Model-Informed Design of Clinical Trial in Patients with Renal Impairment

Evaluating the pharmacokinetics (PK) of renally excreted drugs in patients with renal impairment is essential because reduced kidney function can significantly alter drug clearance, leading to increased systemic exposure, prolonged half-life, and a higher risk of toxicity. Since the kidneys play a key role in eliminating many medications, impaired renal function can compromise the body’s ability to remove the drug effectively. Understanding how renal impairment affects PK enables clinicians to adjust dosing appropriately, ensuring therapeutic effectiveness while minimizing adverse effects.

Physiologically based pharmacokinetic (PBPK) models are valuable tools in this context, as they integrate physiological and drug-specific parameters to simulate drug disposition under various clinical scenarios, including varying degrees of renal impairment. PBPK models can predict how changes in renal function influence drug exposure, allowing for informed dose selection and optimization without the need for extensive clinical trials in high-risk or hard-to-recruit populations. This approach improves safety, supports regulatory decision-making, and facilitates personalized medicine in patients with compromised kidney function.

This presentation describes the use of physiologically based pharmacokinetic (PBPK) modeling to guide dose adjustments of trofinetide, a recently FDA-approved drug for Rett syndrome, in individuals with moderate renal impairment. Given that trofinetide is primarily excreted unchanged in the urine—about 70% of the administered dose—understanding how kidney function affects drug exposure is crucial for ensuring safety and efficacy, especially in special populations. A PBPK model was developed and validated to simulate trofinetide pharmacokinetics. The model was used to predict the required dosing in patients with various levels of renal function. This prediction was tested in a Phase 1, open-label clinical trial, and the measured clinical exposure closely matched PBPK model predictions, confirming the model’s ability to predict systemic exposure in renally impaired individuals. The PBPK model accounted for physiological changes due to renal impairment, including alterations in glomerular filtration rate, hematocrit, and plasma protein binding, although trofinetide is known to have minimal protein binding. The study demonstrates that PBPK modeling is a useful tool for predicting drug pharmacokinetics in renally impaired populations and can inform rational dose adjustments without requiring extensive clinical trials in rare or difficult-to-enroll populations like those with Rett syndrome. The validated model supports a 50% dose reduction for moderate renal impairment and allows for extrapolation to more severe renal conditions and pediatric subgroups, where conducting dedicated trials would be ethically and logistically challenging. These findings enhance the clinical use of trofinetide and demonstrate the value of PBPK modeling in drug development and regulatory decision-making.