Population pharmacokinetic model of blood THC and its metabolites in chronic and occasional cannabis users and relationship with on-site oral fluid testing

Jean Claude Alvarez, Sarah Hartley, Isabelle Etting, Mégane Ribot, Nawal Derridj-Ait-Younes, Céline Verstuyft, Islam-Amine Larabi, Nicolas Simon, Jean Claude Alvarez, Sarah Hartley, Isabelle Etting, Mégane Ribot, Nawal Derridj-Ait-Younes, Céline Verstuyft, Islam-Amine Larabi, Nicolas Simon

Abstract

Aims: To develop a population pharmacokinetic (PP) model of delta-9-tetrahydrocannabinol (THC) and its metabolites in blood and to determine the relationship between blood THC pharmacokinetics and results of on-site oral fluid (OF) testing in chronic (CC) and occasional (OC) cannabis users.

Methods: Fifteen CC (1-2 joints/day) and 15 OC (1-2 joints/week) aged 18-34 years were included, genotyped for their CYP2C9 polymorphisms. Twelve measurements of blood THC, 11-OH-THC and THC-COOH were carried out during the 24-hour period after controlled cross-over random inhalation of placebo, 10 mg or 30 mg of THC. OF tests (DrugWipe® 5S) were performed up to 6 hours and then stopped after two successive negative results. The blood concentrations and their relationship to OF testing results were analysed using a PP approach with NONMEM® and R.

Results: A three-compartment model described the pharmacokinetics of THC, with zero-order absorption, and a two-compartment model the metabolites. The fraction of THC converted to 11-OH-THC was 0.27 and the fraction of 11-OH-THC to THC-COOH was 0.86. Smoking 30 mg of THC decreased the THC bioavailability to 0.68 compared to 10 mg. CC showed a 2.41 greater bioavailability than OC, leading to higher Cmax and AUC for the three compounds for the same dose. The best model describing the probability of a positive OF test included THC blood concentration and the group as covariate: for a similar THC blood concentration, a CC was less likely to be positive than an OC.

Conclusion: OC are more likely to screen positive than CC for a similar blood concentration.

Trial registration: ClinicalTrials.gov NCT02061020.

Keywords: chronic users; occasional users; oral fluid test; pharmacokinetics; smoked cannabis.

© 2021 British Pharmacological Society.

References

REFERENCES

    1. Wilson FA, Stimpson JP, Pagán JA. Fatal crashes from drivers testing positive for drugs in the U.S., 1993-2010. Public Health Rep. 2014;129(4):342-350.
    1. Davey J, Armstrong K, Martin P. Results of the Queensland 2007-2012 roadside drug testing program: the prevalence of three illicit drugs. Accid Anal Prev. 2014;65:11-17.
    1. Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol. 1992;16(5):276-282.
    1. Hartley S, Simon N, Larabi A, et al. Effect of smoked cannabis on vigilance and accident risk using simulated driving in occasional and chronic users and the pharmacokinetic-pharmacodynamic relationship. Clin Chem. 2019;65(5):684-693.
    1. Hunault CC, Mensinga TT, de Vries I, et al. Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC. Psychopharmacology (Berl). 2008;201(2):171-181.
    1. Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80(15):1415-1419.
    1. Bergamaschi MM, Karschner EL, Goodwin RS, et al. Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers' blood on per se drugged driving laws. Clin Chem. 2013;59(3):519-526.
    1. Karschner EL, Swortwood MJ, Hirvonen J, et al. Extended plasma cannabinoid excretion in chronic frequent cannabis smokers during sustained abstinence and correlation with psychomotor performance. Drug Test Anal. 2016;8(7):682-689.
    1. Sachse-Seeboth C, Pfeil J, Sehrt D, et al. Interindividual variation in the pharmacokinetics of Δ9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin Pharmacol Ther. 2009;85(3):273-276.
    1. Dobri SCD, Moslehi AH, Davies TC. Are oral fluid testing devices effective for the roadside detection of recent cannabis use? A systematic review. Public Health. 2019;171:57-65.
    1. Verstraete A. ROSITA Project: Roadside Testing Assessment. 2001. . Accessed January 3, 2021.
    1. Verstraete AG, Raes E. ROSITA-2 project. Final report. Ghent: Academia Press; 2006.
    1. Schulze H, Schumacher M, Urmeew R, et al. Findings from the DRUID project Driving Under the Influence of Drugs, Alcohol and Medicines in Europe-findings from the DRUID project. 2012. . Accessed January 3, 2021.
    1. Spindle TR, Cone EJ, Schlienz NJ, et al. Acute pharmacokinetic profile of smoked and vaporized cannabis in human blood and oral fluid. J Anal Toxicol. 2019;43(4):233-258.
    1. Blencowe T, Pehrsson A, Lillsunde P, et al. An analytical evaluation of eight on-site oral fluid drug screening devices using laboratory confirmation results from oral fluid. Forensic Sci Int. 2011;208(1-3):173-179.
    1. Strano-Rossi S, Castrignanò E, Anzillotti L, et al. Evaluation of four oral fluid devices (DDS®, Drugtest 5000®, Drugwipe 5+® and RapidSTAT®) for on-site monitoring drugged driving in comparison with UHPLC-MS/MS analysis. Forensic Sci Int. 2012;221(1-3):70-76.
    1. Wille SM, Samyn N, Ramírez-Fernández Mdel M, De Boeck G. Evaluation of on-site oral fluid screening using Drugwipe-5(+), RapidSTAT and Drug Test 5000 for the detection of drugs of abuse in drivers. Forensic Sci Int. 2010;198(1-3):2-6.
    1. Pehrsson A, Blencowe T, Vimpari K, Impinen A, Gunnar T, Lillsunde P. Performance evaluation of the DrugWipe® 5/5+ on-site oral fluid screening device. Int J Leg Med. 2011;125(5):675-683.
    1. Gentili S, Solimini R, Tittarelli R, Mannocchi G, Busardò FP. A study on the reliability of an on-site oral fluid drug test in a recreational context. J Anal Methods Chem. 2016;2016:1234581.
    1. Newmeyer MN, Swortwood MJ, Andersson M, Abulseoud OA, Scheidweiler KB, Huestis MA. Cannabis edibles: blood and oral fluid cannabinoid pharmacokinetics and evaluation of oral fluid screening devices for predicting Δ9-tetrahydrocannabinol in blood and oral fluid following cannabis brownie administration. Clin Chem. 2017;63(3):647-662.
    1. Wille SM, Di Fazio V, Toennes SW, van Wel JH, Ramaekers JG, Samyn N. Evaluation of Δ(9)-tetrahydrocannabinol detection using DrugWipe5S(®) screening and oral fluid quantification after Quantisal™ collection for roadside drug detection via a controlled study with chronic cannabis users. Drug Test Anal. 2015;7(3):178-186.
    1. Desrosiers NA, Milman G, Mendu DR, et al. Cannabinoids in oral fluid by on-site immunoassay and by GC-MS using two different oral fluid collection devices. Anal Bioanal Chem. 2014;406(17):4117-4128.
    1. Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction. 1993;88(6):791-804.
    1. Kintz P, Feisthauer E, Abe E, Fetter M, Roux S, Alvarez JC. Testing for cannabidiol after e-cigarettes use. Tox Anal Clin. 2020;32:1-3.
    1. Deveci SE, Deveci F, Acik Y, Ozan AT. The measurement of exhaled carbon monoxide in healthy smokers and non-smokers. Respir Med. 2004;98(6):551-556.
    1. Lacroix C, Saussereau E. Fast liquid chromatography/tandem mass spectrometry determination of cannabinoids in micro volume blood sample after dabsyl derivatization. J Chromatogr B. 2012;905:85-95.
    1. Morin S, Bodin L, Loriot MA, et al. Pharmacogenetics of acenocoumarol pharmacodynamics. Clin Pharmacol Ther. 2004;75(5):403-414.
    1. Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User's Guides (1989-2009). Ellicott City, MD: Icon Development Solutions; 2009.
    1. Holford NH. Wings for NONMEM. . Updated August 19, 2017. Accessed January 3, 2021.
    1. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2016.
    1. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2013;e38(4):2.
    1. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2019.
    1. Bates D, Maechler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67(1):1-48.
    1. Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinf. 2011;7(1):77.
    1. Kuhn M. Building predictive models in R using the caret package. J Stat Softw. 2008;28(5):1-26.
    1. Sing T, Sander O, Beerenwinkel N, Lengauer T. ROCR: visualizing classifier performance in R. Bioinformatics. 2005;21(20):7881.
    1. Wickham H. ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2009.
    1. Heuberger JA, Guan Z, Oyetayo OO, et al. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics. Clin Pharmacokinet. 2015;54(2):209-219.
    1. Sempio C, Huestis MA, Mikulich-Gilbertson SK, Klawitter J, Christians U, Henthorn TK. Population pharmacokinetic modeling of plasma Δ9-tetrahydrocannabinol and an active and inactive metabolite following controlled smoked cannabis administration. Br J Clin Pharmacol. 2020;86(3):611-619.
    1. Englund A, Stone JM, Morrison PD. Cannabis in the arm: what can we learn from intravenous cannabinoid studies? Curr Pharm Des. 2012;18(32):4906-4914.
    1. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327-360.
    1. Marsot A, Audebert C, Attolini L, Lacarelle B, Micallef J, Blin O. Comparison of cannabinoid concentrations in plasma, oral fluid and urine in occasional cannabis smokers after smoking cannabis cigarette. J Pharm Pharm Sci. 2016;19(3):411-422.
    1. Ohlsson A, Lindgren JE, Wahlén A, Agurell S, Hollister LE, Gillespie HK. Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Mass Spectrom. 1982;9(1):6-10.
    1. Lindgren JE, Ohlsson A, Agurell S, Hollister L, Gillespie H. Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis. Psychopharmacology (Berl). 1981;74(3):208-212.
    1. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285-291.
    1. Toennes SW, Ramaekers JG, Theunissen EL, Moeller MR, Kaeurt GF. Pharmacokinetic properties of delta 9-tetrahydrocannabinol in oral fluid of occasional and chronic users. J Anal Toxicol. 2010;34(4):216-221.

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