• Learn & Apply Paradigm to Inform Drug Development & Optimize Clinical Therapeutics in Oncology

      Mehrotra, Shailly; Gobburu, Jogarao (2017)
      Application of learn-apply paradigm in drug development and clinical therapeutics increases efficiency and supports decision making. The current research highlights the role of pharmacometrics to inform trial design and propose individualized management of chemotherapy induced peripheral neuropathy (CIPN) in oncology. The first project focuses on learning from early clinical trial of veliparib to inform future investigations. Population pharmacokinetics and exposure-response analyses were conducted to evaluate the contribution of intrinsic and extrinsic factors on veliparib PK, and assess the adequacy of veliparib dosing for the future trial. A 28% increase in AUC with mild renal impairment increases mucositis by only 7%, thus supporting the inclusion of patients with mild renal impairment in future trials without the need of dose adjustment. Exposure-response for efficacy (objective response rate and overall survival) and safety (mucositis) along with in vitro IC50 information supported 80 mg BID dose for veliparib. Multivariate exposure-response analysis provided supportive evidence to further evaluate veliparib in patients with myeloproliferative neoplasms and with 14 day treatment duration. The second project proposes a novel strategy based on precision therapeutics for the management of CIPN in clinical setting. An indirect response model with linear drug effect was able to describe the longitudinal-CIPN data reasonably well for paclitaxel, nab-paclitaxel and ixabepilone. The model was utilized to identify an early time point of 3 months that predicted later time course of CIPN (concordance probability ~ 75%). Utilizing the dose-CIPN model, a novel strategy to use patients own early CIPN data to predict their future CIPN time course was proposed. 'CIPN management dosing card' and 'CIPN precision therapeutics tool' were developed to prospectively manage CIPN in patients who may be at risk of developing CIPN later in the therapy. For paclitaxel, nab-paclitaxel and ixabepilone, the proposed CIPN management dosing card resulted in 61%, 48% and 35% fewer patients with CIPN after 6 cycles as compared to administering cycle 3 doses for 4th, 5th and 6th chemotherapy cycle. With CIPN precision therapeutics tool, oncologists can visualize the predicted CIPN time course and tailor the dosing to manage CIPN in an individual patient based on overall benefit/risk.