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

J Pharm Pharmacol. 2016 May;68(5):678-91. doi: 10.1111/jphp.12478. Epub 2015 Oct 10.


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. KinetiSol 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.

Keywords: KinetiSol; acetyl-11-keto-beta-boswellic acid; amorphous dispersion; ritonavir; solubility enhancement.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Biological Availability
  • Biotransformation
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors / administration & dosage
  • Cytochrome P-450 CYP3A Inhibitors / chemistry
  • Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics*
  • Dogs
  • Drug Combinations
  • Drug Compounding
  • Intestines / drug effects*
  • Intestines / enzymology
  • Male
  • Ritonavir / administration & dosage
  • Ritonavir / chemistry
  • Ritonavir / pharmacokinetics*
  • Tablets
  • Technology, Pharmaceutical / methods
  • Triterpenes / administration & dosage
  • Triterpenes / chemistry
  • Triterpenes / pharmacokinetics*


  • 11-keto-boswellic acid
  • Antineoplastic Agents, Phytogenic
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Combinations
  • Tablets
  • Triterpenes
  • Cytochrome P-450 CYP3A
  • Ritonavir