Certara Partners with Galderma in Advancing Modeling and Simulation Technology to Attain FDA Approval of AKLIEF® Topical Acne Cream
January 08, 2020 at 01:00 pm
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Certara announced that its Simcyp Population-based Simulator was used to support Galderma’s successful U.S. Food and Drug Administration (FDA) new drug application (NDA) for AKLIEF (trifarotene) Cream, 0.005% for the topical treatment of acne. Trifarotene is the first new retinoid molecule to receive FDA approval to treat acne in more than 20 years. The use of the Simcyp Simulator allowed Galderma to expedite and inform its drug development program, while also providing safety label claim and pediatric dosing information without the need for testing in clinical patients. Specifically, Simcyp’s Mechanistic Dermal Absorption (MechDermA) model was used to predict the outcome of specific drug interactions and provide dosing guidance for pediatric patients aged nine to 17. The Simcyp Simulator’s MechDermA model mimics the diffusion of the drug from the skin epidermis into deep tissue. It enables researchers to estimate local and systemic exposure resulting from either topical or transdermal absorption of different drug doses. It allows a drug ADME and potential interactions to be tested in virtual patient populations of different demographics (ages, sexes, weights, ethnicities, etc…) and with specific skin conditions. This approach helps to overcome the ethical and operational challenges associated with conducting pediatric drug trials and in general to avoid unnecessary drug exposure to both patients and healthy volunteers. Development of Certara’s MechDermA model is the result of a multi-year FDA grant. The MechDermA PBPK model of trifarotene was developed using physicochemical parameters and in vitro metabolism data from CYP profiling, drug-drug interaction (DDI) and drug transporter studies, and a radioisotope tissue distribution study. Its accuracy was verified using clinical PK data including local skin tissue and plasma drug concentration measurements. The MechDermA model was used to determine how the presence of fluconazole, which is a moderate CYP2C9 and CYP3A inhibitor, would impact the systemic exposure of trifarotene. An increase of less than 20% was predicted.Fluconazole is used to treat fungal or yeast infections. The results of this model-based approach were included on the final AKLIEF label. A sensitivity analysis was also performed to examine the impact of complete inhibition of trifarotene metabolism by CYP2C9. It resulted in a predicted average 50% increase in the systemic exposure to trifarotene, a safety margin that is within the accepted range. Use of PBPK modeling resulted in a clinical DDI study with fluconazole not being required by the Agency. MechDermA was also used to simulate trifarotene systemic exposure levels in two virtual pediatric populations. The results obtained from the model were consistent with clinically-observed results.
Certara, Inc. is a provider of biosimulation technology and solutions for using Model-Informed Drug Development in the global biopharmaceutical industry. It is focused on producing medicines using proprietary biosimulation software, technology and services to transform traditional drug discovery and development. Its customers include life sciences companies of all sizes along with contract research organizations, academic institutions, and global regulators. Its software and service are used by approximately 2,400 biopharmaceutical companies and academic institutions across 66 countries, including 38 of the top 40 biopharmaceutical companies. It has operations in the United States, Australia, Canada, China, France, Germany, India, Italy, Japan, Luxembourg, Netherlands, Philippines, Poland, Portugal, Spain, Switzerland, Egypt, and the United Kingdom.