ABSTRACT/SUMMARY An estimated 1.7 million children aged 0-14 were living with HIV, and at least 300,000 children were newly infected with HIV in 2020. Another 120,000 children died from AIDS-related causes during the same period. Combination therapy with antiretroviral (ARV) drugs has significantly improved AIDS-related morbidity and mortality. Among all the factors, adherence to HIV treatment pose major challenges in achieving desired therapeutic outcome. A major barrier to ARV treatment adherence is the lack of dose-flexible pediatric-friendly formulations. One of the combination ARV drugs recommended for children ≥2 to 12 years is tenofovir disoproxil fumarate (TDF) and lamivudine (3TC). Dose flexible formulation of TDF-3TC combination is not available. Pharmacists, thus, have to compound pediatric formulations from adult drug products. However, physicians, FDA, and NIH alike have raised concerns on dose accuracy, stability, sterility, bioavailability, efficacy, safety, and consistency of extemporaneous preparations. The 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 for dose-tailored or flexible solid-dosage forms, which can easily be set-up/prepared in a clinical hospital environment for pediatric use. Based on the aforementioned considerations, and support for deployment at Driscoll Children’s Hospital in South Texas, the objective of the proposal is to demonstrate the feasibility of printing dose-flexible pediatric co-delivery system (printlets) of two drugs, namely 3TC and TDF in a single printlet system. The premise of this proposal is further supported by our preliminary data on TDF, and published work on isoniazid, lopinavir, diclofenac, and clindamycin. Furthermore, the need for a pediatric delivery system of antiretroviral drugs is reported in the NICHD 2020-2021 priority list. Thus, administering TDF/3TC as age-appropriate flexible pediatric co-delivery systems will overcome the limitations of adult dose manipulations for compounding in pharmacies and address a significant unmet medical need in children. Aim I involves mechanistic understanding printing pediatric co-delivery systems, and characterization for quality, stability, and palatability as per FDA and USP requirements. Aim II involves palatability (human), safety and efficacy evaluation of flexible pediatric co-delivery systems (printlets) by pharmacokinetics and pharmacodynamics methods. The proposal will advance scientific knowledge of a dose-flexible delivery system using 3D printing for pediatric HIV treatment that can be applied to other classes of drugs where no pediatric formulation exists. The successful completion of the proposal 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®).

PROJECT NARRATIVE This proposal seeks to mechanistically develop and characterize age-appropriate dose-flexible pediatric co- delivery (combination) system of lamivudine and tenofovir disoproxil fumarate by selective laser sintering 3D printing method. It is expected that the quality, stability, palatability (human), pharmacokinetic and pharmacodynamic (safety and efficacy) profiles of dose-flexible pediatric co-delivery systems would be similar to commercial tablet formulations (Epivir, Viread® or CimduoTM), which are non-flexible. The pediatric delivery systems will meet FDA and USP requirements for eventual deployment in hospitals for pediatric use.