Population Pharmacokinetic Model of THC Integrates Oral, Intravenous, and Pulmonary Dosing and Characterizes Short- and Long-term Pharmacokinetics

  title={Population Pharmacokinetic Model of THC Integrates Oral, Intravenous, and Pulmonary Dosing and Characterizes Short- and Long-term Pharmacokinetics},
  author={Jules A.A.C. Heuberger and Zheng Guan and Olubukayo-Opeyemi Oyetayo and Linda E. Klumpers and Paul D. Morrison and Tim L. Beumer and J.M.A. Gerven and Adam F. Cohen and J. I. Freijer},
  journal={Clinical Pharmacokinetics},
AbstractΔ9-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized… 

Toward a Comprehensive Model of ∆9-Tetrahydrocannabinol Pharmacokinetics Using a Population Pharmacokinetics Approach

  • B. Ginsburg
  • Biology, Medicine
    Clinical Pharmacokinetics
  • 2014
The model developed could improve the therapeutic use of THC and could produce detailed models that are relevant to clinical applications by guiding a dosing strategy that maintains a drug’s concentration within its therapeutic range.

A Δ9-Tetrahydrocannabinol Physiologically-Based Pharmacokinetic Model Development in Humans

A physiologically-based pharmacokinetic (PBPK) model of THC in humans was developed to characterize tissue-specific pharmacokinetics of cannabinoids in organs of interest and resulted in good agreement between the predicted and observed THC concentrations across several studies conducted following IV bolus, IV infusion, oral, and smoking and inhalation.

Minimal Physiologically Based Pharmacokinetic Model of Intravenously and Orally Administered Delta-9-Tetrahydrocannabinol in Healthy Volunteers

The pharmacokinetics of THC and its major metabolites are characterized in healthy volunteers with known CYP2C9 status by non-compartmental analysis, compartmental modeling and minimal physiologically based pharmacokinetic (mPBPK) modeling to partially disentangle the complexity of cannabis disposition in humans.

The pharmacokinetics and the pharmacodynamics of cannabinoids.

The limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing cannabis medicines using a 'start low and go slow' approach, carefully observing the patient for desired and adverse effects.

REVIEW-THEMED ISSUE The pharmacokinetics and the pharmacodynamics of cannabinoids

The pharmacokinetics of cannabinoids and the effects observed depend on the formulation and route of administration, which should be tailored to individual patient requirements.

Using Population Pharmacokinetic Modeling to Estimate Exposure to Δ9-tetrahydrocannabinol in an Observational Study of Cannabis Smokers in Colorado.

People who smoked ad libitum, and used cannabis products with high concentrations of THC were less efficient compared to computer-paced smokers of low potency, NIDA cannabis in a laboratory setting and pharmacokinetic model-derived estimates based on measured THC and metabolite concentrations were underestimated.

Examining the Systemic Bioavailability of Cannabidiol and Tetrahydrocannabinol from a Novel Transdermal Delivery System in Healthy Adults: A Single-Arm, Open-Label, Exploratory Study.

This is the first pharmacokinetic study in humans that demonstrated CBD and THC entering systemic circulation viatransdermal administration and represents an important contribution to understanding the pharmacokinetics of transdermal cannabinoids.



Tolerance and disposition of tetrahydrocannabinol in man.

  • C. A. HuntR. Jones
  • Medicine, Biology
    The Journal of pharmacology and experimental therapeutics
  • 1980
It is concluded that such pharmacokinetic and metabolic changes cannot account for the development of tolerance to the cardiovascular, psychological and skin hypothermic effects of THC.

Pharmacokinetics of delta 9-tetrahydrocannabinol in rabbits following single or multiple intravenous doses.

Plasma clearance values were high, but the large amount of drug sequestered in tissues, reflected by large volumes of distribution, was the main determinant of terminal half-life, suggesting that distribution of delta 9-THC is governed by its physicochemical properties and not by any active transport process or specific barriers.

Modelling of the concentration—effect relationship of THC on central nervous system parameters and heart rate — insight into its mechanisms of action and a tool for clinical research and development of cannabinoids

The relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic—pharmacodynamic (PK-PD) modelling, which provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems.

Plasma delta‐9‐tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking

After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration, suggesting that brain concentrations were increasing as plasma concentrations decreased.

Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects.

Omnisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients and showed promising PK and PD characteristics.

Concentration-effect relationship of delta-9-tetrahydrocannabiol and prediction of psychotropic effects after smoking marijuana.

Simulation of the effect-time course after repeated smoking of marijuana in different intervals and for different dose strengths showed that dose and dosing interval are determinants of the duration of the psychotropic effects of THC.

Surinabant, a selective cannabinoid receptor type 1 antagonist, inhibits Δ9-tetrahydrocannabinol-induced central nervous system and heart rate effects in humans.

The dose-related inhibition by surinabant of CNS effects and heart rate induced by Δ(9) -tetrahydrocannabinol (THC) in humans suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations.

Distribution of tritiated‐1 Δ9‐tetrahydrocannabinol in rat tissues after inhalation

The biological distribution and retention of 3H-A-9-tetrahydrocannabinol (Ag-THC) administered by inhalation in rats at various time intervals is examined.

Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users.

It seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users.