Use of Modeling and Simulation Tools for Understanding the Impact of Formulation on the Absorption of a Low Solubility Compound: Ciprofloxacin.
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.
The Food and Drug Administration, Rockville, MD, USA. marilyn.martinez@fda.hhs.gov.
Marilyn
M
Martinez
The Food and Drug Administration, Rockville, MD, USA.
Bipin
B
Mistry
The Food and Drug Administration, Rockville, MD, USA.
Viera
V
Lukacova
The Food and Drug Administration, Rockville, MD, USA.
Jim
J
Polli
The Food and Drug Administration, Rockville, MD, USA.
Stephen
S
Hoag
The Food and Drug Administration, Rockville, MD, USA.
Thomas
T
Dowling
The Food and Drug Administration, Rockville, MD, USA.
Ravikanth
R
Kona
The Food and Drug Administration, Rockville, MD, USA.
Raafat
R
Fahmy
D000284:Administration, Oral; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002939:Ciprofloxacin; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D010539:Permeability; D012995:Solubility
D002939:Ciprofloxacin
IVIVC; ciprofloxacin; mechanistic model; pharmacokinetics