TY - JOUR

T1 - Adding a Gastric Step to the Intestinal In Vitro Digestion Model Improves the Prediction of Pharmacokinetic Data in Beagle Dogs of Two Lipid-Based Drug Delivery Systems

AU - Klitgaard, Mette

AU - Beilles, Stephane

AU - Sassene, Philip Jonas

AU - Berthelsen, Ragna

AU - Mullertz, Anette

PY - 2020

Y1 - 2020

N2 - Drug release from a lipid-based drug delivery system (LbDDS) is typically studied in vitro using a one-step intestinal digestion model. However, lately the importance of incorporating gastric digestion has been stressed. The aim of the present study was to compare a two-step gastro-intestinal (GI) in vitro digestion model to the commonly used one-step intestinal digestion model. The models were evaluated by studying release of the model drug A1260 from two LbDDSs (F-I and F-II), for which in vivo pharmacokinetic data from oral administration to beagle dogs were available. The amount of A1260 recovered in the aqueous phases during and after the GI digestion of F-I and F-II was related to the Cmax and AUC0- 48h of the plasma concentration-time profiles of each formulation and produced a rank order in vitroin vivo (IVIV) relation. In comparison, a similar IVIV rank ordering was obtained when relating the amount of A1260 recovered in the aqueous phase prior (t = 0 min), and following 15 min of intestinal digestion, to the plasma concentration-time profiles. However, after 60 min of intestinal digestion, the LbDDSs performed equally in the one-step in vitro digestion model, contrary to what was observed in the two-step digestion model, and in vivo. As the GI digestion model produced a clearer distinction in terms of LbDDS rank ordering of the two LbDDSs, compared to the intestinal digestion model, it was found to be a promising in vitro model to study and estimate the LbDDS behavior in vivo.

AB - Drug release from a lipid-based drug delivery system (LbDDS) is typically studied in vitro using a one-step intestinal digestion model. However, lately the importance of incorporating gastric digestion has been stressed. The aim of the present study was to compare a two-step gastro-intestinal (GI) in vitro digestion model to the commonly used one-step intestinal digestion model. The models were evaluated by studying release of the model drug A1260 from two LbDDSs (F-I and F-II), for which in vivo pharmacokinetic data from oral administration to beagle dogs were available. The amount of A1260 recovered in the aqueous phases during and after the GI digestion of F-I and F-II was related to the Cmax and AUC0- 48h of the plasma concentration-time profiles of each formulation and produced a rank order in vitroin vivo (IVIV) relation. In comparison, a similar IVIV rank ordering was obtained when relating the amount of A1260 recovered in the aqueous phase prior (t = 0 min), and following 15 min of intestinal digestion, to the plasma concentration-time profiles. However, after 60 min of intestinal digestion, the LbDDSs performed equally in the one-step in vitro digestion model, contrary to what was observed in the two-step digestion model, and in vivo. As the GI digestion model produced a clearer distinction in terms of LbDDS rank ordering of the two LbDDSs, compared to the intestinal digestion model, it was found to be a promising in vitro model to study and estimate the LbDDS behavior in vivo.

KW - gastro-intestinal digestion

KW - in vitro

KW - in vivo

KW - lipid-based drug delivery system

KW - oral biopharmaceutical tools (OrBiTo)

KW - WATER-SOLUBLE DRUGS

KW - LIPOLYSIS MODEL

KW - GASTROINTESTINAL LIPOLYSIS

KW - VIVO PERFORMANCE

KW - FORMULATIONS

KW - LIPASES

KW - TESTS

KW - BIOAVAILABILITY

KW - ESTABLISHMENT

KW - DISSOLUTION

U2 - 10.1021/acs.molpharmaceut.0c00307

DO - 10.1021/acs.molpharmaceut.0c00307

M3 - Journal article

C2 - 32662647

VL - 17

SP - 3214

EP - 3222

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 9

ER -