A Physiologically Based Pharmacokinetic and Drug-Drug Interaction Model for the CB2 Agonist Lenabasum.
Lenabasum is a synthetic agonist of the cannabinoid receptor type 2 (CB2) with anti-inflammatory and antifibrotic properties. Utilizing Simcyp, we developed a physiologically based pharmacokinetic (PBPK) model based on physicochemical properties, cell culture data, and cytochrome P450 (CYP) phenotyping, inhibition, and induction data. Clinical data from healthy volunteers treated with 20 mg of lenabasum in a single ascending dose (SAD) study were used for model development. The model was verified using lenabasum SAD (10 and 40 mg) data as well as multiple dose (20 mg three times per day) data. Lenabasum is a CYP substrate, and the model predicted lenabasum clearance of 51% by CYP2C9, 37% by CYP2C8, and 12% by CYP3A4. Lenabasum is also an inhibitor of these isozymes. The model accurately described the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C Our model is a useful tool for predicting the pharmacokinetics of lenabasum and adjustments to its dosing in possible drug-drug interaction scenarios.