[C16] Infectious Diseases

[C16-05] Modeling clinical trial design considering differences in IC50 between in vitro and in vivo : A case study for COVID-19

*Shotaro Yamamoto¹, Taiga Miyazaki², Shoya Iwanami¹, Shingo Iwami¹ (1. Nagoya University (Japan), 2. University of Miyazaki (Japan))

Keywords:

Modeling&Simulation,Clinical trials,Drug repurposing,potency reduction factor

The COVID-19 pandemic has demonstrated the global threat of infectious diseases, highlighting the necessity of preparing for future outbreaks. Rapid drug development is a key aspect of this preparedness, requiring well-designed clinical trials. In a clinical trial of nelfinavir (NFV), a candidate of anti-SARS-CoV-2 drug, the required sample size was calculated using a simulation combining in vitro antiviral activity data and a mathematical model of in vivo viral dynamics. However, the trial showed no significant difference in the primary endpoint, i.e., time to viral clearance, suggesting a possible discrepancy between in vitro and in vivo efficacy. We analyzed clinical trial data to quantify the difference in nelfinavir’s antiviral efficacy between in vivo and in vitro. The analysis used salivary viral RNA load data from a open-label randomized controlled trial conducted at 11 sites in Japan from July 2020 to October 2021. We estimated potency reduction factor (prf), representing the ratio between in vivo and in vitro half maximal inhibitory concentration (IC₅₀) using mathematical models while accounting for inter-participant variability. Then, we generated “virtual patients“ from the estimated distribution of model parameters and simulated clinical trials to evaluate the effect of prf on the endpoints. To explore better dosing regimens and conditions, the required sample sizes were calculated under varying scenarios. The estimated prf ranged from 2 to 5, indicating thatConcentrations 2-5 times higher than those expected in vitro were needed to achieve 50% inhibition in vivo. The required sample size was over 4,000 for each group with the reduction of antiviral efficacy in vivo, which was about 70 times larger than the 60 participants designed in the NFV clinical trial. Even with an alternative high-dose regimen, the estimated sample size remained large at approximately 15,000 for each group. Conversely, if in vivo efficacy were assumed to be equal to in vitro efficacy, the required sample size would drop to around 60 for each group. These findings suggest that clinical trial designs should account for discrepancies between in vitro and in vivo drug efficacy. Future research needs to focus on improve the accuracy of clinical trial design, for example, estimating prf values before designing clinical trial by using the patient’s data who received compassionate uses of drug candidates.