PBPK Modeling as a Tool for Predicting and Understanding Intestinal Metabolism of Uridine 5'-Diphospho-glucuronosyltransferase Substrates

Abstract

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug-drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro-in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates.

Keywords: GastroPlus; IVIVE; PBPK; UGT; absorption modeling; gut extraction; intestinal metabolism; oral bioavailability; phase II metabolism.

Figure 1

PBPK Model prediction of (A) 28.2 mg and (B) 30 mg oral solution of cabotegravir. Dark blue curves and light blue points represent predicted versus observed plasma concentration. The tables list: fraction of dose absorbed (Fa), fraction of dose reaching the portal vein (FDp), bioavailability (F), maximum observed total plasma concentration (Cmax), time at which the Cmax was observed (Tmax), and the area under the plasma concentration–time curve from time zero to t (AUC_0–t).

Figure 2

Comparison of simulated to observed Cmax and AUC (AUC_0–t or AUC_tau) from different published studies [67,68,70,71,72,73,74,75,76,77,78] with predictions based on in vitro parameters for dolutegravir interaction with UGT1A1 measured in recombinant UGT1A1 (A,B) and in HLM (C,D). Circles represent fasted studies, triangles represent studies in which dolutegravir was administered with a moderate-fat meal, closed symbols represent single dose, and open symbols represent steady-state data. In each plot, the solid line represents the identity line, and the dashed lines show margins for 1.5-fold errors. AUC = the area under the plasma concentration–time curve, AUC_0–t = AUC from time zero to t, AUC_tau = AUC during the dosing interval, Cmax = maximum observed total plasma concentration, and HLM = human liver microsomes.

Figure 2

Comparison of simulated to observed Cmax and AUC (AUC_0–t or AUC_tau) from different published studies [67,68,70,71,72,73,74,75,76,77,78] with predictions based on in vitro parameters for dolutegravir interaction with UGT1A1 measured in recombinant UGT1A1 (A,B) and in HLM (C,D). Circles represent fasted studies, triangles represent studies in which dolutegravir was administered with a moderate-fat meal, closed symbols represent single dose, and open symbols represent steady-state data. In each plot, the solid line represents the identity line, and the dashed lines show margins for 1.5-fold errors. AUC = the area under the plasma concentration–time curve, AUC_0–t = AUC from time zero to t, AUC_tau = AUC during the dosing interval, Cmax = maximum observed total plasma concentration, and HLM = human liver microsomes.

Figure 3

Comparison of observed Cmax and AUC (AUC_0–t or AUC_tau) from different published studies [67,68,70,71,72,73,74,75,76,77,78] with final model simulations for studies used for model development (A,B) and model validation (C,D). Circles represent fasted studies, triangles represent studies where dolutegravir was administered with a moderate-fat meal, closed symbols represent single dose data, and open symbols represent steady-state data. In each plot, the solid line represents the identity line, and the dashed lines show margins for 1.5-fold errors. AUC = the area under the plasma concentration–time curve, AUC_0–t = AUC from time zero to t, AUC_tau = AUC during the dosing interval, and Cmax = maximum observed total plasma concentration.

Figure 3

Comparison of observed Cmax and AUC (AUC_0–t or AUC_tau) from different published studies [67,68,70,71,72,73,74,75,76,77,78] with final model simulations for studies used for model development (A,B) and model validation (C,D). Circles represent fasted studies, triangles represent studies where dolutegravir was administered with a moderate-fat meal, closed symbols represent single dose data, and open symbols represent steady-state data. In each plot, the solid line represents the identity line, and the dashed lines show margins for 1.5-fold errors. AUC = the area under the plasma concentration–time curve, AUC_0–t = AUC from time zero to t, AUC_tau = AUC during the dosing interval, and Cmax = maximum observed total plasma concentration.