Introduction: Sickle cell anemia (SCA) is a severe and devastating hematological disorder that affects nearly 100,000 persons in the United States and millions more worldwide. There is now ample clinical evidence that hydroxyurea, a once-daily oral medication, is safe and effective for both adults and children with SCA. The 2014 National Heart, Lung, and Blood Institute's evidence-based guidelines for SCA, recommend that hydroxyurea now be offered to all affected children as young as nine months of age, regardless of clinical severity. Despite the overwhelming evidence demonstrating safety and efficacy, hydroxyurea remains underutilized for a variety of reasons. Two of the most significant barriers are the identification of the most effective hydroxyurea dose and the accurate and objective monitoring of hydroxyurea adherence. In this translational trial, Dr. McGann aims to utilize several novel and innovative methods to address these barriers. Candidate and Career Development Plan: Dr. McGann is an Assistant Professor of Pediatrics at Cincinnati Children's Medical Center (CCHMC) in the Division of Hematology. His research focuses on improving outcomes for children with SCA. His short-term goal is to develop an expertise in pediatric clinical pharmacology and pharmacometric modeling through a comprehensive training program and the close mentorship of Dr. Alexander Vinks. He also aims to develop further expertise in clinical research for children with SCA. His long-time mentor, Dr. Russell Ware, will continue to provide close mentorship in the area of pediatric hematology and clinical research for children with SCA and support his continued career development. Dr. McGann's long-term goal is to become an independent investigator with research focused on children with SCA both in the US and in sub-Saharan Africa. The clinical burden of SCA in Africa is in sharp contrast to the lack of resources and clinical research. Dr. McGann aims to use his training in pediateri hematology and pharmacology to improve the therapies and outcomes for children with SCA through innovative clinical research. Research Environment: The research environment at CCHMC provides an exceptional setting for Dr. McGann to develop into an independently funded clinical investigator. CCHMC has a long-history of investment in junior investigators and Dr. McGann has the full support of the Department of Pediatrics and the Division of Hematology. He has developed a strong cadre of mentors across the institution, and has access to a wide range of institutional resources that will allow him to achieve his career goals. Research Strategy: The central hypothesis of this research proposal is that the effectiveness of hydroxyurea treatment for SCA can be improved by using novel pharmacometrics-based dosing and innovative laboratory techniques to measure adherence and response to therapy. The study includes the following Specific Aims: 1) Reduce the time it takes to reach maximum tolerated dose (MTD) of hydroxyurea for children with SCA using a novel population pharmacokinetic/pharmacodynamic (PK/PD) model; 2) To identify a unique urine metabolomics signature from hydroxyurea exposure, that can be used to monitor adherence; 3) Perform pharmacogenomics analyses to identify genetic markers that are associated with the hydroxyurea MTD. Summary: In this K23 application, Dr. McGann is seeking the formal mentorship, training and research support that will allow him to develop into an independently funded clinical investigator with a special focus of improving and personalizing therapy for children with SCA.

Public Health Relevance

Sickle cell anemia is an inherited blood disorder affecting nearly 100,000 persons in the United States. Hydroxyurea is the only widely available medication that significantly reduces the pain and suffering associated with sickle cell anemia, but there are many barriers to the expansion of effective hydroxyurea, including selecting the appropriate dose and monitoring adherence to therapy. The proposed research aims to develop new techniques to more effectively select the correct dose of hydroxyurea and monitor adherence to therapy in order to reduce the pain and suffering associated with this serious disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
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Werner, Ellen
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Cincinnati Children's Hospital Medical Center
United States
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Smart, Luke R; Ambrose, Emmanuela E; Raphael, Kevin C et al. (2018) Simultaneous point-of-care detection of anemia and sickle cell disease in Tanzania: the RAPID study. Ann Hematol 97:239-246
McGann, Patrick T; Williams, Anne M; Ellis, Graham et al. (2018) Prevalence of inherited blood disorders and associations with malaria and anemia in Malawian children. Blood Adv 2:3035-3044
McGann, Patrick T; Williams, Thomas N; Olupot-Olupot, Peter et al. (2018) Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub-Saharan Africa. Am J Hematol 93:537-545
McGann, Patrick T; Hernandez, Arielle G; Ware, Russell E (2017) Sickle cell anemia in sub-Saharan Africa: advancing the clinical paradigm through partnerships and research. Blood 129:155-161
McGann, Patrick T; Hoppe, Carolyn (2017) The pressing need for point-of-care diagnostics for sickle cell disease: A review of current and future technologies. Blood Cells Mol Dis 67:104-113
McGann, Patrick T; Schaefer, Beverly A; Paniagua, Mary et al. (2016) Characteristics of a rapid, point-of-care lateral flow immunoassay for the diagnosis of sickle cell disease. Am J Hematol 91:205-10
McGann, Patrick T (2016) Hydroxyurea for abnormal TCDs: safe to switch? Blood 127:1738-40
McGann, Patrick T (2016) Time to Invest in Sickle Cell Anemia as a Global Health Priority. Pediatrics 137:
McGann, Patrick T; Tshilolo, Léon; Santos, Brigida et al. (2016) Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial. Pediatr Blood Cancer 63:98-104
Marahatta, Anu; Megaraj, Vandana; McGann, Patrick T et al. (2016) Stable-Isotope Dilution HPLC-Electrospray Ionization Tandem Mass Spectrometry Method for Quantifying Hydroxyurea in Dried Blood Samples. Clin Chem 62:1593-1601

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