Usage Examples
- The dose-ranging Phase 1 PK study established linear pharmacokinetics across the evaluated dose range.
- Population PK modeling supported dosing recommendations in renal impairment and pediatric populations.
- Clinical Pharmacology called the PK bridging package inadequate to justify the proposed 505(b)(2) dose.
What is Pharmacokinetics (PK)?
Pharmacokinetics is the quantitative description of what the body does to a drug over time: absorption, distribution, metabolism, and excretion, summarized as exposure parameters such as Cmax, AUC, clearance, and half-life that set dose and dosing interval.
Pharmacokinetics exists because a dose is not an exposure. The same milligram amount produces different plasma concentrations in different patients depending on absorption, hepatic metabolism, renal clearance, and protein binding. Pharmacokinetics converts an administered dose into the concentration-time profile that actually drives efficacy and toxicity, which is the quantity a regulator can reason about when deciding whether a dosing regimen is safe.
Pharmacokinetics covers absorption, distribution, metabolism, and excretion, plus every parameter derived from a concentration-time curve: Cmax, Tmax, AUC, clearance, volume of distribution, and half-life. Pharmacokinetics does not cover what the drug does to the body. Receptor occupancy, effect size, and exposure-response belong to pharmacodynamics, and bioequivalence is a regulatory conclusion drawn from pharmacokinetic data rather than a part of pharmacokinetics itself.
Pharmacokinetics is applied through a defined study set and the modeling built on it: single and multiple ascending dose, food effect, mass balance, renal and hepatic impairment, drug interaction studies, and population analyses that pool sparse samples across trials. In an eCTD submission, pharmacokinetics is summarized in Module 2.7 and reported in full in Module 5.3.
Not to be confused with
- Pharmacodynamics (PD)
- pharmacodynamics measures effect against concentration, what the drug does to the body. Pharmacokinetics measures concentration against time, what the body does to the drug. PK sets the exposure; PD determines what that exposure achieves.
- Bioavailability
- bioavailability is one quantity derived from pharmacokinetic data, the rate and extent to which the active moiety reaches systemic circulation. Pharmacokinetics is the full concentration-time characterization from which bioavailability is calculated.
- Bioequivalence
- bioequivalence is a regulatory conclusion that two products deliver comparable exposure. Pharmacokinetics is the measurement discipline that produces the Cmax and AUC data the conclusion is tested against; 21 CFR 320.24 ranks the acceptable ways to produce it.
- Toxicokinetics
- toxicokinetics applies the same concentration-time measurement inside nonclinical toxicology studies, to tie animal exposure to observed toxicity and set safety margins. Clinical pharmacokinetics characterizes human exposure to support a dosing regimen.
Pharmacokinetic obligations attach to the applicant, not the CRO or the bioanalytical vendor. These are the anchors in the NDA content rule and 21 CFR Part 320.
What you must do
- 1File a human pharmacokinetics and bioavailability section in the NDA that presents the human pharmacokinetic and bioavailability data, or the information supporting a waiver of in vivo bioavailability data21 CFR 314.50(d)(3)
- 2Include in every full new drug application either evidence measuring the in vivo bioavailability of the drug product or information permitting FDA to waive that evidence21 CFR 320.21(a)
- 3Generate the pharmacokinetic evidence as an in vivo test in humans measuring active-ingredient or active-moiety concentration, and where appropriate active metabolites, in whole blood, plasma, serum, or other appropriate biological fluid as a function of time21 CFR 320.24(b)(1)
- 4Select the study approach from FDA's ranked list, which orders acceptable in vivo and in vitro approaches in descending order of accuracy, sensitivity, and reproducibility21 CFR 320.24
- 5Demonstrate that the bioanalytical method is accurate and of sufficient sensitivity to measure, with appropriate precision, the actual concentration achieved in the body21 CFR 320.29
Common mistakes
Assuming an earlier PK package carries a late formulation change
21 CFR 320.21(a) puts the burden on the applicant to submit in vivo bioavailability evidence, or a waiver justification, in the application itself. Teams that change formulation or manufacturing site during Phase 3 and file on the old data find the gap at filing review, when closing it costs a fresh study and a review cycle.
Reporting concentrations from a bioanalytical method never shown fit for purpose
the standard in 21 CFR 320.29 is accuracy and sufficient sensitivity to measure the actual concentration achieved in the body. An assay whose lower limit of quantitation sits above terminal-phase concentrations truncates AUC and half-life, and every downstream clearance estimate, dose justification, and interaction conclusion inherits that error.
Dosing humans for data a waiver or a lower-tier approach could have supported
21 CFR 314.50(d)(3) accepts information supporting a waiver of in vivo bioavailability data in place of the data itself, and 21 CFR 320.24 ranks acceptable in vivo and in vitro approaches in descending order of accuracy, sensitivity, and reproducibility. Enrolling subjects for a study a biowaiver package would have covered costs clinic budget and months of timeline.
When This Matters
- The dose-ranging Phase 1 PK study established linear pharmacokinetics across the evaluated dose range.
- Population PK modeling supported dosing recommendations in renal impairment and pediatric populations.
- Clinical Pharmacology called the PK bridging package inadequate to justify the proposed 505(b)(2) dose.
Frequently Asked Questions
Pharmacokinetics is what the body does to the drug; pharmacodynamics is what the drug does to the body. Pharmacokinetics measures concentration against time and yields Cmax, AUC, clearance, and half-life. Pharmacodynamics measures effect against concentration. Dose selection needs both, linked through exposure-response analysis, because exposure alone does not justify a regimen.
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