Strategic application of PK modeling in 505(b)(2) development for a new pediatric formulation

Objectives: The objectives of this work were to establish a scientific bridge between a new oral solution and the approved tablet formulation (i.e., Listed Drug) using a comparative bioavailability (BA) study in healthy adult volunteers and extrapolate the adult exposure data to pediatric patients using population pharmacokinetic (PK) modeling. The US Food and Drug Administration’s (FDA) 505(b)(2) New Drug Application pathway allows the use of safety and efficacy data for approved drugs after the establishment of a scientific bridge between the new and approved drug products. Clinical programs can be substantially reduced and accelerated by using a combination of clinical PK data along with PK modeling and simulations to establish a scientific bridge to approved drugs under the 505(b)(2) pathway and extrapolate across various patient populations (e.g., extrapolation from adults to pediatrics or special populations). Methods: Adult healthy volunteer comparative PK data (solution versus tablet) were collected in Phase 1, open-label, randomized, 3-period, 3-sequence, single dose crossover comparative bioavailability (BA) and food effect study to establish a scientific bridge to the Listed Drug. A population PK model was then developed combining the adult PK data for the oral solution in fasted and fed states as well as that of the tablet in a fed state. The final model included the effect of weight on PK parameters. The performance of the model was validated by goodness of fit, standard diagnostics and predictive checks methods, as well as the comparison of exposures for observed versus simulated profiles. The model was subsequently used to simulate exposures in the pediatric population by utilizing allometric scaling and to determine weight-based dosing for pediatric patients. Results: The adult exposures for the new proposed oral solution were demonstrated to be similar to the exposures for the previously approved tablets, establishing a scientific bridge to the safety and efficacy information from the tablet FDA approval for adults. To determine the appropriate doses of the new oral solution for pediatric patients but avoid dose ranging study, population PK modeling analysis was conducted to simulate exposure levels in the pediatric population and to match with the levels observed in adults from the BA study. The modeling and simulation provided an assessment of the weight-based dosing needed for pediatric subjects aged 2-16 years old within the 10 to 60 kg weight range. The proposed doses for pediatric patients provided efficacious exposure levels based on the efficacious levels in adults and similar disease progression between the adult and pediatric patients and at the same time supported the safety of administration. Conclusions: The tablet formulation was not previously approved in the pediatric population. The new oral solution formulation was developed to facilitate dosing in pediatric patients. The combination of the comparative BA PK data in adults and population PK modeling and simulations allowed the avoidance of Phase 2 dose ranging study in pediatric patients, as well as Phase 3 efficacy and safety in adults and provided refined dose determinations for a relatively small pediatric clinical safety and efficacy study.