According to the guideline, assessment of the PK of a drug in healthy subjects and/or patients is considered critical to designing dosing strategies and titration steps, to anticipating the effects of concomitant drug use, and to interpreting observed pharmacodynamic differences. These assessments should provide a description of the body's handling of a drug over time, focusing on maximum plasma concentrations (peak exposure), area-undercurve (total exposure), clearance, and accumulation of the parent drug and its metabolite(s), in particular those that have pharmacological activity. The PK studies are generally designed to (i) measure plasma drug and metabolite concentrations over time, (ii) measure drug and metabolite concentrations in urine or feces when useful or necessary, and/or (iii) measure drug and metabolite binding to protein or red blood cells.
On occasion, PK studies may include measurement of drug distribution into other body tissues, body organs, or fluids (e.g., synovial fluid or cerebrospinal fluid). These studies should characterize the drug's PK and provide information about the absorption, distribution, metabolism, and excretion of a drug and any active metabolites in healthy subjects and/or patients. Studies of mass balance and changes in PK related to dose (e.g., determination of dose proportionality) or time (e.g., due to enzyme induction or formation of antibodies) are of particular interest. Additional studies can also assess differences in systemic exposure as a result of changes in PK due to intrinsic (e.g., age, gender, racial, weight, height, disease, genetic polymorphism, and organ dysfunction) and extrinsic (e.g., drug-drug interactions, diet, smoking, and alcohol use) factors. In addition to standard multiple-sample PK studies, population PK analyses based on sparse sampling during clinical studies can also address questions about the contributions of intrinsic and extrinsic factors to the variability in the dosePK-response relationship. Thus, the guideline identifies the following types of studies as Human PK studies: Healthy subject PK and initial tolerability; Patient PK and initial tolerability; Intrinsic factor PK; Extrinsic factor PK; and Population PK.
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