Abstract
Tenofovir disoproxil fumarate (TDF), the bisphosphonate ester prodrug of tenofovir (TFV), has poor bioavailability due to intestinal degradation and efflux transport. Reformulation using U.S. Food and Drug Administration–approved esterase and efflux inhibitors to increase oral bioavailability could provide lower dose alternatives and reduce costs for patients with HIV in resource-limited settings. Inhibition of mucosal and intracellular esterases was studied in human and rat intestinal extracts (S9), where TDF was protected by the carboxylesterase inhibitor bis-para-nitrophenylphosphate, the ester mix EM1, and the generally recognized-as-safe (GRAS) excipient propylparaben. Permeability studies using Madin-Darby canine kidney and Caco-2 cell monolayers demonstrated that TDF was a substrate for the permeability glycoprotein with permeability glycoprotein inhibitors reducing basolateral to apical transport of TDF. These studies also showed that transport was increased by esterase inhibitors. TDF, TFV, and tenofovir monophosphonate ester transport across Caco-2 monolayers with esterase and efflux inhibitors revealed a maximum 38.7-fold increase in apical to basolateral TDF transport with the potent non-GRAS combination of EM1 and GF120918. Transport was increased 22.8-fold by the GRAS excipients, propylparaben, and d-a-tocopheryl polyethylene glycol 1000 succinate (a vitamin E derivative). TFV pharmacokinetics in rats following oral administration of TDF and GRAS esterase and efflux inhibitors confirmed enhanced bioavailability. Area under the curve increased 1.5- to 2.1-fold with various combinations of parabens and d-a-tocopheryl polyethylene glycol 1000 succinate. This significant inhibition of TDF hydrolysis and efflux in vivo exhibits the potential to safely increase TDF bioavailability in humans.
Highlights
37 million people worldwide were living with HIV/AIDS in 2015, and as of June 2015, less than half of them had access to antiretroviral therapy (ART).[1]
We showed that the following treatments were statistically different from the control based on 95% CIdEM1 þ GF918, PP þ tocopheryl polyethylene glycol succinate (TPGS), BP þ TPGS, EP þ TPGS, and TPGSdwhereas the following treatments were not statistically different from the control based on 95% CIdCsA alone, TPGS alone, EM1 alone, and cyclosporin A (CsA) þ BNPP
Two significant factors that limit oral bioavailability are the degradation of tenofovir disoproxil fumarate (TDF) in the gastrointestinal tract and the P-gp-mediated efflux of the absorbed drug back into the intestinal tract
Summary
37 million people worldwide were living with HIV/AIDS in 2015, and as of June 2015, less than half of them had access to antiretroviral therapy (ART).[1] Initiatives such as 90-90-902 and Test and Treat[3] have set the stage for 90% of patients with diagnosed HIV to be placed onto sustained ART by 2020. To avoid a financial crisis in the clinical management of 37 million people. Living with HIV/AIDS, the global health community is exploring every option possible to improve healthcare efficiencies. The first Conference on Antiretroviral Dose Optimization (CADO)[4] identified several realistic opportunities to refine treatment regimens through improvements in process chemistry, product dosage formulation, and dose optimization. One of CADO’s top priorities was to reformulate tenofovir disoproxil fumarate (TDF) to increase the product’s bioavailability
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