DMPK in Small-Molecule Development: Key Regulatory Guidelines for IND/CTA and NDA/MAA

DMPK (drug metabolism and pharmacokinetics) is a core scientific discipline in drug discovery and development, and programs that underinvest in DMPK strategy early often pay for it later.

At the discovery stage, the DMPK objective is to optimize key PK parameters (CLpu, Fpo, t1/2, MRT) and balance target-relevant exposure against potency, off-target risk, and drug-drug interaction (DDI) potential to meet the Research Target Profile (RTP), while building PK/PD understanding where feasible.

As programs move into development, DMPK efforts focus on full in vitro ADME and DDI characterization, preclinical PK & PK/PD, human PK, dose and DDI predictions, and demonstrating adequate exposure of the parent drug and relevant human metabolites in safety species. Together, these data form a key component of the regulatory package supporting IND/CTA authorization and, ultimately, NDA/MAA review and approval.

Which DMPK-related regulatory guidelines actually matter when moving from discovery to development?

To support this transition, I’ve prepared the table below listing key DMPK-related regulatory guidelines, with direct links to the original PDF documents. Selected biopharmaceutics and clinical pharmacology guidances closely linked to DMPK are also included, along with a brief abbreviations section for reference.

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DMPK-related regulatory documents and guidelines for small molecules

Bioanalysis

-ICH M10 Bioanalytical method validation and study sample analysis (2022) -ICH M10 Questions & Answers (2022)

Preclinical ADME, PK & TK

-ICH M3(R2) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (2009)

-ICH M3(R2) Questions &Answers (R2) (2012)

-ICH S3A Note for guidance on toxicokinetics: The assessment of systemic exposure in toxicity studies (1994) -ICH S3A Questions and Answers (2017)

-ICH S3B Guidance for repeated dose tissue distribution studies (QWBA) (1994)

-ICH S9 Nonclinical evaluation for anticancer pharmaceuticals (2009)

-ICH S9 Questions &Answers (2018)

-FDA MIST Safety testing of drug metabolites (2020)

Drug-Drug Interactions (DDI)

-ICH M12 Drug Interaction Studies (DDI) (2024)

-ICH M12 Questions & Answers (DDI) (2024)

-EMA Implementation Strategy of ICH M12 on drug interactions studies (2024)

Physiologically based pharmacokinetic (PBPK) analyses (only if used)

-FDA PBPK analyses - Format & Content (2018)

-EMA Guideline on the reporting of PBPK modelling and simulation (2018)

Regulatory submission format

-ICH M4S(R2) The common technical document for the registration of pharmaceuticals for human use: Safety.  Nonclinical overview and nonclinical summaries of module 2 & organization of module 4 (2002)

Biopharmaceutics-related guidelines relevant to DMPK

-ICH M9 Biopharmaceutics classification system-based biowaivers (BCS) (2019) -ICH M9 Questions and Answers (2019)

-FDA Food-Effect Bioavailability and fed bioequivalence studies (2002)

Clinical pharmacology guidelines relevant to DMPK

-FDA Clinical pharmacology considerations for human radiolabeled mass balance studies (hADME) (2024)

-FDA Evaluation of gastric pH-dependent drug interactions with acid-reducing agents (2023)

-FDA Clinical drug interaction studies with combined oral contraceptives (2023)

-FDA PKs in patients with impaired renal function (2024)

-EMA Guideline on the evaluation of the PKs of medicinal products in patients with decreased renal function (2015)

-FDA PKs in patients with impaired hepatic function (2003)

-EMA Guideline on the evaluation of the PKs of medicinal products in patients with impaired hepatic function (2005)

-FDA Population PKs (2022)

-EMA Guideline on reporting the results of population PK analyses (2007)

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Abbreviations

EMA: European Medicines Agency

European regulatory authority coordinating the scientific evaluation of medicines in the EU.

FDA: U.S. Food and Drug Administration

U.S. regulatory agency responsible for reviewing and approving drugs.

ICH: International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use.

Organization that develops harmonized regulatory guidelines across regions.

ICH “M” guidelines: Multidisciplinary guidelines

Guidelines covering cross-functional topics relevant across disciplines

ICH “S” guidelines: Safety guidelines

Guidelines focused on nonclinical safety topics, including toxicokinetics and tissue distribution.

CTA: Clinical Trial Application (EU and other regions)

Regulatory submission to national competent authorities (and ethics committees, where applicable) requesting authorization to conduct clinical trials.

IND: Investigational New Drug (U.S.)

Regulatory submission to the FDA seeking authorization to initiate clinical trials in humans.

NDA: New Drug Application (U.S.)

Marketing application submitted to the FDA seeking approval to market a new drug.

MAA: Marketing Authorization Application (EU and other regions)

Marketing application submitted to regulatory authorities (e.g. EMA or national agencies) seeking approval to market a medicinal product.

Note: Once implemented, ICH guidelines generally serve as the primary reference, while regional FDA and EMA guidelines may still apply where ICH guidance is silent, high-level, or supplemented by regional expectations (e.g. EMA Implementation Strategy of ICH M12).