Description
This guidance is intended to assist sponsors and applicants of new drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug applications (ANDAs), and investigational new drugs (IND) applications in the application of population pharmacokinetic (PK) analysis. Population PK analysis is frequently used to guide drug development and inform recommendations on therapeutic individualization (e.g., through tailored dosing) (Marshall et al. 2015; Lee et al. 2011; Bhattaram et al. 2005). Adequate population PK data collection and analyses submitted in marketing applications have in some cases alleviated the need for postmarketing requirements or postmarketing commitments.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
4alternative for evaluating the bioequivalence of long-acting injectables
Subject of GDUFA and related meeting processes.
Proteins that reduce proinflammatory cytokines and affect CYP enzyme expression
prior PK knowledge about the study drug
Stakeholders
1Entity responsible for submitting applications under section 524B
Regulatory Context
Regulatory Activities
6New Drug Application
Drug approval process under section 505 of the FD&C Act.
facilitate the regulatory review of population PK models
Biologics License Application
Abbreviated New Drug Application
Investigational New Drug submissions
Document Types
8Cybersecurity information should be included in device labeling
Recommended format for accompanying population PK analysis results
promotional materials in module 1 of the electronic common technical document (eCTD); eCTD format for submissions; eCTD submission standards and operations; Format for electronic submissions.
Defines the standard of veterinary practice and limits for anesthetic regimens
Document specifying analytic methods, sample size, and plans for resolving discrepancies
preliminary examination of the data should be described in the report
format and content for population PK reports submitted to the Agency
Prespecified questions in the population PK data analysis plan
Attributes
6intrinsic factor contributing to variability
Typical estimates used to illustrate drug-concentration profiles
Parameter accounted for in simulations to show range of individual predictions
When parameter shrinkage is high, EBEs might be less reliable
design should be sufficient to assess the presence and magnitude of effect
relationship between body weight and drug exposure
Technical Details
Substances
3variations in the pharmacokinetics of a drug over time due to anti-drug antibodies
measurement of creatinine for renal function assessment
Acid-reducing medications generally not permitted as concomitant use
Testing Methods
10Pharmacokinetic Data Analysis method; standard analysis approach for nested DDI studies; Method typically used to evaluate nested DDI studies.
Software used for assessment of type I error rates and covariate effects
General concepts and software for population PK/PD models
Used for diagnosing and modeling population pharmacokinetics
Exposure-response analyses for safety and efficacy
scenarios when non-compartmental analysis (NCA) becomes challenging
approaches for covariate analysis
approaches for covariate analysis
Used to examine the influence of a QC algorithm assuming a worst-case scenario.
simulation-based diagnostics; Type of GOF plot used for model validation
Processes
7effects of food on drug absorption
Impaired renal function can alter drug metabolism
Sponsors can combine sparse sampling with intensive PK data for population PK analysis.
Absorption, distribution, metabolism, and excretion properties evaluated for extrapolation.
Model development methods and best practice recommendations
Determining suitability of a model by challenging it with independent test data.
covariate analysis can be performed based on several approaches
Clinical Concepts
10Comorbidity affecting pharmacokinetics
Assessing uncontrolled drug-drug interactions in population PK analyses
GOF plots stratified by cytochrome (CYP) polymorphisms
influence of anti-drug antibodies on drug exposure
Safety findings including deaths and post-mortem examinations
intrinsic factor affecting drug concentrations
inform dosing regimens for testing in clinical trials
Conducting drug-drug interaction evaluations early in drug development may inform selective dosing.
Guidance does not address the development of drugs for the prevention of PONV in pediatric patients.
Condition assessed in clinical studies for PK/PD influence
Standards & References
Specifications
5Maximal concentration used as a PK parameter for BE
Exposure metric used in forest plots to illustrate covariate effects
PK measure mentioned in context of multiplicative models
Individual patient exposure metrics are generated based on Empirical Bayes Estimates (EBEs)
data below the limit of quantification (LOQ)
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter