Model Informed Drug Development (MIDD)

IQSP researchers have a long history of computational modeling, integrating biological, physical, engineering, computational and clinical sciences, in order to achieve the goal of “delivering the right drug at the right concentration at the right time to the right target”. An early example, with more than two decades of successful follow-up, was our work on the pharmacological basis of intravesical therapy for bladder cancer, which culminated in the design and execution of a randomized phase III trial. Through a series of preclinical and clinical studies, our group established the quantitative pharmacology of mitomycin C and other agents used to treat non-muscle invading bladder cancer, and determined inadequate drug delivery as a major cause of treatment failures. We hypothesized that treatment outcome can be calculated by comparing the drug CxT at target site and the response (i.e., pharmacokinetics vs. pharmacodynamics). Using this concept, we computer-simulated the therapeutic benefits from seven potential protocol changes, alone and in combination. The results showed that changing one parameter at a time would require >10,000 patients per parameter, but that simultaneous changes of 5 parameters would result in substantial improvement that can be demonstrated with only 230 patients in a 1:1 randomized trial. The simulation results further indicated that additional dose increase or dwell time increase would not further improve the cure rate. We conducted the above phase III trial in 230 patients; the observed increase in 5-year progression-free survival closely aligned with the simulation-predicted outcome (19% vs. 18-20%).  Our treatment protocol has since become a standard-of-care.

Wientjes MG, Dalton JT, Badalament RA, Dasani BM, Drago JR, Au JL. A method to study drug concentration-depth profiles in tissues: mitomycin C in dog bladder wall. Pharm Res 1991; 8:168-173.
Wientjes MG, Badalament RA, Au JL. Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer. Cancer Chemother Pharmacol 1993; 32:255-262.
Wientjes MG, Badalament RA, Wang RC, Hassan F, Au JL. Penetration of mitomycin C in human bladder. Cancer Res 1993; 53:3314-3320.

Wientjes MG, Badalament RA, Au JL. Penetration of intravesical doxorubicin in human bladders. Cancer Chemother Pharmacol 1996; 37:539-546.
Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, Pollifrone DL, Harbrecht JD, Chin JL, Lerner SP, Miles BJ. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001; 93:597-604.

Au JL, Wientjes MG. Intravesical chemotherapy of superficial bladder cancer: optimization and novel agents. In: Lerner SP, Schoenberg MP, Sternberg CN, editors. Textbook of bladder cancer. Taylor&Francis; 2006. p 341-352.