Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin
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This study explored the utility of mechanistic absorption models to describe the in vivo performance of a low solubility/low permeability compound in normal healthy subjects. Sixteen healthy human volunteers received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by HPLC. In vitro ciprofloxacin release from the oral tablets was tested under a variety of conditions. A mechanistic model was used to explore in vivo dissolution and intestinal absorption. Although dissolution rate influenced the location of drug release, absorption challenges appeared to be associated with permeability limitations in the lower small intestine and colon. The apparent relationship between drug solubilization within the upper small intestinal and formulation overall bioavailability suggested the presence of an intestinal absorption window in many individuals. Failure to absorb drug within this window appeared to be linked with the likelihood of in vivo drug precipitation. Challenges encountered during this modeling exercise included large intersubject variability in product in vivo dissolution and the apparent limitations in ciprofloxacin absorption. Although transporter activity was not included as a model parameter, this evaluation demonstrated how identifying the location of drug absorption across several formulations provided an opportunity to identify factors to consider when formulating similar low solubility/low permeability compounds. The use of mechanistic models was invaluable for our understanding of in vivo product performance and for the assessment of individual profiles rather than means. The latter was essential for understanding the potential challenges that may be encountered when introducing a formulation into a patient population.
KEY WORDSciprofloxacin IVIVC mechanistic model pharmacokinetics
- 1.Zhang H, Xia B, Sheng J, Heimbach T, Lin TH, He H, et al. Application of physiologically based absorption modeling to formulation development of a low solubility, low permeability weak base: mechanistic investigation of food effect. AAPS PharmSciTech. 2014;15:400–6.CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Sjögren E, Abrahamsson B, Augustijns P, Becker D, Bolger MB, Brewster M, et al. In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects. Eur J Pharm Sci. 2014;57:99–151.CrossRefPubMedGoogle Scholar
- 5.Merck Manual http://www.merck.com/product/usa/pi_circulars/c/cipro/ciproIV_pi.pdf Accessed 06/04/2015.
- 6.Fahmy R, Kona R, Dandu R, Xie W, Claycamp G, Hoag SW. Quality by design I: application of failure mode effect analysis (FMEA) and Plackett-Burman design of experiments in the identification of “main factors” in the formulation and process design space for roller-compacted ciprofloxacin hydrochloride immediate-release tablets. AAPS PharmSciTech. 2012;13:1243–54.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Claycamp HG, Fahmy R, Kona R, Hoag SW. Quality-by-design II: application of quantitative risk analysis to the formulation of ciprofloxacin tablets. AAPS PharmSciTech. 2015 Jul;23 (epub ahead of print).Google Scholar
- 9.Tissue BM (2009). Basics of Analytical Chemistry and Chemical Equilibria. http://www.tissuegroup.chem.vt.edu/a-text/spreadsheets.html Accessed 06/08/ 2015.
- 10.SimulationsPlus science + Software = Success (2015). http://www.simulations-plus.com/ Accessed 06/08/2015.
- 19.Jakubiak P, Wagner B, Grimm HP, Petrig-Schaffland J, Schuler F, Alvarez-Sánchez R. Development of a unified dissolution and precipitation modeland its use for the prediction of oral drug absorption. Mol Pharm. 2016 Jan 5. [Epub ahead of print].Google Scholar