Background and objectives: Trofinetide, the first approved treatment for Rett syndrome (RTT), is primarily excreted unchanged in the urine; therefore, it is important to assess the extent to which the exposure is affected in patients with renal impairment. Pharmacokinetic modeling overcomes the challenge of dose finding in phase 1 studies that include special populations where there is the potential for increased exposure to study drug. The objectives of this phase 1 study were to evaluate trofinetide pharmacokinetics, safety, and tolerability in a population with moderate renal impairment and normal renal function. The observed pharmacokinetic profiles were used to validate the dosing adjustments in moderate renal impairment that were previously predicted using a physiologically-based pharmacokinetic (PBPK) model.
Methods: The PBPK model was first used to predict dose adjustments that are necessary to achieve similar exposure in the four stages of renal impairment (mild, moderate, severe, end stage renal disease) as in healthy controls. The predicted dose adjustment from 12 to 6 g for the moderate renal impairment category was then applied to the phase 1 clinical study. Subsequent validation of the PBPK model was achieved by comparing the model-predicted and clinically observed exposures in subjects with moderate renal impairment. In a phase 1, open-label study, trofinetide exposure was assessed in healthy (n = 10) and moderate renal impairment (n = 10) participants receiving single oral doses of 12 g or 6 g, respectively. Observed exposures [area under the blood concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were compared with predicted exposures from simulations in virtual healthy and moderate renal impairment populations (n = 100) to validate a PBPK model of renal impairment that had previously predicted doses across renal impairment categories.
Results: Dose-normalized geometric mean ratios for Cmax were comparable [1.02 (90% CI 0.69-1.50)] while AUCinf was approximately two-fold higher [1.81 (90% CI 1.31-2.50)] in moderate renal impairment participants compared with healthy controls. These observed values closely aligned with predicted distributions. Treatment-emergent adverse events were reported in two (20.0%) participants with moderate renal impairment and four healthy participants (40.0%).
Conclusion: PBPK modeling of trofinetide in a virtual population with moderate renal impairment predicted a 50% dose reduction compared to individuals with normal renal function. Comparison of observed pharmacokinetic results from a phase 1 study in subjects with moderate renal impairment and matched healthy participants to the model-predicted exposures validated this dose reduction. No new safety concerns for trofinetide emerged.
Trofinetide is the first approved treatment for Rett syndrome, a rare genetic condition that affects brain development. People with Rett syndrome do not usually experience problems with their kidneys but, because trofinetide is mostly removed from the body in the urine, it is important to check if the dose needs to be reduced when the kidneys do not work properly. Researchers first used computer modeling to predict how much the recommended dose of trofinetide in people with normal kidney function would have to be reduced in virtual populations with mild, moderate, or severe kidney disease, or kidney failure. To check if the computer model was correct, the blood levels of trofinetide were compared between 10 people with moderate kidney disease given a 50% reduced dose as predicted by the model and 10 healthy people given the recommended dose. The levels of trofinetide measured in people with moderate kidney disease were similar to the levels in healthy people and were similar to the predicted levels in the model, so together these results supported the 50% dose reduction in people with moderate kidney disease. The similarity between the results in the study and the model confirms that the model is good at predicting how much the dose needs to change in people with kidney disease.
© 2024. The Author(s).