Ricardo Diaz De Leon Ortega 1, Vanessa Zann 1, Sean Joseph 2, Kyoung-Jin Lee 2, Dannielle Ravenhill 1
1 Quotient Sciences (Nottingham, United Kingdom), 2 Calibr – Skaggs (La Jolla, United States)
Introduction:
CLF065 is a long-acting glucagon-like peptide 2 (GLP 2) receptor agonist in development by Calibr–Skaggs for the treatment of inflammatory bowel disease. Reported physiological effects of GLP 2 receptor agonists include increased intestinal blood flow (IBF), elevated gastric pH (GpH), prolonged gastric (GTT) and small intestine transit times (ITT), and proliferation of intestinal crypt cells [1,2]. In a clinical drug–drug interaction (DDI) study, CLF065 increased acyclovir exposure by approximately two-fold, consistent with an absorption-mediated interaction with this BCS Class 3 victim drug (low-permeability with fraction absorbed (Fabs) < 50 % and, high solubility). Physiologically based pharmacokinetic (PBPK) modelling was used to (i) identify the dominant physiological mechanisms required to reproduce the observed acyclovir DDI and (ii) explore how these same mechanisms could affect drugs spanning distinct absorption limitations.
Objectives:
(1) To identify the dominant physiological mechanisms consistent with CLF065 exposure that explains the observed increase in acyclovir exposure using PBPK modelling.
(2) To predict potential DDI risks for drugs with low, medium, and high predicted Fabs (cyclosporin A, itraconazole, and ethinylestradiol, respectively).
Methods:
PBPK modelling was conducted using PK Sim® v11.3 (Open Systems Pharmacology [3]). Acyclovir model development incorporated published parameters [4], literature plasma concentration–time (Cp–t) profiles [5], and clinical data generated at Quotient Sciences (QS). Sensitivity analyses were performed using the ospsuiteR v11.2.25 package within the R software v4.4.2 [6,7] to quantify the influence of GpH, GTT, ITT, IBF, and surface enhancement factor (SEF) representing increased small intestinal surface area due to crypt cell proliferation. Virtual populations (n = 16) reflecting QS study demographics were generated. All parameters remained unchanged except effective surface area variability factor and small intestinal transit time, which were resampled from normal distributions (SD = 15% of the mean) using the R software. Published PBPK models were used to evaluate the extrapolated physiological changes for cyclosporin A (oral solution, 700 mg) [8], itraconazole (capsule, 200 mg) [9], and ethinylestradiol (tablet, 0.03 mg) [10]. All simulations were performed under fasted conditions with single dose administration, except itraconazole, which was also evaluated under fed conditions. 90% confidence intervals (CIs) of the DDI were estimated using Phoenix WinNonlin v8.3.4.295 (Certara, UK).
Results:
In sensitivity analysis, ITT prolongation and an increased SEF were identified as the primary contributors to the observed increase in acyclovir exposure (AUC and Cmax), while changes in GpH, GTT and IBF did not meaningfully improve the model performance for this highly soluble compound. A 1.8-fold increase in SEF combined with a 1.29-fold increase in ITT reproduced the observed DDI ratios within 20% accuracy. Applying these physiological changes to the test victim drugs, models yielded the following predicted DDI ratios and 90% CIs (Cmax and AUC0–t, respectively): cyclosporin A: 1.86 (1.65–2.09) and 1.76 (1.53–2.02); itraconazole (fasted): 1.28 (1.13–1.46) and 1.33 (1.12–1.58); itraconazole (fed): 1.87 (1.56–2.24) and 1.68 (1.30–2.17); ethinylestradiol: 1.04 (0.98–1.10) and 1.04 (0.92–1.16). The exposure of cyclosporin A, which has a permeability limited absorption, was predicted to increase. For itraconazole (a medium permeability compound), solubility limitations reduced sensitivity to the physiological changes in the fasted state, while increased solubility in the fed state produced greater exposure. Ethinylestradiol (a high permeability compound) exhibited near complete absorption; therefore, enhanced permeability had minimal effect.
Conclusion:
PBPK modelling identified small intestine transit time prolongation and increased intestinal surface area as the key CLF065 mediated physiological changes responsible for increased acyclovir exposure, whereas changes in gastric pH, gastric transit time and intestinal blood flow did not materially contribute in this setting. Exploratory extrapolation to other drugs indicates that the magnitude of potential absorption-mediated DDIs depends strongly on compound specific solubility and permeability characteristics. These findings support the mechanistic use of PBPK modelling to anticipate potential DDIs for GLP 2 receptor agonists.
References:
References:
[1] Zhu, C., & Li, Y. The Journal of international medical research. 2022, 50(3)
[2] Jeppesen P. B. The Journal of nutrition. 2003, 133(11), 3721–3724.
[3] https://www.open-systems-pharmacology.org/
[4] García MA, et al. J Pharm Sci. 2022 Jan;111(1):262-273
[5] Laskin OL, et al. Antimicrob Agents Chemother. 1982 Mar;21(3):393-8
[6] https://cran.r-project.org/
[7] https://www.open-systems-pharmacology.org/OSPSuite-R/
[8] Schaller S, et al. Drugs R D. 2025 Mar;25(1):1-17
[9] Hanke N, et al. CPT Pharmacometrics Syst Pharmacol. 2018 Oct;7(10):647-659
[10] Kanacher T, et al. Pharmaceutics. 2020 Dec 8;12(12):1191.
Reference: PAGE 34 (2026) Abstr 12105 [www.page-meeting.org/?abstract=12105]
Poster: Drug/Disease Modelling - Absorption & PBPK