Using Clinical Pharmacology Principles to Develop New Therapeutics

Clinical Center

Investigators

Abstract

The CPL has analyzed the PK data from drug-drug interaction studies designed to address clinically important questions in human immunodeficiency virus (HIV) therapy. These were conducted in healthy volunteers due to ethical concerns with conducting the research in people living with HIV. The laboratory developed and validated bioanalytical assays and analyzed the differences in drug exposure for the following drugs using noncompartmental analysis: tenofovir alafenamide and metabolite exposure when given in addition to a once weekly rifapentine based tuberculosis treatment regimen and rivaroxaban exposure when given in addition to cobicistat alone or cobicistat with darunavir. More recently, the CPL has provided collaborative support for various early phase I/II clinical trials. The laboratory analyzed levels of metformin when given alone and in combination with liraglutide in African American youth with type 2 diabetes. We also analyzed the drug exposure of multiple Bruton’s tyrosine kinase inhibitors (ibrutinib, acalabrutinib, zanubrutinib) in an observational study evaluating the associated cardiotoxicity of the drug class. An assay was also developed, validated, and analyzed using noncompartmental methods for eltrombopag in people with Fanconi anemia. Pharmacokinetic and pharmacogenomic analysis was conducted on post-transplant cyclophosphamide in patients with sickle cell disease on two nonmyeloablative haploidentical protocols. Projects also included three further studies investigating post-transplant cyclophosphamide and multiple metabolites of interest for hematologic malignancies and two studies on post-transplant alemtuzumab. Moreover, the laboratory developed and validated assays for PF-5190457 and an active metabolite in alcohol use disorder, collaborating with the research team to analyze the PK/PD data. We also analyzed miransertib population PK in Proteus syndrome. The CPL also measured PK drug concentrations in plasma for specific patients using previously validated bioanalytical assays, for research purposes. Additionally, the CPL began setting up capabilities to analyze biologics in human serum, in addition to small molecule drugs through ELISA. This led to a collaboration on a post-transplant alemtuzumab PK study. We also continued to expand our biologics capabilities by further developing ECLIA assays to characterize the PK of an investigational drug, ZMA001, in healthy volunteers. Additionally, the CPL collaborated on a preclinical study for siltuximab, utilizing a LC-MS/MS method. The CPL also further worked on pharmacometric specific projects, by comparing pharmacokinetic softwares available on the market and collaborating with the Pharmacy Department to assist with therapeutic drug monitoring for busulfan. Finally, the laboratory also collaborates with other institutes on select preclinical studies. Examples include the National Eye Institute on a preclinical study for a potential drug candidate for retinal diseases.