Efficacy assessment for dosing regimen simplification via Phase 3 PK/PD modeling and simulation
Xuezhou Mao, sanofi  *Zhaoling Meng, sanofi  Hui Quan, Sanofi  Sandrine Turpault, sanofi  Lisa Von Moltke, sanofi 

Keywords: PK/PD modeling and simulaiton, alternative dosing evaluation, efficacy prediction

To ensure desired drug exposure for efficacy while minimizing the risk of excessive exposures in patients with differential drug metabolizing abilities, a dose titration scheme was implemented based on monitoring of drug concentration at early treatment phase in drug’s Phase 2 and pivotal Phase 3 studies. This method of dose titration, although being successful in resulting desired clinical outcomes, has limitations for use in clinical practice including the dependence of dosing timing to accurately determine the dose escalation, the requirement of multiple visits to reliably evaluate individual patient’s exposure level, the specified titration threshold lacking clinical support and being potentially confusing to patients and clinicians. Therefore, a patient metabolizer phenotype-based dosing regimen was evaluated as an alternative for the final commercial dose regimen to achieve consistent exposures and comparable safety and efficacy as observed in the Phase 2 and Phase 3 trials. The evaluation of such a phenotype-based dosing regimen was not straightforward based on available data from the Phase 2/3 program because the studies were not designed for the purpose. A pharmacokinetic/ pharmacodynamic (PK/PD) modeling and simulation (M&S) approach was used in the evaluation. The treatment effects under the proposed metabolizer phenotype-guided dosing scheme were first predicted and then compared to the observed results for validation.