Research Physician Janssen Pharmaceuticals Merksem, Antwerpen, Belgium
Background: Historically, rifampicin was used as perpetrator in many DDI trials, due to its favorable safety profile and strong inducer capacities for CYP3A and others. Due to recent findings of impurities in rifampicin batches, FDA strongly suggested to switch from using rifampicin in healthy volunteer trials, to other strong inducers like carbamazepine or phenytoin. Because both compounds have different characteristics and a less favorable safety profile, rifampicin can’t be swapped without a significant impact on logistics and safety management. The strategic decision was taken to use carbamazepine as preferred compound for future DDI trials. Methods: Before the start of its first DDI trial with carbamazepine, a new safety risk management and mitigation plan was created. Safety mitigation steps were put in place, such as a slow dose up titration scheme. An impact analysis on increased screen fails and dropout rate was performed. Results: A total of 15 healthy volunteers were dosed with carbamazepine. Screen fail rate was 73%, compared to 50% average in healthy volunteer trials. A 20% dropout rate was recorded, compared to an average dropout rate of 5%. We recorded 5.3 adverse events per subject, compared to an average of 1.7 adverse events per subject overall in phase 1 research. A total of 80 adverse events were reported, 75% were considered at least possibly related to carbamazepine. No serious adverse events were reported. Conclusion: This first DDI trial, at our company, with carbamazepine was completed successfully. Apart from the operational and safety challenges, there were no operational incidents that jeopardized the smooth execution of the trial, nor were there any major safety incidents or serious adverse events reported. A first prudent conclusion is that carbamazepine is safe to use in a DDI trial in healthy volunteers.
