Physicochemical Interactions Between Concomitantly Administered Anti-Retroviral and Anti-Malarial Drug

Abstract

Purpose

To investigate the physicochemical interactions between concomitantly administered anti-malarial and antiretroviral drugs.

Methods

The physicochemical interactions between antimalarial fixed dose combination i.e., Artemether (A) and Lumefantrine (L) with Nevirapine (N) or Efavirenz (E) were investigated separately. The physical mixtures (ALE and ALN) were subjected to solubility, pH shift dissolution (in phosphate and biorelevant media), solid-state characterisation and ex-vivo permeability studies.

Results

For Artemether-Lumefantrine + Efavirenz (ALE) system, the pH shift dissolution study revealed that artemether concentration in mixture decreased to half of its pure drug dissolution in the presence of Lumefantrine and Efavirenz. Further, solid state characterisation confirms the in-situ conversion of artemether into amorphous form in the presence of Lumefantrine and Efavirenz. Similarly, in the ex-vivo everted gut sac permeability study, permeability of Artemether in the presence of Lumefantrine and Efavirenz decreased by half compared to the permeability of Artemether alone, due to physicochemical interactions. For Artemether-Lumefantrine + Nevirapine (ALN) system, there was no significant change in the dissolution of artemether from the combination and alone. However, the permeability of Artemether was decreased to half of its pure drug permeability in the presence of Lumefantrine and Nevirapine, which may be attributed to the inducation of Cytochrome P450 3A4 and P-glycoprotein enzyme by Nevirapine.

Conclusion

The dissolution and permeability of Artemether in the mixtures were reduced to half of its pure drug dissolution and permeability in the presence of antiretroviral drugs due to physicochemical interactions, which may lead to a decrease in bioavailability. This study’s results reveal concomitant administration of these drugs could lead to treatment failure due to physicochemical interactions.