Pharmacometrics
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This document discusses pharmacometrics, which involves analyzing and interpreting pharmacological data through quantitative models to improve drug development and patient outcomes. It describes using pharmacokinetic, pharmacodynamic, and pharmacokinetic/pharmacodynamic models to understand dose-exposure-response relationships and optimize dosing strategies. Population modeling and stochastic simulation are also covered as tools to estimate parameters from sparse data and evaluate study designs. Examples demonstrate how pharmacometrics informed decisions that improved drug development or approval processes. Software and online resources relevant to pharmacometrics are also listed.
Pharmacometrics
- 1. Pharmacometrics- Quantitative Systems Pharmacology Shivankan Kakkar, MD Assistant Professor, SMS Medical College Hospital, Jaipur, INDIA
- 2. “Measuring Pharmacology” Through- Pharmacokinetic (PK) models, Pharmacodynamic (PD) models, Pharmacodynamic-biomarker–outcomes link models, Data visualization, Statistics, Stochastic Simulation, and Computer Programming.
- 4. Introduction Pharmacometrics is concerned with the analysis and interpretation of pharmacological data. The aim is to enhance the quantitative understanding of how drug treatments impact human biology and to improve outcomes for patients. Through pharmacometrics one can quantify the uncertainty of information about model behavior and rationalize knowledge-driven decision making in the drug development process.
- 5. Pharmacometrics Drug Development and Pharmacotherapy When applied to drug development, pharmacometrics often involves the development or estimation of pharmacokinetic, pharmacodynamic, pharmcodynamic–outcomes linking, and disease progression models. These models can be linked and applied to competing study designs to aid in understanding the impact of varying dosing strategies, patient selection criteria, differing statistical methods, and different study endpoints. In the realm of pharmacotherapy, pharmacometrics can be employed to customize patient drug therapy through therapeutic drug monitoring and improved population dosing strategies.
- 6. PK, PD and PK/PD modeling PK linked to PD Pharmacometrics begins with pharmacokinetics PK. Rational drug therapy is based on the assumption of a causal relationship between exposure and response. PK has great utility when linked to pharmacodynamics PD and the examination of PD is of paramount importance. PD most often involves mathematical models, which relate some concentration (serum, blood, urine) to a physiologic effect (blood pressure, liver function tests) and clinical outcome (survival, adverse effect). PK/PD modeling provides the seamless integration of PK and PD models to arrive at an enlightened understanding of the dose–exposure–response relationship. PK/PD modeling can be done either sequentially or simultaneously.
- 7. ● NONMEM ● WinNonlin ● XLMEM ● Boomer ● JGuiB ● TOPFIT ● ADAPT II Softwares used in PK/PD modeling
- 8. Biomarkers Biomarkers Definitions Working Group (BDWG) “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic process or pharmacologic responses to a therapeutic intervention.” Biomarkers often have the advantage of changing in drug therapy prior to the clinical endpoint that will ultimately be employed to determine drug effect, thus providing evidence early in clinical drug development of potential efficacy or safety. A surrogate endpoint is “a biomarker that is intended to substitute for a clinical endpoint.”
- 9. Population Modeling The PM With the advent of population approaches, one could now obtain estimates of PM parameters from sparse data from large databases and also obtain improved estimates of the random effects (variances) in the parameters of interest. These models first found great applicability by taking massive amounts of data obtained during therapeutic drug monitoring (TDM) from which typical values and variability of PK parameters were obtained. These are helpful in estimating initial doses optimizing the dosing strategies. Population methods are applied to pharmacokinetics, pharmacodynamics, and models linking biomarkers to clinical outcomes.
- 10. Stochastic Simulation Stochastic is “Random probable distribution” Stochastic simulation is another step forward in the arena of pharmacometrics. Simulation had been widely used in the aerospace industry, engineering, and econometrics prior to its application in pharmacometrics. “Simulation is a useful tool to provide convincing objective evidence of the merits of a proposed study design and analysis. Simulating a planned study offers a potentially useful tool for evaluating and understanding the consequences of different study designs”
- 11. Examples of benefits 1. Propose best doses 2. Rescue discarding good drug 3. Maximizing value of prior data 1. Highly variable PK of Tacrolimus between ulcerative colitis patients in Phase II studies presented challenges to further development. Simulation of dose titration based on exposure-response was effective for identifying target trough concentration, demonstrating effectiveness and justifying Phase III studies. 2. A new dosing regimen was selected based on pharmacometric analyses and evaluated in an additional clinical trial. Nesiritide was finally approved by FDA. 3. Approval of oxcarbazepine monotherapy in pediatrics was based on demonstrating similar exposure –response relationship for seizure frequency in pediatrics and adults using prior data from adjunctive therapy trials. No additional monotherapy pediatric trials were required.
- 12. Materials
- 13. DDMoRe DDMoRe Foundation: http://www.ddmore.foundation The Drug Disease Model Resources (DDMoRe) Foundation maintains and drives development of a universally applicable, open source, model based framework, intended as the gold standard for future collaborative drug and disease Modelling & Simulation. The DDMoRe Model Repository provides a community-driven, fully-searchable hub for storing published and unpublished pharmacometric models. The DDMoRe Language Community provides a resource for encoding models with model description language MDL, helps with understanding MDL structure and features, and provides a place for logging bugs, issues, feature requests and suggestions.
- 14. 1 Interactive Clinical Pharmacology The site has been designed to increase understanding of important and sometimes difficult concepts and principles in Clinical Pharmacology. It has been developed using JavaScript to enable user interaction. A hands-on exercise will help understanding the utility of this website. A must visit site based on Instant Clinical Pharmacology by Evan J. Begg.
- 15. Online Learning Options A Basic understanding of Pharmacokinetic and Clinical Pharmacology principles may be useful prior to more in depth study of pharmacometrics. The following are some online resources in these two disciplines. Pharmacokinetic Courses: Basic Pharmacology. A course by David Bourne from the University of Oklahoma. Clinical Pharmacology Course: Principles of Clinical Pharmacology. This is a comprehensive course sponsored by NIH Clinical Center. It has videos of lectures and downloadable slides.