How to support first-in-human (FIH) dose selection with PK?

Selecting the first-in-human (FIH) dose in clinical trials is a critical step that can significantly influence the success of drug development. Pharmacokinetics (PK) plays a pivotal role in informing this decision, ensuring safety, efficacy, and optimal therapeutic outcomes. This blog will explore the key considerations and methodologies for supporting FIH dose selection through PK.

Understanding Pharmacokinetics in Drug Development

Pharmacokinetics refers to the study of how a drug moves through the body, encompassing absorption, distribution, metabolism, and excretion (ADME). By understanding these processes, researchers can predict how a drug behaves in humans based on preclinical data. PK studies provide valuable insights into the drug's potential efficacy and safety profiles, which are crucial for determining the appropriate starting dose in FIH trials.

Preclinical PK Studies: The Foundation

Before moving to FIH trials, comprehensive preclinical PK studies are conducted using in vitro and in vivo models. These studies aim to characterize the drug's ADME properties, identify potential metabolites, and assess exposure-response relationships. Key parameters such as bioavailability, clearance, half-life, and volume of distribution are determined to establish a preliminary PK profile.

Translating Preclinical Data to Human Studies

Translating preclinical PK data to humans involves allometric scaling and physiologically based pharmacokinetic (PBPK) modeling. Allometric scaling uses mathematical models to predict human pharmacokinetic parameters based on animal data, considering body size and physiology. PBPK modeling, on the other hand, integrates anatomical and physiological details of humans to simulate drug behavior. These methodologies help estimate the starting dose, ensuring it is within a safe and effective range.

Safety Considerations and the Maximum Tolerated Dose

Safety is paramount in FIH trials. To minimize risks, the starting dose is typically set at a fraction of the no observed adverse effect level (NOAEL) identified in animal studies. The goal is to ensure the dose is well below the maximum tolerated dose (MTD) for humans. PK data guide the selection of this conservative starting dose, with subsequent dose escalation based on emerging safety and PK data from the trial.

Impact of PK Variability

Inter-individual variability can significantly impact PK parameters, affecting drug exposure and response. Factors such as age, gender, genetics, and health status can influence drug metabolism and clearance. Therefore, PK variability must be carefully considered during FIH dose selection. Population PK studies and simulations can provide insights into potential variability, aiding in the design of dosing regimens that accommodate diverse patient populations.

Incorporating Pharmacodynamics in Dose Selection

While PK focuses on drug concentration, pharmacodynamics (PD) examines the drug's biological effects. Integrating PK and PD data allows for a more comprehensive understanding of the drug's action. By establishing the PK/PD relationship, researchers can identify the optimal therapeutic window and refine the dose selection process. This integrated approach ensures that the chosen dose achieves the desired biological effect with minimal side effects.

Continuous Monitoring and Dose Adjustment

The FIH trial is a dynamic process that requires ongoing PK monitoring. Real-time PK data collection allows for the adjustment of dosing regimens based on observed drug exposure and patient response. Adaptive trial designs, which include predefined criteria for dose modification, enhance the safety and efficacy of FIH studies. Continuous monitoring ensures that the trial remains responsive to emerging data, optimizing patient outcomes.

Conclusion

Pharmacokinetics plays a crucial role in guiding FIH dose selection, providing a scientific foundation for safe and effective clinical trials. By leveraging preclinical data, predictive modeling, and real-time monitoring, researchers can make informed decisions that prioritize patient safety while exploring the therapeutic potential of new drugs. As drug development continues to evolve, the integration of PK with other scientific disciplines will remain essential in enhancing the success of FIH trials.