As FIH clinical trials are studies during which a drug is administered to humans for the first time, and mostly performed with healthy participants, they serve the purpose of establishing a safe dose range for further clinical development. Our client needed to make sure that the FIH trial yielded results relevant to the intended target population. It was therefore imperative that the doses chosen for the trial were likely to be both effective and safe in patients with schizophrenia.
We conducted a complete review of the pre-clinical data. During this review we recognised that the active pharmaceutical ingredient was a substrate for cytochrome P450 (CYP) 3A4 and had little involvement with other clearance pathways.
CYP enzymes are a protein superfamily involved in the metabolism of many drugs. Within the CYP superfamily there are many isoforms; CYP3A4 is one of them. CYP enzymes control the extent and speed at which drugs are broken down, and consequently also the duration that drugs are present in the body. Therefore, CYP enzymes are often studied for their drug-drug interactions (DDIs). If a CYP enzyme is inhibited, drugs are metabolised at a slower rate resulting in higher concentrations and longer exposure – this is a potential risk with respect to safety and toxicity. If the CYP enzyme is induced, drugs are metabolised at an increased rate resulting in lower concentrations and shorter exposure, thus rendering the drug ineffective – the patient will not benefit from taking the drug. Our client’s drug appeared to be solely metabolised by CYP3A4, making it particularly susceptible to CYP3A4 DDIs.
When considering the target population, we anticipated that a high proportion of patients would be smokers and, by extension, more likely to be smoking cannabis. When smoking cannabis, schizophrenic patients would be exposed to both tetrahydrocannabinol (THC) and cannabidiol (CBD), both of which have the potential to inhibit CYP3A4. As the drug under development was a substrate for CYP3A4, inhibition of CYP3A4 by smoking cannabis was thought to possibly lead to an increase in exposure, which in turn could increase the risk of adverse events or safety issues. It was important for our client to recognise and take this into account when designing the FIH trial.
Based on the in-depth analysis and insights we provided it was anticipated that, because of the CYP3A4-mediated DDI, drug exposure and variability in exposure could be higher in the target population of schizophrenic patients than in healthy participants. The initial dose range suggested by the client for the FIH study in healthy participants may not have reflected the exposure in patients. We gave guidance to optimise the initial design to include additional dose levels in order to generate sufficient exposure and subsequently achieve a wider safety margin versus the efficacious exposure, in case a clinically relevant DDI in patients is observed.
It is clear that understanding the target population at an early stage of drug development is important. This allows for an optimised design for FIH and other early-phase clinical pharmacology trials in healthy participants, ensuring that the results will be applicable, and can be extrapolated, to the target population.
Hazel Ross is a Clinical Pharmacokinetics (PK) Consultant at Venn Life Sciences, a role she has held since 2020, and a specialist in metabolism and PK. After completing a BSc in Pharmacology from the University of Sheffield in the UK, she has since gained over 15 years of experience in the pharma industry. Her expertise includes PK/PD design, analyses and reporting for both pre-clinical and clinical studies, with strong clinical and regulatory knowledge for Phase I/II trials.
