Drugs with a narrow therapeutic index (NTI) can cause mortality. For these drugs, small differences in concentrations may lead to serious toxicities or therapeutic failures. Consequently, in the setting of generic drug development, it is critical that NTI generic drugs achieve exposures similar to reference products. To enhance the therapeutic equivalence of drugs with NTI, the Food and Drug Administration has tightened their bioequivalence standards. However, broad implementation of these new standards is challenging because some drugs do not have an established NTI classification. This can be due to a lack in characterization of the drugs'therapeutic range or dose/concentration-response relationship. Therefore, there is an urgent and unmet need for a systematic approach to identify and classify drugs with a NTI. This proposal will use a unique infrastructure to integrate clinical practice data with statistical tools to characterize the drug dose/concentration- response relationship and classify drugs with NTI. The central hypothesis of this proposal is that the proposed systematic approach will result in successful classification of drugs with a NTI. Dr. Cohen-Wolkowiez will evaluate this hypothesis by performing a comprehensive search of publicly available data (literature and databases) to extract information and allow classification of drugs with NTI. Because the amount of detail included in publicly available databases is variable, Dr. Cohen-Wolkowiez will supplement this data with information extracted from medical records at the Duke University Medical Center. If sufficient data is available from these two sources, he will then characterize the concentration-response relationship of candidate drugs with NTI using population pharmacokinetics (PK)-pharmacodynamic (PD) methodologies. This project evaluates a novel, systematic approach to classify drugs with NTI. If the combination of publicly available data, supplemental data from medical records, and population PK-PD methodologies can classify drugs with NTI, this will substantially affect public health and streamline applicability of new FDA standards for bioequivalence of generic drugs with NTI.

Public Health Relevance

The proposed project will evaluate the use of clinical practice data to classify drugs with narrow therapeutic index. This goal will be accomplished using a comprehensive search of the medical literature, publicly available databases, and medical records in combination with statistical tools (population pharmacokinetic (PK)/pharmacodynamics (PD) models) that can characterize the drug concentration-response relationship to classify drugs with narrow therapeutic index. This classification will result in a drug list that will be used by the Food and Drug Administration to evaluate new bioequivalence standards of generic products with narrow therapeutic index.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1)
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Duke University
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Gonzalez, Daniel; Palazzi, Debra L; Bhattacharya-Mithal, Leena et al. (2016) Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents. Antimicrob Agents Chemother 60:2572-6
Ku, Lawrence C; Wu, Huali; Greenberg, Rachel G et al. (2016) Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine. Ther Drug Monit 38:728-737
Hill, Kevin D; Sampson, Mario R; Li, Jennifer S et al. (2016) Pharmacokinetics of intravenous sildenafil in children with palliated single ventricle heart defects: effect of elevated hepatic pressures. Cardiol Young 26:354-62
Gonzalez, Daniel; Delmore, Paula; Bloom, Barry T et al. (2016) Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants. Antimicrob Agents Chemother 60:2888-94
Greenberg, Rachel G; Melloni, Chiara; Wu, Huali et al. (2016) Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach. Clin Neuropharmacol 39:232-40
Zimmerman, Kanecia O; Wu, Huali; Greenberg, Rachel et al. (2016) Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal Transplant Patients. Ther Drug Monit 38:600-6
Thakkar, N; Gonzalez, D; Cohen-Wolkowiez, M et al. (2016) An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants. J Perinatol 36:744-7
Wang, Laura A; Cohen-Wolkowiez, Michael; Gonzalez, Daniel (2016) Advances in Pediatric Pharmacology, Therapeutics, and Toxicology. Adv Pediatr 63:227-54
Autmizguine, Julie; Hornik, Christoph P; Benjamin Jr, Daniel K et al. (2015) Anaerobic antimicrobial therapy after necrotizing enterocolitis in VLBW infants. Pediatrics 135:e117-25
Harskamp-van Ginkel, Margreet W; Hill, Kevin D; Becker, Kristian C et al. (2015) Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review. JAMA Pediatr 169:678-85

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