Best Practices for Preclinical Dose Range Finding Studies

Dose range finding (DRF) studies are the foundation of preclinical drug development, providing crucial information on safety data to assist in the dose level selection before advancing into toxicology studies. These studies establish the minimum effective dose (MED) and maximum tolerated dose (MTD) to guide the design of subsequent studies while reducing unnecessary research animal use.

Following best practices enables researchers to reliably generate reproducible, regulatory-compliant data to inform the next stages of a study. In this blog, we explore:

• the purpose and importance of dose range finding studies in preclinical research;
• key considerations for study design;
• best practices in assessing safety, pharmacokinetics (PK), and biomarkers; and
• Altasciences’ expertise in DRF studies.

The Importance of Dose Range Finding in Preclinical Studies

Dose range finding studies characterize the dose-response relationship of test compounds to identify potential toxicity, tolerability, and systemic exposure at various dose levels. They support the selection of appropriate doses for subsequent toxicology assessments, providing critical data to refine dose selection for GLP-compliant studies and ensuring that these are conducted at ethical and scientifically justified levels.

Typically, they are conducted in both rodent and non-rodent species to determine the MTD—A study designed to determine the highest dose of a test article that can be administered without causing severe toxicity or unacceptable adverse effects.

4 Best Practices for Dose Range Finding Studies

Dose range finding studies generate essential data to guide toxicology assessments, but designing them requires careful consideration. From selecting the right animal model to defining dosing strategies, each step influences study outcomes and regulatory acceptance. Here are four best practices to improve data reliability, refine dose selection, and support the transition to later-stage studies.

1. Selecting the Right Animal Model

Species selection is critical because it directly impacts the relevance, accuracy, and translational value of the data for human risk assessment. Initial assessments often use rodents, such as rats or mice, while larger non-rodent species, like canines or nonhuman primates (NHPs) or minipigs, may be selected based on the drug’s pharmacological profile. These selections must consider drug absorption, distribution, metabolism, and excretion (ADME), as well as receptor expression and physiological relevance.

Appropriate species selection ensures that the dose-limiting toxicity profile is accurately characterized, allowing for a safe and effective translation to human clinical trials. This selection must be based on species metabolism, target engagement, sensitivity to toxicity, and regulatory considerations to optimize both data quality and ethical standards. 

2. Choosing the Appropriate Study Design and Dosing Strategies

A well-designed DRF study includes multiple dosing levels to establish a dose-response relationship using prior PK and pharmacodynamic (PD) data, or studies from similar compounds.

The starting dose should be based on prior PK, PD, or in vitro studies. From there, the dose should gradually be increased until significant toxicity is observed. If severe toxicity occurs, researchers may test an intermediate dose to fine-tune the MTD. This helps ensure that the dose is both safe and effective for future studies.

The choice of strategy in dose escalation studies is essential, and logarithmic dose increments (e.g., 2x, 3x) are commonly used in preclinical studies to achieve broad coverage while minimizing unnecessary high doses. This approach ensures systematic exposure increases while maintaining safety and identifying an effective range. However, dose escalation ratios can vary across studies, with increments in clinical phases typically following predefined patterns to balance risk and information gain.

The study director determines the appropriate dose escalation schema for each study and may modify it based on discussions in safety review committee (SRC) meetings.

The route of administration in most cases matches the intended clinical use (e.g., intravenous, oral, subcutaneous, or intrathecal) for relevance. For gene therapy candidates, biodistribution assessments help evaluate tissue-specific exposure.

3. Conducting Comprehensive Safety and Toxicity Assessments

Monitoring for toxicity is essential in refining dose selection and preventing excessive exposure. Clinical observations, food effect, body weight tracking, and pathology assessments—including hematology, serum chemistry, and urinalysis—provide valuable insights into systemic toxicity.

Researchers should conduct a gross necropsy followed by preliminary histopathology to identify organ-specific toxicities. Immunogenicity assessments for biologics and gene therapies may be performed at this point, as the immune response can influence safety and efficacy. 

4. Evaluating Pharmacokinetics and Biomarker Evaluation

Incorporating PK and biomarker evaluations into DRF studies plays a critical role in optimizing dose selection and enhancing our understanding of drug safety and efficacy. The PK profile and ADME properties of a drug are essential for informing dose selection.

Measuring exposure metrics—such as maximum concentration (Cmax), area under the curve (AUC), and half-life—offers insights into dose-exposure relationships, supports cross-species dose extrapolation, and helps assess systemic exposure across dose levels. Additionally, these metrics can help evaluate sex differences in exposure and the potential for accumulation in multiple-dose studies.

Biomarkers are used to evaluate target engagement and PD effects, providing early indicators of toxicities, confirming PD outcomes, and assessing immune responses in biologics and gene therapies, such as adeno-associated viruses (AAVs). Biomarkers also play a key role in evaluating tissue tropism and persistence. Together, PK and biomarker data work in tandem to inform dose selection, optimize study design, and enhance the safety of subsequent safety studies, including first-in-human (FIH) trials.

Altasciences’ Dose Range Finding Study Expertise 

Dose range finding study results inform no observed adverse effect levels (NOAELs), which are key for regulatory filings and FIH dose selection. By analyzing these dose-response trends, researchers can determine whether safe margins exist between efficacious and toxic doses, reducing the likelihood of adverse events in clinical trials.

At Altasciences, our team of toxicologists design these tailored studies to align with regulatory requirements. Our state-of-the-art facilities enable us to conduct comprehensive safety assessments, PK evaluations, and biomarker analyses, ensuring optimal data collection for dose selection. Whether you need guidance on species selection, study design, or regulatory compliance, our experts are here to support you.

Ready to optimize your preclinical program? Contact us today to discuss how our expertise can help you navigate the path to regulatory submission with confidence.