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A physiologically-based pharmacokinetic model for cannabidiol in healthy adults, hepatically-impaired adults, and children .

Sumit BansalMayur K LadumorMary F PaineJashvant D Unadkat
Published in: Drug metabolism and disposition: the biological fate of chemicals (2023)
Cannabidiol (CBD) is available as a prescription oral drug that is indicated for the treatment of some types of epilepsy in children and adults. CBD is also available over-the-counter and is used to self-treat a variety of other ailments, including pain, anxiety, and insomnia. Accordingly, CBD may be consumed with other medications, resulting in possible CBD-drug interactions. Such interactions can be predicted in healthy and hepatically-impaired (HI) adults and in children through physiologically based pharmacokinetic (PBPK) modeling and simulation. These PBPK models must be populated with CBD-specific parameters, including the enzymes that metabolize CBD in adults. In vitro reaction phenotyping experiments showed that UGTs (80%), particularly UGT2B7 (64%), were the major contributors to CBD metabolism in adult human liver microsomes. Among the CYPs tested, CYP2C19 (5.7%) and CYP3A (6.5%) were the major CYPs responsible for CBD metabolism. Using these and other physicochemical parameters, a CBD PBPK model was developed and validated for healthy adults. This model was then extended to predict CBD systemic exposure in HI adults and children. Our PBPK model successfully predicted CBD systemic exposure in both populations to within 0.5 to 2-fold of the observed values. In conclusion, we developed and validated a PBPK model to predict CBD systemic exposure in healthy and HI adults and children. This model can be used to predict CBD-drug or CBD-drug-disease interactions in these populations. Significance Statement OOur PBPK model successfully predicted CBD systemic exposure in healthy and hepatically-impaired adults, as well as children with epilepsy. This model could be used in the future to predict CBD-drug or CBD-drug-disease interactions in these special populations.
Keyphrases
  • young adults
  • high throughput
  • depressive symptoms
  • chronic pain
  • spinal cord injury
  • genetic diversity