When a promising compound reaches its first-in-human (FIH) trial, precision is everything. But what if healthy volunteers don’t represent the patients who’ll ultimately receive the drug? In a recent schizophrenia-focused project, insights from real-world patient behaviours, including cannabis use, transformed the way dosing strategies were planned—highlighting how deeply patient-driven insights can shape smarter, safer development paths.
Developing new therapeutics for complex conditions like schizophrenia demands more than just scientific rigour—it requires an intimate understanding of the patient population. In the earliest phases of clinical research, particularly first-in-human studies, the default is often to test new drugs on healthy volunteers. This approach aims to establish initial safety profiles and dose ranges. However, a key challenge arises when these findings may not adequately reflect the experiences of the actual patients the drug is intended for. That was precisely the issue facing a recent client preparing a FIH trial for a schizophrenia treatment.
We began by examining the drug’s metabolic profile in depth. The compound was found to be a substrate for cytochrome P450 (CYP) 3A4, a member of a vital enzyme family that metabolises a significant proportion of pharmaceuticals. Unlike many drugs which engage multiple metabolic pathways, this particular compound relied almost exclusively on CYP3A4 for clearance. This characteristic heightened its sensitivity to interactions with other substances that inhibit or induce the same enzyme, creating a potential risk of unpredictable drug exposure levels.
Understanding that the target population included a high percentage of individuals who smoke, and more specifically smoke cannabis, added another layer of complexity. Cannabis contains compounds such as tetrahydrocannabinol (THC) and cannabidiol (CBD), both known inhibitors of CYP3A4. For schizophrenic patients using cannabis, inhibition of CYP3A4 could significantly slow the drug’s metabolism. This would elevate systemic exposure, potentially increasing the risk of adverse effects—an outcome that wouldn’t be apparent if only healthy non-smoking volunteers were studied.
These patient-specific insights were critical in rethinking the FIH trial design. The original dose range proposed by the client for healthy participants didn’t account for the elevated exposure levels likely in patients due to CYP3A4 inhibition. By applying this foresight, we recommended adjusting the dose range and including additional dose levels. This approach was designed to achieve a more comprehensive understanding of the drug’s pharmacokinetics and provide a broader safety margin, ensuring that any future drug-drug interactions observed in the target population wouldn’t compromise efficacy or safety.
Our strategic adjustments helped anticipate and mitigate clinical risks before the drug ever reached the patient population. It underscored the value of integrating patient behaviour, lifestyle factors, and metabolic nuances early in drug development. This case exemplifies how proactive, patient-focused planning enables better extrapolation from healthy volunteer data to patient outcomes—ultimately accelerating safer and more effective therapies to market.
Understanding the target population isn’t just a clinical formality—it’s a strategic imperative. By factoring in lifestyle influences like cannabis use and their metabolic impact, our client was able to fine-tune a FIH study that generated truly applicable insights. It’s a testament to the power of integrating patient-driven data into early-phase trial design, ensuring not only regulatory success but real-world relevance.
hVIVO plc (formerly Open Orphan plc) is a rapidly growing specialist contract research organisation (CRO) and the world leader in testing infectious and respiratory disease vaccines and antivirals using human challenge clinical trials, providing end-to-end early clinical development services for its broad and long-standing client base of biopharma companies.
