Hydroxyurea Pharmacokinetic Profiles in Children Treated for Extreme Thrombocytosis after Total Pancreatectomy with Islet Cell Autotransplant Demonstrate Poor Absorption

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.4893-4893
• Main Authors: Boucher, Alexander A, Dong, Min, Marahatta, Anu, Hausfeld, Adriane, Howard, Thad A., Nathan, Jaimie D, Vinks, Alexander A., McGann, Patrick T., Ware, Russell E., Luchtman-Jones, Lori
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-127378

Background Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical treatment for chronic recurrent pancreatitis that involves splenectomy, pancreatectomy and creation of a Roux-en-Y, followed by re-injection of the pancreatic islets into the portal vein. Postoperatively, patients develop a sustained and extreme thrombocytosis (ExT) with platelets ≥1000 K/μL, a response more exaggerated than the typical post-splenectomy course (Gurria JP et al, Pancreas 2019). Empiric aspirin (antiplatelet effect) and hydroxyurea (cytoreduction) are initiated postoperatively per a standard protocol. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of hydroxyurea have not been studied in children other than young children with sickle cell disease; neither dose nor dose interval have been evaluated in TPIAT patients. Recently a population PK model was developed to support individualized hydroxyurea dosing in patients with sickle cell anemia (SCA; Dong M et al, Br J Clin Pharmacol 2016). In a prospective evaluation as part of the Therapeutic Response Evaluation and Adherence Trial (TREAT, McGann PT et al, Am J Hematol 2019), PK-guided individualized dosing resulted in better clinical and laboratory benefits than with conventional weight-based dosing. This study aimed to determine if a hydroxyurea PK model could be developed for non-SCA children dosed postoperatively for control of TPIAT-associated ExT, and if so, to compare it to previously published models for SCA. Methods A prospective single-site pilot study was performed in patients ages 0-21 years who underwent TPIAT between April 2018 and June 2019. Whole blood was collected via finger stick or venipuncture at 3 time points (20 minutes, 1 hour, 4 hours) after the initial hydroxyurea dose (15-20 mg/kg), given between postoperative day 5-7 (PK1). Plasma hydroxyurea was quantified by high performance liquid chromatography on 150-200 μL plasma. Testing was repeated once 2-6 months postoperatively (PK2) to determine whether PK profiles changed over time in relation to surgery. PK analyses and estimation of the area under the concentration-time curve (AUC) as a measure of exposure were performed using MW/Pharm (Mediware, Prague, Czech Republic). PK data from HUSTLE (NCT00305175) were used for comparison to SCA patients. Results Of 19 enrolled subjects, 15 had evaluable results: 7 had both PK collections while 8 had a single collection (5 only had PK1, 3 only had PK2). All 5 patients with only PK1 me