Tenofovir Disoproxil

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are nucleoside reverse transcriptase inhibitors (NRTIs) used together against HIV. After intracellular phosphorylation, they compete with natural deoxynucleoside triphosphates (dNTPs) for incorporation into viral DNA, causing chain termination. A mathematical model of the molecular mechanism of action was used to test two possible direct drug-drug interactions: depletion of dNTP pools and dead-end complex (DEC) formation, where FTC-TP binds to a TFV-DP-terminated primer and blocks excision. The model predicts that dNTP pool depletion explains the synergistic effect at clinically relevant concentrations, whereas DEC formation plays only a minor role. Without direct interactions, no synergy is observed. DEC formation may become more relevant when non-nucleoside reverse transcriptase inhibitors (NNRTIs) are added. Thus, dNTP depletion is the primary mechanism of synergy between TDF and FTC.

Fig. 1 Model of the molecular mechanisms of action of NRTls and drug interactions. (Iannuzzi S, von Kleist M. 2021)

A pH-sensitive chitosan-g-poly(acrylamide-co-acrylic acid) hydrogel was developed for controlled delivery of tenofovir disoproxil fumarate (TDF), an anti-hepatitis B drug. Free radical polymerization was used, and the hydrogel exhibited good thermal stability, a porous fibrous surface, and pH- and ionic strength-dependent swelling. Swelling was low at acidic pH but higher at neutral and basic pH. Cytotoxicity tests on HeLa cells confirmed biocompatibility. Encapsulation efficiency reached 96% with 10% drug loading. In vitro release studies showed a pH-dependent profile: TDF release at pH 7.4 was up to five times higher than at pH 1.2 over 96 hours. This hydrogel is a promising smart oral delivery system for TDF.

Fig. 2 SEM microphotographs and EDS spectrum of the chitosan-g-poly hydrogel. (Safari J B.; et al. 2021)