(T1430-02-08) Leveraging Buprenorphine as a Tool Molecule to Develop a Novel PBPK Model Accounting for Intestinal Lymphatic Absorption

Purpose: Intestinal lymphatic absorption presents an additional oral absorption pathway alternative to the portal uptake for highly lipophilic drugs (log P > 5), with the potential of bypassing the hepatic first pass metabolism. However, traditional PBPK models seldom include this intestinal lymphatic absorption. In this study, we developed an innovative GI-Lymph-PBPK model that accommodates compartmental absorption in the gastro-intestine and intestinal lymphatic uptake. We used published in vitro permeability and metabolic stability and in vivo rat PK data on buprenorphine and its ester prodrugs to construct this model.

Methods: The intestinal and hepatic extractions for Buprenorphine were determined utilizing published metabolic stability data, which included liver and intestinal microsomes, in conjunction with plasma protein binding data[1]. The absorption rate of Buprenorphine was evaluated using the published Caco2 permeability data[2]. We used the model developed by Olivers et al. that accounts for simplified compartmental absorption[3] in the gastro-intestine. We modified the model by integrating the intestinal and hepatic extraction to predict Buprenorphine's hepatic clearance and oral bioavailability. The model's performance was validated by comparing its predictions with published rat PK data[4]. We then extend this model to incorporate an additional compartment to represent the intestinal lymphatic uptake for buprenorphine ester prodrugs, which effectively allows the prodrug to directly enter systemic circulation, bypassing hepatic first-pass elimination. The degree of intestinal lymphatic absorption was informed by the published mesenteric lymph duct cannulation study[4]. We then utilized the PBPK model to predict the enhancement in oral absorption due to intestinal lymphatic absorption. The GI-Lymph-PBPK model was developed utilizing Berkeley Madonna software (version 10.4.2).

Results: The hepatic extraction ratio of Buprenorphine was estimated as 0.75, suggesting a rapid hepatic clearance of 3060 mL/kg/h in rats. Despite the extensive intestinal absorption, the PBPK model indicates a considerably low oral bioavailability for Buprenorphine at just 4%, caused by extensive hepatic and intestinal extractions (the latter estimated at 0.84). The predicted PK profiles from the PBPK model align well with the observed rat PK data (Figure B). The degree of dose recovery in the lymph informed the PBPK model about the extent of intestinal lymphatic absorption, which enabled the model to accurately capture the enhancement in oral absorption (Figure B). The PBPK model suggests that intestinal lymphatic absorption bypasses the first pass metabolism, increasing Buprenorphine's oral bioavailability by 10 to 15 fold.

Conclusion: Our GI-Lymph-PBPK model bridges the gap in traditional oral absorption PBPK modeling by incorporating intestinal lymphatic absorption. This model can support drug design for lymphatic targeted delivery and serve to enhance oral bioavailability. Subsequent model development will consider the in-vitro and in-vivo correlation for translating between species' first pass metabolism difference and for allometric scaling concerning intestinal lymphatic absorption, thereby enabling human PK prediction.

References: 1. Mistry, M. and J.B. Houston, Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metabolism and Disposition, 1987. 15(5): p. 710-717.
2. Hassan, H.E., et al., Differential involvement of P-glycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: in vitro and in vivo evaluation. Journal of pharmaceutical sciences, 2009. 98(12): p. 4928-4940.
3. Olivares-Morales, A., et al., Development of a novel simplified PBPK absorption model to explain the higher relative bioavailability of the OROS® formulation of oxybutynin. The AAPS journal, 2016. 18: p. 1532-1549.
4. Quach, T., et al., Triglyceride-Mimetic Prodrugs of Buprenorphine Enhance Oral Bioavailability via Promotion of Lymphatic Transport. Frontiers in Pharmacology, 2022. 13: p. 879660.