Transport and Permeation Properties of Dapivirine: Understanding Potential Drug-Drug Interactions

Area of Science:

• Pharmacology
• HIV Prevention Research
• Drug Interactions

Background:

• The dapivirine (DPV) vaginal ring is a microbicide for HIV prevention.
• Concomitant use of DPV and miconazole (MIC) alters DPV pharmacokinetics.
• The mechanism behind this DPV-MIC interaction requires investigation.

Purpose of the Study:

• To investigate if DPV transport and permeation contribute to the DPV-MIC interaction.
• To evaluate DPV interaction with key transporters in the female reproductive tract.
• To assess the impact of DPV/MIC on cellular tight junctions and tissue permeability.

Main Methods:

• Vesicular and cellular assays to test DPV interaction with MRP1, MRP4, P-gp, BCRP, and ENT1 transporters.
• Ussing chamber experiments to monitor transepithelial electrical resistance and assess tight junction integrity.
• Human cervical tissue explants to evaluate MIC's effect on DPV permeability and tissue levels.

Main Results:

• DPV was not a substrate for MRP1, MRP4, P-gp, BCRP, or ENT1 transporters, nor did it inhibit their activity.
• DPV and MIC, alone or combined, did not disrupt cellular tight junctions.
• MIC did not alter DPV tissue permeability but significantly reduced DPV tissue concentrations.

Conclusions:

• The observed DPV-MIC interaction is unlikely due to the tested transporters (MRP1, MRP4, P-gp, BCRP, ENT1).
• Altered tight junction integrity or tissue permeability are not the cause of the DPV-MIC pharmacokinetic changes.
• Further research is needed to elucidate the mechanism behind the reduced dapivirine tissue levels in the presence of miconazole.