Preterm labor is a major cause of neonatal morbidity and mortality. Evidence for individualized therapy choice, a key tenant of personalized medicine, is lacking in many areas of obstetric medicine, including in the treatment choices for preterm labor. Incorporating principle components of clinical pharmacology, including pharmacogentics, pharmacokinetics, and quantitative models, into obstetrical research enriches the ability to individualize drug choice and dosing. The objective of this K23 proposal is to provide the advanced training and expertise necessary for the applicant to develop quantitative pharmacology models specific to the obstetric population. The candidate, Dr. Sara Quinney, Pharm.D., Ph.D., is a clinical pharmacologist and Assistant Research Professor in the Department of Obstetrics and Gynecology at the Indiana University School of Medicine (IUSM). Dr. Quinney's career goal is to combine laboratory and clinical data into quantitative pharmacometric models to optimize drug therapy in pregnant women. IUSM hosts a robust academic environment with a strong history of clinical research and a commitment to mentoring young faculty members. The mentors and advisors to this proposal will bring strengths in the areas pertinent to Dr. Quinney's career development. The primary mentor, Dr. David Flockhart, M.D., Ph.D., is an internationally recognized clinical pharmacologist who has shown a commitment to training translational investigators. The Department of Obstetrics and Gynecology at IUSM is home to an exceptional OB/GYN residency program and has excellent resources for translational research, including an established staff of clinical research assistants that are available to Dr. Quinney. The Center for Computational Biology and Bioinformatics (CCBB) provides access to computational resources needed for the completion of the proposal. The central hypothesis of the proposed research study is that nifedipine treatment can be optimized by a novel pharmacokinetic/ pharmacodynamic model that allows clinicians to select an optimum dosing regimen for nifedipine. A clinical trial will be conducted to test the hypothesis that women exposed to higher plasma concentrations of nifedipine are more likely to respond to nifedipine tocolysis and delay delivery at least 48 hours. Pharmacogenetic variations in nifedipine pathway genes, e.g. CYP3A4, CYP3A5, CACNA1C, and CACN1C, will be tested for association with tocolytic response to nifedipine. Secondly, using in vitro data on nifedipine metabolism and the results of the clinical study, a quantitative model that incorporates patient-specific covariates will be developed with the aim to of identifying optimal, individualized dosing regimens of nifedipine for preterm labor through more individualized treatment. This study is significant in that understanding of the factors associated with the variable response to nifedipine can improve the treatment of preterm labor. In addition, this study will lay the foundation for quantitative models of other drugs used in the treatment of preterm labor and other conditions of pregnancy, and for a successful career in obstetrical pharmacology for the candidate.
|Nader, Ahmed M; Quinney, Sara K; Fadda, Hala M et al. (2016) Effect of Gastric Fluid Volume on the In Vitro Dissolution and In Vivo Absorption of BCS Class II Drugs: a Case Study with Nifedipine. AAPS J 18:981-8|
|Zhang, P; Du, L; Wang, L et al. (2015) A Mixture Dose-Response Model for Identifying High-Dimensional Drug Interaction Effects on Myopathy Using Electronic Medical Record Databases. CPT Pharmacometrics Syst Pharmacol 4:474-80|
|Han, X; Quinney, S K; Wang, Z et al. (2015) Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach. Clin Pharmacol Ther 98:321-7|
|Du, L; Chakraborty, A; Chiang, C-W et al. (2015) Graphic Mining of High-Order Drug Interactions and Their Directional Effects on Myopathy Using Electronic Medical Records. CPT Pharmacometrics Syst Pharmacol 4:481-8|
|Blue, Emily K; Ballman, Kimberly; Boyle, Frances et al. (2015) Fetal hyperglycemia and a high-fat diet contribute to aberrant glucose tolerance and hematopoiesis in adult rats. Pediatr Res 77:316-25|
|Quinney, Sara K; Patil, Avinash S; Flockhart, David A (2014) Is personalized medicine achievable in obstetrics? Semin Perinatol 38:534-40|
|Haas, David M; Benjamin, Tara; Sawyer, Renata et al. (2014) Short-term tocolytics for preterm delivery - current perspectives. Int J Womens Health 6:343-9|