~~~~ The objectives of the Bioanalytical Core are to develop and apply validated analytical methods for determination of drug levels for preclinical studies proposed in Projects 1 and 2 and for a pre-Phase I clinical study proposed in Project 3. The Core will also prepare intravaginal rings (IVRs) under Good Manufacturing Practice (GMP) to deliver tenofovir disoproxil fumarate (TDF), a more potent prodrug of tenofovir (TFV) with an excellent preclinical safety profile for a pre-Phase I pharmacokinetic (PK) study. The Core has developed and optimized bioanalytical methods to detect TDF and related metabolites for in vitro studies and will expand this work and validate as per ICH guidelines methods for quantification of GS7340, an alternative potent prodrug of tenofovir (TFV), as well as for IQP-0528, a pyrimidinedione with reverse transcriptase and entry inhibitory activity and maraviroc (MVC). The Core will also validate methods to detect intracellular concentrations of 2'deoxyadenosine triphosphate (dATP), the natural substrate and competitive analogue of tenofovir diphosphate (TFV-DP). Dr. Craig Hendrix, co-investigator, who is a leader in the development and validation of assays to measure TFV and TFV-diphosphate (the active metabolite) in blood, peripheral blood mononuclear cells (PBMCs), cervicovaginal lavages (CVL) and cervicovaginal (CV) aspirates, rectal sponges, and vaginal and cervical biopsy tissue for clinical trials, will expand the clinically validated UPLC/MS/MS methods established in his laboratory and develop assays to quantify TDF in clinical samples. Once validated to ICH and FDA standards, these assays (along with established TFV and TFV-DP assays) will be applied to the analysis of samples obtained in a pre-Phase I PK study proposed in Years 4 and 5 in Project 3. This will include measurements of TDF and appropriate metabolites in CV aspirates, cervical and vaginal biopsies, rectal sponges, and blood. The Core will leverage the ongoing work at Particle Sciences in the development of the TDF polyurethane intravaginal ring, regulatory testing, and filing of an IND and will support the development of the product and provide clinical supplies for the pre-Phase I vaginal ring study.
The Core will develop and validate bioanalytical methods to measure drug levels that are critical to the evaluation of antiretroviral pharmacokinetics for preclinical and clinical studies and provide intravaginal rings for a pre-Phase I clinical study. The bioanalytical assays will have implications for oral and other vaginal formulations that include any of the antiretroviral drugs that are the focus of this Program and thus will advance the HIV prevention field.
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