4.2.2.3 — Distribution

Tissue distribution studies including plasma protein binding and tissue uptake

Requirements by Phase

IND Phase 1: basic IND Phase 2: full IND Phase 3: required NDA: required

Content Requirements

• Tissue distribution studies (quantitative whole-body autoradiography or similar)
• Protein binding and distribution in blood cells
• Placental transfer studies
• Volume of distribution estimates

Expected Deliverables

• Tissue distribution study report
• Protein binding summary table
• Placental transfer report (if performed)

ICH Guidelines: M3(R2)

Regulatory Requirements (FDA IND PHASE 1)

• [All phases] If known, this section should contain: 1) a description of the pharmacologic effects and mechanism(s) of actions of the drug in animals, and 2) information on the absorption, distribution, metabolism, and excretions of the drug.
• [All phases] A summary report, without individual animal records or individual study results, usually suffices for pharmacology and drug distribution.
• [All phases] If pharmacology and drug distribution information is not known, it should simply be so stated.

Regulatory Requirements (FDA IND PHASE 2 3 CMC)

• [Phase 2] Data on particle size distribution and other physical properties should be generated and submitted when appropriate.
• [Phase 2] Data on the particle size distribution and/or polymorphic form of the drug substance used in clinical trial materials should be included when appropriate.
• [Phase 3] Data on the particle size distribution and/or polymorphic form of the drug substance used in clinical trial materials should be included when appropriate.

Regulatory Requirements (ICH M3R2)

• [before Phase 1] In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data in repeated-dose toxicity study species should be evaluated before initiating human clinical trials.
• [before Phase 3] Further PK information (absorption, distribution, metabolism, excretion) and in vitro biochemical information relevant to potential drug interactions should be available before exposing large numbers of human subjects or treating for long duration (generally before Phase III).
• If significant human phototoxicity risk is indicated, a subsequent evaluation of nonclinical drug distribution to skin and eye should be completed.
• If a direct assessment of phototoxic potential in a nonclinical or clinical study is negative, early eye/skin distribution studies and clinical protective measures are not called for.

Regulatory Requirements (ICH Q1AR2)

• [Pre-approval] Stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.

Regulatory Requirements (ICH Q1B)

• [Registration] For both options 1 and 2, a pharmaceutical manufacturer/applicant may rely on the spectral distribution specification of the light source manufacturer.
• [Registration] A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm should be used.

Regulatory Requirements (ICH Q6A)

• [Marketing Approval] Particle size testing for particle size distribution should be carried out using an appropriate procedure with acceptance criteria for new drug substances intended for use in solid or suspension drug products where particle size significantly affects dissolution rates, bioavailability, and/or stability.
• [Marketing Approval] Particle size distribution: Quantitative acceptance criteria and a procedure for determination of particle size distribution may be appropriate for oral suspensions, performed at release or as an in-process test if justified.
• [Marketing Approval] Acceptance criteria for particle size distribution should include acceptable percent of total particles in given size ranges, with well-defined mean, upper, and/or lower limits, based on observed variation, dissolution profiles, and intended use.
• [Marketing Approval] Particle size distribution: Quantitative acceptance criteria and a procedure for determination of particle size distribution may be appropriate for injectable suspensions, performed at release or as an in-process test if justified.
• [Marketing Approval] Acceptance criteria for particle size distribution should include acceptable percent of total particles in given size ranges, with well-defined mean, upper, and/or lower limits, based on observed variation, dissolution profiles, and intended use.

Regulatory Requirements (ICH S9)

• [Nonclinical/Clinical] Further information on absorption, distribution, metabolism and excretion of the pharmaceutical in animals should normally be generated in parallel with clinical development.

Source: ICH M3(R2)