Prisys Biotech is a leading CRO specializing in nonhuman primate pharmacology and disease models. We provide comprehensive solutions for pharmacology efficacy studies and toxicology research, utilizing innovative animal model technologies. Our services cover a wide range of species, including nonhuman primates, canines, offering robust preclinical models for drug development. Our expertise significantly enhances the predictability of biomedical research, reducing clinical trial failure risks and accelerating the translation of new therapies from bench to bedside.
Before a drug molecule enters human clinical trials, a series of preclinical or nonclinical toxicity studies must be conducted to ensure safety. While regulatory standards vary across regions, the ICH guidelines have harmonized many of the requirements.
Duration and Design of General Toxicology Studies
The duration and number of doses in toxicology studies depend on the drug's characteristics and the expected human exposure. Safety regulations require explicit toxicity studies in at least one animal species, often two, based on metabolism, pharmacokinetics, species tolerance, and pharmacological activity of the molecule in the chosen species. In early drug discovery, in vitro and computational models, as well as structure-activity relationship assessments, provide this information. Later stages involve in vivo systems for more predictive data on metabolism, systemic bioavailability, PK, and toxicity, guiding the choice of species for final toxicology studies.
Despite careful species selection before human exposure, new data from initial clinical trials may necessitate reconsidering one or more nonclinical species. The final species choice is based on the relative comparability of collected human data to prior animal screening data.
Dose Selection and Administration Route
A crucial design element in toxicology studies is selecting appropriate doses and administration routes. Generally, a high dose should produce observable toxicity (e.g., reduced body weight or food consumption, changes in clinical pathology parameters, or organ-related changes) without causing death. High doses are determined based on one of five criteria:
- Maximum Tolerated Dose (MTD): A dose causing target organ toxicity without death.
- Maximum Feasible Dose (MFD): The highest dose achievable due to technical or physicochemical limitations.
- 50-fold Margin Dose: A dose based on a 50-fold safety margin of the clinical dose.
- Limit Dose: Typically 5000 mg/kg or another specified value for toxicity evaluation.
- Exposure Saturation Dose: The minimum dose at which systemic exposure is saturated.
Studies also need appropriate low and mid doses to cover the dose-response relationship, identifying the No Observed Effect Level (NOEL) and No Observed Adverse Effect Level (NOAEL). The assumption behind high dose selection is that systemic exposure increases with dose, which is directly assessed by exposure saturation, correlating systemic exposure with dose, sex, species, and study duration.
Administration Route
The administration route is usually determined by the drug's clinical use. For oral formulations, animals are typically dosed by gavage, while injectables are administered intravenously or subcutaneously. Advances in drug development have introduced new routes like intraventricular, intrathecal, and intranasal administration, considering bioavailability, local tolerability, and technical feasibility.
Types of Studies for General Toxicology Evaluation
Acute Toxicity Studies
Acute toxicity studies are foundational in nonclinical toxicology evaluation, aiming to determine the Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD). These data guide dose selection in safety pharmacology studies and critical IND-supportive toxicology studies. Acute studies usually include a control group and at least three test dose groups, with rodents typically having five animals per sex per dose and non-rodents two to three per dose. Key data include body weight, food consumption, clinical observations, and survival rates, with necropsy and anatomical evaluation of surviving animals for significant changes.
Repeated Dose Toxicity Studies
While global alignment has improved for repeated dose toxicity study requirements supporting human clinical trials, regional differences in study duration remain. For instance, the US and EU typically require two-week rodent and non-rodent studies for single or short-term repeated dose human trials, whereas Japan may require four-week rodent and two-week non-rodent studies. As clinical trial phases progress, the focus shifts to determining the NOAEL.
Subacute Toxicity Studies (2 to 4 weeks)
Subacute toxicity study duration aligns with Phase I trial duration, treatment indication, and planned dosing cycles. Two-week studies may suffice for some indications, but four-week studies are generally necessary, especially for multi-dose trials. These studies follow acute and dose range-finding studies, strengthening toxicity data and identifying the first NOAEL.
Subchronic Toxicity Studies (13 weeks)
Subchronic toxicity studies in rodents typically involve 20-25 animals per sex per group, with additional animals for toxicokinetic evaluation. Sampling occurs at study start, midpoint, and end, with extra animals for recovery phase evaluation. A common design includes 25 animals per group, with 20 dissected post-dosing and the remainder in recovery. For non-rodents like dogs and nonhuman primates, 13-week studies are common, with additional toxicokinetic sampling points.
Chronic Toxicity Studies (6 months and beyond)
Chronic toxicity studies support clinical trials exceeding six months, with six-month rodent and nine-month non-rodent studies. These studies aim to comprehensively characterize drug toxicity over prolonged exposure, including potential target organ toxicity, dose-related effects, and reversibility. Cumulative toxicity and long-term exposure effects are critical, as some toxicities emerge only with extended exposure.
Prisys Biotech remains committed to advancing biomedical research through our state-of-the-art animal models and comprehensive preclinical services. Our extensive experience in large animal pharmacology and toxicology studies ensures reliable and translatable results, supporting the successful development of new drugs and therapies. By continually expanding our disease model repertoire and maintaining the highest standards of research quality, we strive to be a pivotal partner in the global biopharmaceutical industry.
