By Benjamin Ross

February 5, 2020 | In October 2019, the U.S. Food and Drug Administration (FDA) approved a new drug application for the topical treatment of acne. The treatment, called AKLIEF (trifarotene) Cream, is the first new retinoid molecule to receive FDA approval to treat acne in more than 20 years.

The treatment was developed by Galderma and supported by Simcyp, a division of Certara that used their Simcyp Population-based Simulator to expedite and inform Galderma’s drug development program, while also providing safety label claim and pediatric dosing information without the need for testing in clinical patients.

The Simcyp Simulator analyzes a range of key drug development questions such as drug-drug interactions (DDI) and dosing in different patient populations in silico using a simulation of the human body and its organs, Ellen Leinfuss, Chief Corporate Affairs Officer at Certara, tells Clinical Research News. She says the simulator has generated remarkable results, having been made available to a consortium of now 37 pharmaceutical companies, who use Simcyp’s tech and work together in a pre-competitive environment to discuss and incorporate annual updates to its simulator.

“There are about 70 drugs that are on the market whose label has been informed specifically by the Simcyp Simulator, resulting in about 200 combined specific label claims performed in silico as opposed to having to do in vivo trials,” says Leinfuss.

The simulator generates drug absorption, distribution, metabolism, and excretion (ADME) predictions using transparent algorithms. These algorithms can be implemented at any stage of the clinical trial process, though Leinfuss says the earlier the better.

“There’s value in building the in silico model in pre-clinical before you do first-in-human, extrapolating your pre-clinical data into what could be a first-in-human dosing,” she says. “But if you don’t build it then, there’s certainly value in using it on Phase I data or later. Often, we get involved closer to [the New Drug Application stage]. The ones that learn the most, obviously, are those that iterate throughout the course of the development of the project because we’re adding more and more data.”

In an official statement, Certara said that for Galderma’s acne cream, 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 seventeen.

According to Dr. Nikunjkumar Patel, Senior Consultant and Scientific Advisor at Certara’s Simcyp Division, there’s a certain level of difficulty that comes when running clinical trials to assess metabolic DDIs for topical and locally-acting drug products, especially in special populations. By design, such drug products are not intended to reach systemic circulation. Hence, to quantify likely metabolic DDI, patients need to be exposed to supra-therapeutic doses to achieve significant systemic exposure and a large patient population might be required to account for  inherent variability in systemic absorption of such drug products and population variability in enzyme expressions.

“Basically, the same enzyme may be expressed differently in a Chinese versus Japanese population, and those might be different than the expression in Caucasian adults,” Dr. Patel tells Clinical Research News. “The same can be said with pediatrics. Pediatric patients obviously do not have the same body weight as an adult, but assuming pediatric patients are simply reduced body weight adults is an over-simplification. So when we create a model for a pediatric population, the different physiological functions are based on the maturation rates that are known to us from historical research on the human body. Commonly known as ontogeny functions, they can mature at different rates to the body weight increase with age. So the pediatric function is not just a reduced body weight adult, but it’s actually—as much as possible—a realistic simulation of a pediatric subject.”

The MechDermA model mimicked the diffusion of the drug from the skin surface to the epidermis into deeper tissues and the systemic circulation. According to Dr. Patel, this enabled researchers to estimate local and systemic exposure resulting from the topical absorption of different drug doses. Moreover, the model also accounts for regional differences in skin physiology. For example, skin on the face has different barrier properties to skin on the torso and male and female subjects have different skin physiology even when normalized by age group.

“We know a lot about the human body, and we know its processes,” Dr. Patel says. “For example, if you put a cream on your skin, we have a mathematical description for how the drug would be liberated from the formulation based on first principles. That would depend on the drug, the formulation, as well as the location on the body.”

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.

Does this mean simulators like Simcyp are a replacement for running trials? Not at all, according to Leinfuss, who says companies like Galderma still need to test clinical patients in the process of getting their drug approved. The simulator is used to optimize clinical trial decision-making to expedite time to market, and where appropriate, eliminate additional studies needed to determine DDI. On January 23, the FDA released final guidance on both in vitro and clinical DDI studies, identifying physiologically-based pharmacokinetic (PBPK) modeling, such as with the Simcyp Simulator, as an accepted alternative to certain DDI studies and to support dose selection.

“[With the simulator,] projects can take some period of weeks to months, which is a much shorter timeframe than running a clinical trial... and much less expensive,” Leinfuss says. “It’s a wonderful thing for the sponsor company to be able to avoid a clinical trial in general because that speeds up the process and reduces their costs. But the simulator is also used for advising along the way, selecting patients that can go into the trials so they progress faster and are more efficient.”

Certara is still finding ways to refine Simcyp’s models, oftentimes turning to consortium members who describe new features they’d like to see incorporated into the simulator. Both Patel and Leinfuss say this collaborative approach is the key to the simulator itself.

“The interesting thing about this technology is that it’s evolving in its ability to be used to make reliable predictions about how drugs will behave under different circumstances that weren’t necessarily tested,” says Leinfuss. “It can give you a head start on knowing to go down a specific avenue, or sometimes it can be the avenue.”