Summary:
Purpose: To evaluate precipitation in and supersaturation of intestinal
contents, after administration of pharmacologically relevant doses of
dipyridamole and ketoconazole to twelve fasted healthy adults. Τo develop an in
vitro methodology for prediction of concentrations and potential precipitation
of highly permeable, lipophilic weak bases in fasted upper small intestine,
based on luminal data. To evaluate the usefulness of the in vitro methodology
in predicting precipitation in fasted upper small intestine of two Class II
weak bases under development, AZD0865 and SB705498, based on plasma data.
Methods: On two separate days each subject was administered in stomach 240 mL
aqueous solutions of two dipyridamole doses (30 mg and 90 mg) and two
ketoconazole doses (100 mg and 300 mg). Physicochemical characteristics, total
drug content, and drug concentration were measured in individual intestinal
contents aspirated at specific times post-dosing. Drug concentration after
incubation (37C/48h) of the relevant supernatants and equilibrium solubility
were also measured. For the in vitro experiments, a three-compartment setup was
used. Depending on the dosage form administered in the human study, a solution
or a suspension was placed in gastric compartment. A solution simulating the
luminal environment (FaSSIF-V2plus) was initially placed in duodenal
compartment. In both human and in vitro studies crystallinity of precipitates
was evaluated with X-rays.
Results: Intraluminal precipitated fraction was minimal (dipyridamole, 7 %) or
limited (ketoconazole, 16 %). Ketoconazole precipitates were mostly amorphous.
After incubation, crystalline precipitates were found in almost all samples. In
vitro dipyridamole and ketoconazole concentrations and precipitated fractions
adequately reflected luminal data. However, unlike luminal precipitates, in
vitro ketoconazole precipitates were crystalline. In vitro AZD0865 data
confirmed previously published human pharmacokinetic data suggesting that
absorption rates are not affected by luminal precipitation. In vitro SB705498
data predicted that significant luminal precipitation occurs after a 100 mg or
400 mg but not after a 10 mg dose, consistent with human pharmacokinetic data.
Conclusions: Intraluminal precipitation of weakly alkaline, Class II drugs may
not be substantial. Estimating intestinal supersaturation in regard to free
base is inadequate as other phases may precipitate. An in vitro methodology for
predicting concentrations and potential precipitation of slightly soluble,
highly permeable, lipophilic weak bases in fasted upper small intestine was
developed and evaluated for its predictability in regard to luminal
precipitation in humans.
Keywords:
Precipitation, Supersaturation, Weak bases, In vivo, In vitro setup
