Certara®, the global model-informed drug development and decision support leader, today 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. 

“We are proud to support Galderma’s successful NDA for AKLIEF (trifarotene) Cream, 0.005%. It is important for patients, particularly pediatric patients, to have effective new options available to treat their acne,” said Certara’s Simcyp President and Managing Director Rob Aspbury, PhD. “Our MechDermA model can simulate systemic exposure levels in patients of different ages and ethnicities. As children grow, the thickness, hydration, and composition of their skin changes, so it is ethically and scientifically important to be able to investigate a new topical drug’s behavior in virtual versus real pediatric patients.”

“We were pleased to partner with Certara to develop this detailed physiologically-based pharmacokinetic (PBPK) model of trifarotene, which helped to demonstrate the safety of our new drug and also provide additional prescribing information for our new drug label,” said Nathalie Wagner, Senior Clinical PK Manager at Galderma. “As a leader in modern research and development of scientifically-defined and medically-proven solutions for the skin, we embrace new technologies such as modeling and simulation that improve our effectiveness.”

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.

TrifaroteneModeling

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.

Galderma presented the data from this program on Nov. 8 during an AAPS webinar entitled “Clinical Development of a Topical Dermatological Drug Product: Focus on Clinical Pharmacology.” Visit the AAPS Topical and Transdermal Community website to learn more.

FDA continues to encourage the use of modeling and simulation as an integral part of drug development, and it is featured in the current Prescription Drug User Fee Act, Generic Drug User Fee Act, and the 21st Century Cures Act.

Interested parties can learn more about Certara’s MechDermA model in the following Simcyp Simulator webinar: https://www.certara.com/webinar-archive/whats-new-in-the-simcyp-simulator-v17/?ap%5B0%5D=PBPK&UTM_LeadSource=12052017.

About Galderma

Galderma, the world's largest independent global dermatology company, was created in 1981 and is now present in over 100 countries with an extensive product portfolio of prescription medicines, aesthetics solutions and consumer care products. The company partners with health care practitioners around the world to meet the skin health needs of people throughout their lifetime. Galderma is a leader in research and development of scientifically-defined and medically-proven solutions for the skin. For more information, please visit www.galderma.com

About Certara

Certara optimizes R&D productivity, commercial value and patient outcomes through its unique portfolio of model-informed drug development, regulatory science, and market access solutions. In fact, 90+% of all novel drugs approved by the US FDA in the past four years were supported by Certara software or services. Its clients include 1,600 global biopharmaceutical companies, leading academic institutions, and key regulatory agencies across 60 countries. For more information, visit www.certara.com.