P31.03
Background: Combinations of antiretroviral (ARV) drugs, Tenofovir (TFV), Dapivirine (DPV) and Darunavir (DRV), provide enhanced antiviral activity compared to single agents when tested in vitro. However, the impact of co-formulation on drug absorption after delivery to the colo-rectal mucosa is unclear, and methods are required to screen drug-drug interactions. The aim of this study is to investigate the permeability of TFV, DPV and DRV across the colo-rectal epithelium, any role of transporters in regulating absorption and assess the effect of co-administering the microbicidal agents on their transport.
Methods: Permeability of TFV, DPV and DRV was investigated in vitro using the Caco-2 epithelial cell model grown on Transwell® inserts for 21- 28 days. The permeability of ARV drugs was measured, interactions with transporter and effect of co-administration of these ARV drugs, were evaluated.
Results: The respective absorptive and secretory permeability of TFV across Caco-2 cell monolayer was 0.12±0.04×10−6 cm/s and 0.13±0.05×10−6 cm/s. DPV demonstrated high permeability coefficient, 36±2.9×10−6 cm/s and 27±2.5×10−6 cm/s in the absorptive and secretory directions, respectively. TFV and DPV flux was not influenced by the presence of transporter inhibitor verapamil or co-administration with other ARV. Transepithelial transport of DRV was 6-fold greater in the secretory direction compared to absorptive direction. Modulation of the transport of DRV at 10 μM by verapamil was shown (ER decreased from 6 to 1). Co-administration of DRV with TFV, DPV and DPV/TFV in combinations resulted in equivalent transport as single agent.
Conclusions: TFV and DPV were passively transported across Caco-2 cells (non-vectorial and concentration independent). Transport of DRV was vectorial, concentration dependent and affected by transporter inhibitors, suggesting that DRV is a substrate of P-glycoprotein. Tested ARV drugs were unaffected by the presence of double or triple combinations.
