Using PBPK modelling to identify physiological changes induced by CLF065, a GLP 2 receptor agonist

Using PBPK modelling to identify physiological changes induced by CLF065, a GLP 2 receptor agonist, on the pharmacokinetics of acyclovir and to predict potential drug–drug interactions with other compounds

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 (200 mg) 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 consistent with CLF065 exposure that explains the observed increase in acyclovir exposure and (ii) explore how these same mechanisms could affect drugs with low, medium, and high predicted Fabs (cyclosporin A, itraconazole, and ethinylestradiol, respectively)