Pediatric toxoplasmosis: Addressing unmet medical need with 3D printed dose flexible delivery systems of pyrimethamine, sulphadiazine and leucovorin

ABSTRACT / PROJECT SUMMARY Toxoplasmosis is a life-threatening food-borne/congenital disease that can have severe implications in immuno-compromised children. The US Center for Disease Control (CDC) estimates that 11% of the US population of age six years and older carry the parasite, Toxoplasma gondii. Congenital and acquired toxoplasmosis in pediatric patients are treated with pyrimethamine and sulfadiazine plus leucovorin for 12 months or longer. However, no pediatric formulation of pyrimethamine is commercially available, and the high cost of available adult products (Daraprim and generic pyrimethamine 25 mg tablet prices are $790.1 and 677.6/tablet, respectively) makes the treatment cost-prohibitive even when using a single drug, and FDA- approved formulations of sulfadiazine have been discontinued. Currently, pharmacists compound pediatric formulations from drug substance of sulfadiazine and pyrimethamine or adult pyrimethamine tablets, but physicians, the FDA, and NIH have raised concerns about dose accuracy, quality, stability, bioavailability, efficacy, safety, and the consistency of extemporaneous preparations. Dose adjustment/flexibility is difficult to achieve in solid-dosage forms, as each dose strength must be manufactured separately. However, newer manufacturing methods such as 3D printing can be used to produce dose-tailored or flexible solid-dosage forms, which can easily be prepared in a clinical hospital environment for pediatric use. Based on these considerations and support for deployment at Driscoll Children’s Hospital in South Texas, the objective of this proposal is to demonstrate the feasibility of a 3D printed dose-flexible pediatric delivery system (printlets) of three drugs (i.e., pyrimethamine, sulfadiazine, and leucovorin calcium) individually and in combination in a single printlet system. Administering these drugs as age-appropriate flexible pediatric delivery systems is expected to overcome the limitations of adult dose manipulations for compounding in pharmacies and address a significant unmet medical need in children. Aim I involves developing, assessing palatability, and characterizing a dose-flexible delivery system that will meet FDA and USP requirements for drug identity, quality, purity, and stability. Aim II involves pharmacokinetic and pharmacodynamic evaluation in animal models and palatability evaluation in a human taste panel. The project is expected to advance scientific knowledge regarding the feasibility and utility of a dose- flexible delivery system using 3D printing for pediatric toxoplasmosis treatment that could be applied to other classes of drugs where no pediatric formulation exists. Successful completion of the project will have a significant positive impact on the realization of the delivery system in clinical use and deployment in hospitals with further development and regulatory filing to the FDA for broader use. The PI and his team have ample experience with the proposed studies. The PI led the FDA team of scientists and reviewers through the approval of the first and only 3D-printed drug product (Spritam®).