Abstract

Mechanistic oral absorption simulation of nonlinear dose dependence for BCS Class III transporter substrates is an important objective in preclinical development of NCEs as well as in generic formulation and bioequivalence. This study demonstrates the application of the mechanistic Advanced Compartmental Absorption and Transit (ACAT™) model to simulate the nonlinear dose dependence of gabapentin and celiprolol absorption. Modeling of transcellular, paracellular, and carrier‐mediated absorption across a range of doses illustrates the significance of the paracellular pathway for these types of substrates.

We used in vitro data for Kmand fitted the in vivoVmaxvalue for interaction of gabapentin with Organic CationTransporter 1 (OCTN1) and L‐Type Amino acid Transporter 2 (LAT2, SLC7A8) [1] [2] and for the interaction of celiprolol with Organic Anion Transporter 2B1 (OATP2B1) and P‐glycoprotein (P‐gp) [3] [4]. A mechanistic oral absorption PBPK model that describes the pharmacokinetics of gabapentin and celiprolol in healthy humans was developed using GastroPlus™ (Simulations Plus, Inc.). Physicochemical and biopharmaceutical parameters required for the mechanistic dissolution, absorption, and pharmacokinetic distribution were obtained from the literature or from ADMET Predictor™ (Simulations Plus, Inc.). Tissue:plasma partition coefficients (Kps) were calculated using the Lukacova approach with an experimental value for fraction unbound in plasma.
For gabapentin at a dose of 400 mg, the simulation results show approximately 70% absorbed (Fa) with 20% from the paracellular pathway and 50% from the carrier‐mediated pathway (CMP). When the dose is increased to 1600 mg, Fa= 40% with 20% from the paracellular pathway and 20% from the carrier‐mediated pathway.

When celiprolol is administered using microdosing (at 37.5 μg) the passive transcellular absorption is directly offset by the influence of P‐gpand all of the productive absorption (~2%) occurs via the paracellular pathway. At therapeutic doses (100 mg), celiprolol percent absorbed is 53% with the transcellular and the carrier‐mediated pathways each contributing approximately 25% with the paracellular pathway again contributing about 2%.
Absorption of BCS Class III compounds that are substrates for influx and efflux transporters can be complex and requires the accurate calculation of the paracellular contribution to absorption in order to accurately simulate the nonlinear dose dependence. For gabapentin concentrations below the value of the in vitroKm, carrier‐mediated transport is dominant. However, when the OCTN1 and LAT2 transporters are saturated, the paracellular pathway becomes equivalent to the transporter pathway. For celiprolol, a substrate for influx and efflux transporters, microdosing results in concentrations below the Km for P‐gp, resulting in low absorption due only to the passive transcellular component. At therapeutic doses, celiprolol saturates P‐gpand OATP2B1 carrier‐mediated absorption dominates.

10th International Conference on Modelling and Measurement in Medicine and Biology, April 24-26, 2013, Budapest, Hungary

By Michael B. Bolger, Viera Lukacova, and Walter S. Woltosz