Bioavailability enhancement of a BCS IV compound via an amorphous combination product containing ritonavir

Abstract

Oral absorption of AKBA is substantially limited by intestinal CYP3A activity and poor aqueous solubility. Consequently, AKBA's oral bioavailability is maximized by administration from a supersaturating formulation in conjunction with a CYP3A inhibitor. The AKBA-RTV combination tablet presented herein represents a breakthrough in the oral delivery of the compound facilitating future use as a drug therapy for broad spectrum cancer treatment.

Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol®: a Review

“…16 for the plasma concentration profiles. These results demonstrated the utility of KinetiSol processing to enhance oral absorption of the challenging AKBA molecule through both solubility enhancement by amorphous dispersion and delivery of a solubility challenged enzyme inhibitor (50).…”

“…The profile was also in sync with the AKBA release profile ensuring similar time and location exposure in-vivo. This new formulation matched the drug load and dissolution requirements for a fixed-dose combination product with AKBA (50). The AKBA portion of the combination product is further explored in its section below.…”

“…Specifically, Kruger et al demonstrated that metabolic enzymes in the intestinal tract led to extensive metabolism of the compound (106). Miller et al hypothesized that inhibition of these metabolic enzymes could be utilized to enhance the permeability of AKBA, further boosting its oral bioavailability (50). Ritonavir was known to be an effective CYP3A enzyme inhibitor as evidenced by its success with Kaletra, a combination product which included amorphous ritonavir to boost the permeability of the highly metabolized lopinavir (83).…”

“…Ritonavir was known to be an effective CYP3A enzyme inhibitor as evidenced by its success with Kaletra, a combination product which included amorphous ritonavir to boost the permeability of the highly metabolized lopinavir (83). To this end, Miller et al (50) processed amorphous compositions of AKBA like the work performed by Bennett et al (36) as well as separate amorphous dispersions for ritonavir by KinetiSol. Tablets were made of the blended amorphous dispersions and dosed in an in vivo dog study.…”

“…They have a beneficial synergistic effect on drug concentration with polymers through promotion of micelles and colloids to prevent crystallization in solution (71,72). Docusate sodium is one such example explored by KinetiSol (50).…”