2 research outputs found
Utilization of Gastrointestinal Simulator, an in Vivo Predictive Dissolution Methodology, Coupled with Computational Approach To Forecast Oral Absorption of Dipyridamole
Weakly basic drugs exhibit a pH-dependent
dissolution profile in
the gastrointestinal (GI) tract, which makes it difficult to predict
their oral absorption profile. The aim of this study was to investigate
the utility of the gastrointestinal simulator (GIS), a novel in vivo
predictive dissolution (iPD) methodology, in predicting the in vivo
behavior of the weakly basic drug dipyridamole when coupled with in
silico analysis. The GIS is a multicompartmental dissolution apparatus,
which represents physiological gastric emptying in the fasted state.
Kinetic parameters for drug dissolution and precipitation were optimized
by fitting a curve to the dissolved drug amount-time profiles in the
United States Pharmacopeia apparatus II and GIS. Optimized parameters
were incorporated into mathematical equations to describe the mass
transport kinetics of dipyridamole in the GI tract. By using this
in silico model, intraluminal drug concentration–time profile
was simulated. The predicted profile of dipyridamole in the duodenal
compartment adequately captured observed data. In addition, the plasma
concentration–time profile was also predicted using pharmacokinetic
parameters following intravenous administration. On the basis of the
comparison with observed data, the in silico approach coupled with
the GIS successfully predicted in vivo pharmacokinetic profiles. Although
further investigations are still required to generalize, these results
indicated that incorporating GIS data into mathematical equations
improves the predictability of in vivo behavior of weakly basic drugs
like dipyridamole
<i>In Vivo</i> Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract under Fed and Fasted Conditions
<i>In vivo</i> drug dissolution
in the gastrointestinal (GI) tract is largely unmeasured. The purpose
of this clinical study was to evaluate the <i>in vivo</i> drug dissolution and systemic absorption of the BCS class IIa drug
ibuprofen under fed and fasted conditions by direct sampling of stomach
and small intestinal luminal content. Expanding current knowledge
of drug dissolution <i>in vivo</i> will help to establish
physiologically relevant <i>in vitro</i> models predictive
of drug dissolution. A multilumen GI catheter was orally inserted
into the GI tract of healthy human subjects. Subjects received a single
oral dose of ibuprofen (800 mg tablet) with 250 mL of water under
fasting and fed conditions. The GI catheter facilitated collection
of GI fluid from the stomach, duodenum, and jejunum. Ibuprofen concentration
in GI fluid supernatant and plasma was determined by LC–MS/MS.
A total of 23 subjects completed the study, with 11 subjects returning
for an additional study visit (a total of 34 completed study visits).
The subjects were primarily white (61%) and male (65%) with an average
age of 30 years. The subjects had a median [min, max] weight of 79
[52, 123] kg and body mass index of 25.7 [19.4, 37.7] kg/m<sup>2</sup>. Ibuprofen plasma levels were higher under fasted conditions and
remained detectable for 28 h under both conditions. The AUC<sub>0–24</sub> and <i>C</i><sub>max</sub> were lower in fed subjects
vs fasted subjects, and <i>T</i><sub>max</sub> was delayed
in fed subjects vs fasted subjects. Ibuprofen was detected immediately
after ingestion in the stomach under fasting and fed conditions until
7 h after dosing. Higher levels of ibuprofen were detected in the
small intestine soon after dosing in fasted subjects compared to fed.
In contrast to plasma drug concentration, overall gastric concentrations
remained higher under fed conditions due to increased gastric pH vs
fasting condition. The gastric pH increased to near neutrality after
feedingbefore decreasing to acidic levels after 7 h. Induction of the fed state reduced systemic levels but increased gastric levels of ibuprofen, which suggest that slow gastric emptying and transit dominate the effect for plasma drug concentration. The finding of high levels of ibuprofen in stomach and small intestine 7 h post dosing was unexpected. Future work is needed to better understand the role of various GI parameters, such as motility and gastric emptying, on systemic ibuprofen levels in order to improve <i>in vitro</i> predictive models