A successful Investigational New Drug (IND) submission requires a comprehensive testing approach. From Drug Metabolism and Pharmacokinetic (DMPK) studies to determine the drug’s behavior within the body, nonclinical toxicology assessments to meticulously examine its safety profile, and Bioanalytical studies to measure drug concentrations in biological samples, the process plays a critical role in drug development.
These studies shape the regulatory narrative, offering vital insights for subsequent clinical trials and advancing the goal of delivering safe therapeutics to patients. This article explores the components of DMPK, toxicology, and bioanalytical studies.
DMPK Studies
Drug Metabolism and Pharmacokinetic (DMPK) studies help understand how a drug metabolizes and behaves in the body. There are five core components that a typical DMPK study includes:
- Bioavailability studies: These studies quantify the portion of an orally administered drug that enters systemic circulation and is available for therapeutic effects.
- Drug-Drug Interaction (DDI) studies: DDI studies evaluate potential interactions between the investigational drug and other commonly used drugs, providing insights into the safety and efficacy when administered together.
- Pharmacokinetic (PK) studies: Evaluate the drug’s concentration in the blood over time. PK studies may include single-dose studies, which examine the drug’s behavior after a single dose, and multiple-dose studies which assess how the drug accumulates or is eliminated, through repeat dosing.
- Formulation studies: Formulation studies assess how various formulations, such as tablets or capsules, affect the drug’s bioavailability and pharmacokinetics.
- Absorption, Distribution, Metabolism, and Excretion (ADME) studies: Here’s a breakdown of what each component of ADME studies entails:
- Absorption studies: Evaluates how the drug is absorbed into the bloodstream after either oral or intravenous administration.
- Distribution studies: Assesses the drug’s distribution to different tissues and organs.
- Metabolism studies: Investigates how the drug is metabolized in the body and identifies metabolites.
- Excretion studies: Once metabolites are identified, the excretion study determines how the drug and metabolites are eliminated from the body, most often focusing on urine and feces.
These five DMPK studies help comprehend the drug’s behavior in humans to guide dosage recommendations and ensure safety in future clinical trials. The studies evaluate the drug’s pharmacokinetic properties, enabling regulators to make informed decisions regarding its suitability for human use.
Toxicology Studies
Before clinical trials commence, developers must establish the drug’s safety profile through in vivo studies and other necessary IND enabling tests.
Toxicology studies are essential throughout each clinical phase to assess a drug’s safety, with a final set of tests required for the New Drug Application (NDA). Starting with nonclinical toxicology studies is key to a successful clinical process. The specific nonclinical safety assessment program varies based on the type of molecule and clinical plan. There are five sets of tests required for nonclinical toxicology, per ICH M3(R2) guidance.
- Pharmacology: Safety pharmacology studies evaluate the potential toxicity of the molecule across key organ systems, including the CNS, cardiovascular, respiratory, and sometimes gastrointestinal and renal systems (optional depending on target tissues).
- General toxicology: Determines the highest dose that can be administered in clinical trials by assessing the molecule’s potential adverse effects after single or repeated exposure. Typically, they include single-dose and 14-day, 28-day dosing periods. If the clinical program exceeds a 28-day dosing period, 13-week studies can be conducted.
- Reproductive toxicology: Assesses the reproductive safety of the drug after repeated or chronic exposure in three stages:
- Segment I: Fertility and early development (FEED) to implantation
- Segment II: Definitive embryo-fetal development (EFD)
- Segment III: Pre and postnatal development toxicology (PPND)
- Genotoxic studies: Evaluate the drug’s potential to cause gene mutations or chromosomal abnormalities.
- Toxicokinetic studies: Toxicokinetic (TK) evaluations are conducted along with general and reproductive toxicology studies to develop PK and TK profiles under longer dosing conditions, supporting the clinical plan.
Bioanalytical Studies
The final core group of studies are bioanalytical, providing quantitative measurements of drug concentrations and their metabolites in biological samples. Bioanalytical studies are typically done in conjunction with toxicology evaluations, but drug-drug interaction (DDI) studies are done separately. Core bioanalytical studies typically include:
- Method development and validation: Developing and validating analytical methods quantify the investigational drug and its metabolites in biological samples, including blood, plasma, and urine, helping to ensure the accuracy, precision, and reproducibility of the method.
- Determination of bioavailability: Assesses the fraction of the administered oral dose reaching systemic circulation for therapeutic action.
- DDI studies: Investigates potential interactions between the drug and other drugs that may be co-administered.
- Immunogenicity Assays: Assess immune responses to the drug. Detection of anti-drug antibodies (ADA) can impact drug efficacy and exposure. Although ADA formation may not directly translate to clinical effects, evaluating it during preclinical studies helps interpret toxicity and toxicokinetic data.
- Assay of drug concentrations: Measures drug concentrations over time, confirming exposure and evaluating pharmacokinetics. Includes assays for both the drug and relevant metabolites.
- Bioequivalence studies: Compares the pharmacokinetics of different formulations or routes of administration of the drug.
- Assessment of stability: Evaluates the stability and compatibility of the drug in biological samples during collection, processing, and storage
- Determination of Maximum Tolerated Dose (MTD): Identifies the highest dose of the drug that does not cause unacceptable toxicity. These bioanalytical studies provide quantitative data, helping to understand drug pharmacokinetics, bioavailability, and safety. Rigorous method development and validation ensure data reliability, supporting regulatory evaluation for subsequent clinical trials. Note, these studies are usually done as an individual study before repeat dose studies occur.
To create a strong IND submission, drug developers must leverage these critical studies, while formulating a comprehensive testing program, tailored to a specific molecule, indication, and other pertinent parameters. Due to the many variables across study programs, insufficient planning is one of the most common pitfalls for drug developers.
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