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- Title
Bioavailability enhancement of a BCS IV compound via an amorphous combination product containing ritonavir.
- Authors
Miller, Dave A.; Keen, Justin M.; Brough, Chris; Ellenberger, Daniel J.; Cisneros, Marshall; Williams, Robert O.; McGinity, James W.
- Abstract
Objectives To evaluate the effect of ritonavir ( RTV) co-administration on the bioavailability of an amorphous dispersion of acetyl-11-keto-beta-boswellic acid ( AKBA) and to develop a pharmaceutically acceptable AKBA-RTV combination tablet. Methods A pharmacokinetic ( PK) study in rats was conducted to evaluate the influence of RTV co-administration on the oral bioavailability of an AKBA amorphous dispersion. Kineti Sol was utilized to enable production of an improved RTV formulation that facilitated the development of an AKBA-RTV combination tablet. Following in-vitro characterization, the PK performance of the tablets was evaluated in male beagles. Key findings Co-administration of RTV increased oral absorption of AKBA by about fourfold over the AKBA dispersion alone and approximately 24-fold over the pure compound. The improved RTV amorphous dispersion exhibited similar purity and neutral-phase dissolution to Norvir. The AKBA-RTV combination tablets yielded a substantial increase in AKBA's bioavailability in dogs. Conclusions 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.
- Subjects
RITONAVIR; BIOAVAILABILITY; PHARMACOKINETICS; DISPERSION (Chemistry); CANCER treatment
- Publication
Journal of Pharmacy & Pharmacology, 2016, Vol 68, Issue 5, p678
- ISSN
0022-3573
- Publication type
Academic Journal
- DOI
10.1111/jphp.12478