Predicting Impact of Food and Feeding Time on Oral Absorption of Drugs with a Novel Rat Continuous Intestinal Absorption Model

Abstract

Intricacies in intestinal physiology, drug properties, and food effects should be incorporated into models to predict complex oral drug absorption. A previously published human continuous intestinal absorption model based on the convection-diffusion equation was modified specifically for the male Sprague-Dawley rat in this report. Species-specific physiologic conditions along intestinal lengthexperimental velocity and pH under fasted and fed conditions, were measured and incorporated into the intestinal absorption model. Concentration-time (C-t) profiles were measured upon a single intravenous and peroral (PO) dose for three drugs: amlodipine (AML), digoxin (DIG), and glyburide (GLY). Absorption profiles were predicted and compared with experimentally collected data under three feeding conditions: 12-hour fasted rats were provided food at two specific times after oral drug dose (1 hour and 2 hours for AML and GLY; 0.5 hours and 1 hour for DIG), or they were provided food for the entire study. Intravenous versus PO C-t profiles suggested absorption even at later times and informed design of appropriate mathematical input functions based on experimental feeding times. With this model, AML, DIG, and GLY oral C-t profiles for all feeding groups were generally well predicted, with exposure overlap coefficients in the range of 0.80-0.97. Efflux transport for DIG and uptake and efflux transport for GLY were included, modeling uptake transporter inhibition in the presence of food. Results indicate that the continuous intestinal rat model incorporates complex physiologic processes and feeding times relative to drug dose into a simple framework to provide accurate prediction of oral absorption. SIGNIFICANCE STATEMENTA novel rat continuous intestinal model predicts drug absorption with respect to time and intestinal length. Feeding time relative to dose was modeled as a key effect. Experimental fasted/fed intestinal pH and velocity, efflux and uptake transporter expression along intestinal length, and uptake transporter inhibition in the presence of food were modeled. The model uses the pharmacokinetic profiles of three model drugs and provides a novel framework to study food effects on absorption.

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

“…The details of the chromatographic separation of GLY and MS detection and quantitation are as described in our previous report. 12 The lower limit of quantitation (LLOQ) for GLY was 12.5 ng/mL. The interand intraday percent accuracy and percent precision were within ±15% over a range of 12.5−500 ng/mL GLY in rat plasma.…”

“…As described in detail previously, the following Michaelis–Menten saturation functions were developed to model intestinal uptake and efflux activity via OATP and P-gp, respectively: normald normald t C 1 ( x , t ) = − V normalm , OATP ( x ) 0.25em C 1 ( x , t ) ( K m , OATP + C 1 false( x , t false) ) a ( x ) + V normalm , normalP − gp ( x ) 0.25em C 2 ( x , t ) ( K m , P − gp + C 2 false( x , t false) ) a ( x ) normald normald t C 2 ( x , t ) = − V ...…”

“…Also, at FT = 2 h, for each particle size (4 and 0.4 μm), the impact of OATP as well as P-gp inhibition was simulated. In order to simulate an increased velocity in the intestine to mimic the osmotically active excipient activity, the velocity function was doubled from the velocity function based on experimental data and C – t profiles simulated. The equations for the original (vel( x )) and doubled (veldouble( x )) velocity function are as follows. vel ( x ) = a 1 a ( x ) ( 2.4 − 1.96 1 + e − 20 false( prefix− 0.45 + x false) − 0.19 1 + e − 15 false( prefix− 1.05 + x false) − 0.2 1 + e − 30 false( prefix− 1.2 + x false) − 0.06 1 + e − 20 false( prefix− 1.35 + x false) ) veldouble ( x ) = a 1 a ( x ) ( 4.8 − 4.36 1 + e − 20 false( prefix− 0.45 + x false) − 0.19 ...…”

“…We previously developed input functions based on slowed stomach emptying due to the presence of food. 12 The same functions were used here as follows, with three unit pulses for input. The first pulse represents 10% of the dose to enter the intestine immediately, the second pulse represents the drug released into the intestine where lag = 0.1 h, PL t1 = 0.1 h, PL t2 = FT, and PL t3 = 22 h; FT is the time when food was reintroduced to animals after dosing the drug.…”

“…The systematic disposition functions were previously generated from the experimentally collected IV data model by two-compartmental PK models. 12 The systemic disposition functions were combined with the input function (eq 32) to simulate oral PK profiles.…”