LB-007 - ASSESSING POTENTIAL DRUG-DRUG INTERACTIONS INVOLVING Δ-9-TETRAHYDROCANNABINOL AND CANNABIDIOL IN HEALTHY ADULTS USING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS

L. Qian¹, T. Zhang², J. Dinh³, M. Paine⁴,Z. Zhou¹; ¹City University of New York, , , ²Binghamton University, The State University of New York, , , ³SimCYP Ltd/Certara, , , ⁴Washington State University, , .

Background: ∆-9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most extensively studied cannabinoids in cannabis. THC is eliminated mainly by cytochrome P450 (CYP) 2C9-mediated metabolism, with a minor role by CYP3A, whereas CBD is eliminated mainly by CYP2C19- and CYP3A-mediated metabolism. As cannabis use for myriad conditions continues to grow, understanding potential pharmacokinetic interactions between THC or CBD and other drugs remains an urgent public health need. The objective of this work was to develop and verify physiologically based pharmacokinetic (PBPK) models of THC and CBD to assess these potential adverse interactions.

Methods: PBPK models for intravenous (IV) THC (1.25-5 mg) and CBD (20 mg) were developed using the Simcyp™ PBPK Simulator (v22). Physicochemical and pharmacokinetic input parameters were either collected from the literature or optimized. Models for the oromucosal spray route were next developed for a range of cannabinoid doses (THC: 5.4-21.6 mg; CBD 5-20 mg). All PBPK models were optimized and verified using data obtained from published clinical studies involving healthy adults who were administered THC or CBD alone or with known CYP3A and CYP2C precipitant drugs.

Results: PBPK model-predicted plasma AUC and Cmax of THC and CBD at all cannabinoid doses were within 0.51- to 1.68-fold of the observed values obtained from 12 clinical studies (Fig. 1). The models also well-captured THC and CBD AUC and Cmax in the presence of three precipitant drugs, specifically rifampicin (CYP3A/CYP2C inducer), ketoconazole (CYP3A inhibitor), and omeprazole (CYP2C19 inhibitor); predicted AUC and Cmax for THC and CBD were within 0.65- to 2.24-fold of observed values. Predicted AUC ratios (AUC of THC or CBD in the presence to absence of precipitant) were within 0.68- to 1.54-fold of observed ratios.

Conclusion: PBPK models for both IV and oromucosal spray administration of THC and CBD were developed and verified. The models will be further refined by optimizing the absorption model for additional extravascular administration routes. The verified models could be used to help address critical public health needs, including predicting changes in THC or CBD systemic exposure in combination with other enzyme inhibitors/inducers to assess potential safety concerns.