and each potential covariate individually added to the base model if graphical trends were shown.

In our research, the covariate of weight was described by allometric scaling equation: Bootstrap A nonparametric bootstrap analysis was used to assess the stability of the parameter estimates and to confirm the robustness of the models.

Results Patients Sixty-four patients were enrolled from four hospitals in Tianjin from November to January Table 1 The demographic profile summary for subjects. Open in a separate window. Fixed Dose and Concentration of Warfarin In the two periods, the fixed doses of warfarin were 3. Table 2 The fixed dose and blood concentrations for patients in the first and second period.

Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

Table 3 The INR value, four indicators of blood coagulation, and seattle angina questionnaire SAQ for patients in the first and second period. Covariate Models for PK Models Once the base structural models were established, potentially significant covariates were evaluated as described.

RE sd 0. RE sd 0 FIX. RE SD 0. Discussion In this study a total of blood samples, instead of as required by protocol eight for each patient , were collected for warfarin assay. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References Agarwal N. A phase I clinical trial of the effect of belinostat on the pharmacokinetics and pharmacodynamics of warfarin. Cancer Chemother. Oral anticoagulation to reduce risk of stroke in patients with atrial fibrillation: Aging 8 75— Quantitative assessment of CYP2C9 genetic polymorphisms effect on the oral clearance of S -Warfarin in healthy subjects.

The effect of compound Danshen dripping pills, a Chinese herb medicine, on the pharmacokinetics and pharmacodynamics of warfarin in rats. Timely initiation of therapy and rigorous adherence to the prescribed treatment are imperative for successful management of ACS. Failure to comply with these requirements, e. Ho et al. Interventions, such as follow up by phone, checking refill histories or monitoring clinical registries, have resulted in significantly improved compliance to clopidogrel therapy [ , ].

In recent years, variability in clopidogrel response has become an increasingly important clinical issue with potentially severe consequences [ 3 ]. Therefore, it becomes imperative to understand the key factors that contribute to the high between-subject variability in response to clopidogrel treatment, particularly to clopidogrel resistance.

In this paper we systematically reviewed known pharmacokinetic, pharmacodynamic as well as genetic and non-genetic factors that contribute to interindividual differences in response to clopidogrel therapy and evaluated how they relate to clinical outcome cf. Summary of factors that may affect clopidogrel pharmacokinetics, pharmacodynamics and clinical outcome.

Summary of demographic, genetic, drug- and disease-mediated factors influencing antiplatelet therapy with clopidogrel. To date, numerous clinical studies have been conducted to investigate the potential cause of clopidogrel resistance.

Most of these studies were either conducted to answer one specific question e. This in part due to the fact that suboptimal response to clopidogrel treatment, both in terms of efficacy and safety, is a multifactorial problem that is difficult to address in one-off clinical trials that evaluate only one or only a few factors at a time.

These quantitative approaches in combination with clinical trials may help to overcome this limitation as they allow to interpret and to compare information from head-to-head clinical trials and to evaluate the impact of different genetic and non-genetic factors as well as their interplay on clinical outcome. The use of quantitative approaches may further allow to performing cost-effectiveness analyses for single as well as combination antiplatelet therapy and, ultimately, guide clinical and health-policy decision-making.

In order to understand the relative contribution of each of these factors to the overall variability in treatment response, sufficient understanding of the underlying pharmacokinetics PK and pharmacodynamics PD is needed.

Once established and qualified, this qualitative and quantitative link can then be used to translate genetic and clinical information into actionable dosing recommendations and thus help to personalize clopidogrel therapy on a patient-by-patient basis.

National Center for Biotechnology Information , U. Clin Pharmacokinet. Author manuscript; available in PMC Nov 8. Author information Copyright and License information Disclaimer. Stephan Schmidt, Ph.

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Copyright notice. The publisher's final edited version of this article is available at Clin Pharmacokinet. See other articles in PMC that cite the published article. Abstract Acute coronary syndromes ACS remain life-threatening disorders that are associated with high morbidity and mortality.

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Introduction Cardiovascular disease CVD is currently the leading cause of death worldwide [ 1 ]. Open in a separate window. Figure 1. Figure 2. Summary and future perspectives In recent years, variability in clopidogrel response has become an increasingly important clinical issue with potentially severe consequences [ 3 ]. Table 1 Summary of factors that may affect clopidogrel pharmacokinetics, pharmacodynamics and clinical outcome. Increase in both cardiovascular events [ 5 , 16 , 42 — 44 ] and bleeding [ 45 , 46 ].

Obesity Lower systemic exposure to clop-AM [ ] Higher on-treatment platelet reactivity [ 14 , 41 , 47 ]. Inconclusive obesity paradox [ 16 , 42 , 45 , 52 , 53 ]. Minimal impact on cardiovascular risk [ , — ] Statins No negative effect on systemic exposure to clop- AM [ ]. No negative effect on on-treatment platelet reactivity [ , , — ].

Table 2 Summary of demographic, genetic, drug- and disease-mediated factors influencing antiplatelet therapy with clopidogrel. References 1. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Executive summary: J Am Coll Cardiol.

Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants. Br J Clin Pharmacol. Clopidogrel discontinuation after acute coronary syndromes: Role of clopidogrel in managing atherothrombotic cardiovascular disease.

Annals of internal medicine. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. Pharmacogenomics of anti-platelet therapy: Journal of human genetics.

Clopidogrel resistance?

Thromb Res. Identification of the human cytochrome P enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite.

Drug Metab Dispos.

Reduced effectiveness of Plavix clopidogrel in patients who are poor metabolizers of the drug. Association of cytochrome P 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. Phenotyping vs. J Thromb Haemost. Genetic determinants of response to clopidogrel and cardiovascular events. Cytochrome P 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.

Cytochrome p polymorphisms and response to clopidogrel. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms CYP2C19, ABCB1, PON1 , noncompliance, diet, smoking, co-medications including proton pump inhibitors , and pre-existent variability in platelet function. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate.

Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation. J Pharmacol Exp Ther. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. Journal of chromatography B, Analytical technologies in the biomedical and life sciences. Absorption, metabolization, and antiplatelet effects of , , and mg loading doses of clopidogrel: Pharmacokinetics of clopidogrel.

Semin Thromb Hemost. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. High doses of clopidogrel to overcome genetic resistance: Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers.

Pharmacokinetics and pharmacodynamics of febuxostat under fasting conditions in healthy individuals

J Clin Pharmacol. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of prasugrel.

Clinical pharmacokinetics. High platelet reactivity and antiplatelet therapy resistance. High on treatment platelet reactivity.

Heart Lung Circ. Platelet function monitoring in patients with coronary artery disease. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: High platelet reactivity and clinical outcome - fact and fiction.

Thromb Haemost. Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients.

Am J Cardiol. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: Genetic determinants of clopidogrel responsiveness in Koreans treated with drug-eluting stents. International journal of cardiology. Impact of cytochrome P 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement.

Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes. Clopidogrel use and early outcomes among older patients receiving a drug-eluting coronary artery stent. Circulation Cardiovascular quality and outcomes. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.

Profile of bleeding and ischaemic complications with bivalirudin and unfractionated heparin after percutaneous coronary intervention. Safety of clopidogrel in older patients: Platelet aggregation according to body mass index in patients undergoing coronary stenting: J Invasive Cardiol. Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients.

J Thromb Thrombolysis. Impact of obesity on drug metabolism and elimination in adults and children. Regulation of carboxylesterase 1 CES1 in human adipose tissue. Biochemical and biophysical research communications. Depot-specific expression of lipolytic genes in human adipose tissues--association among CES1 expression, triglyceride lipase activity and adiposity.

Journal of atherosclerosis and thrombosis. Is there an obesity paradox after percutaneous coronary intervention in the contemporary era? An analysis from a multicenter Australian registry. The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease.

Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents

Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. Diabetes and mortality following acute coronary syndromes. No association of ABCB1 CT genotype with clopidogrel response or risk of stent thrombosis in patients undergoing coronary stenting. Circ Cardiovasc Interv. The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response.

Predicting clopidogrel response using DNA samples linked to an electronic health record. PLoS One. Standard-Dose Clopidogrel. The functional GE variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.

Pharmacogenet Genomics. A single nucleotide polymorphism in the carboxylesterase gene is associated with the responsiveness to imidapril medication and the promoter activity.

Hypertension research: CES1A C as a genetic marker to predict greater platelet clopidogrel response in patients with percutaneous coronary intervention. J Cardiovasc Pharmacol. Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes. The pharmacogenomics journal. Clinical significance of the cytochrome P 2C19 genetic polymorphism. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment.

Cytochrome P 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients.

Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. No association of paraoxonase-1 QR genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel.

Challenges and Limitations in the Interpretation of Systematic Reviews: The relation between CYP2C19 genotype and phenotype in stented patients on maintenance dual antiplatelet therapy. Am Heart J. Mechanism-based inactivation of human cytochrome P 2B6 by clopidogrel: Mol Pharmacol.ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The bootstrap sample datasets were re-sampled from random sampling with replacement from the original data using individual as sampling unit.

Clopidogrel and PPI interaction: Propofol readily crosses the blood—brain barrier BBB and causes rapid loss of consciousness sometimes within the time it takes for a drug to pass through the circulation once [ 27 ].

These factors may induce aberrant metabolism of purines resulting in excessive UA formation 2 , 3.

Journal of atherosclerosis and thrombosis. Dual-antiplatelet therapy with aspirin and clopidogrel has shown to reduce cardiovascular events in patients with ACS. The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease. Renal function and outcomes in acute coronary syndrome:

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