Assessment of the absorption of a standardized whole plant extract of cannabidiol and tetrahydrocannabinol in comparative ratios in patients with glioblastoma multiforme or high grade glioma.

Abstract

Twenty participants (n=20) from from a phase II double blind randomised clinical control trial assessing the tolerability of medicinal cannabis in patients with stage 4 or recurrent glioblastoma multiforme (GBM) were assessed in a secondary data analysis. The primary clinical trial protocol has been designed in part to collect data for this projects' purpose. The aim was to assess two medicinal cannabis ratios [THC:CBD, 1:1 (5.8mg/ml:5.6mg/ml) and 4:1 (15mg/ml:3.8mg/ml)] and dosing to the measurable levels of plasma cannabinoids and cannabis metabolites collected at four time points via validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) [5]. This assay was chosen to identify any correlation to medicinal cannabis ratio and the individual dose. Individual tolerability was subjectively measured via ADLs. Participants were instructed to titrate the dose of the intervention by 0.2ml/daily until an individual tolerability was reached. The analysis for absorption includes the results of each measured cannabinoid for every participants over the four time points using repeated measures. Difference in plasma cannabinoids levels over time was described using multiple linear regression to predict the value of the independent variable. Spearman's Correlation determined the strength and direction of a non-linear, monotonic relationship between variables. To examine the combined and the unique influences of the independent variables of BMI, weight, gender, age and dose a hierarchical regression over the 3 time points for each cannabinoid and cannabinoid metabolite was conducted. Medicinal cannabis was shown to have an individual dose tolerability, and that inter-individual variability from the dose input is influenced by multiple dynamic pharmacokinetic variables that also demonstrate intra-individual variance in cannabinoids and cannabinoid metabolites over time. There was a positive correlation between certain plasma cannabinoids and cannabinoid metabolites and the dose of medicinal cannabis at some time points, however the known influences of the pharmacokinetic parameters of metabolism in this population did not significantly predict plasma cannabinoid metabolites. There was a positive correlation between dose and plasma THC in linear regressions, however after controlling for age, gender, weight and BMI in hierarchical regression, the effect of dose was not significant at any time point. This finding suggests that dose is supported by the variables of age, gender, weight and BMI, but no one was more indicative than another. This is the first study of this type to examine the dose variability and metabolism of plasma cannabinoids and cannabinoid metabolites of an oral cannabis based medicine in patients with glioblastoma multiforme or high grade glioma. A secondary analysis of existing data from a Phase II double blind randomised clinical trial assessing the tolerability of medicinal cannabis in patients with high grade glioma or recurrent GBM (ACTRN 12617001287325) has been analysed to measure a correlation of orally administered medicinal cannabis ratios and dosing to the measurable levels of cannabinoids and cannabinoid metabolites. This project provides an unique insight on the pharmacokinetics of medicinal cannabis (MC) with respect to the absorption of two different ratios of MC and the individual dose effect variables in oncology.

Full text

Danielle Brown1, Michael Watson1, Janet Schloss1,2
1. Endeavour College of Natural Health, Australia 2. Australian Research Centre in Complementary and Integrative Medicine (ARCCIM), UTS, Australia
Twenty participants (n=20) from from a phase II double blind randomised clinical control trial
assessing the tolerability of medicinal cannabis in patients with stage 4 or recurrent
glioblastoma multiforme (GBM) were assessed in a secondary data analysis. The primary
clinical trial protocol has been designed in part to collect data for this projects’ purpose.
The aim was to assess two medicinal cannabis ratios [THC:CBD, 1:1 (5.8mg/ml:5.6mg/ml) and
4:1 (15mg/ml:3.8mg/ml)] and dosing to the measurable levels of plasma cannabinoids and
cannabis metabolites collected at four time points via validated liquid chromatography–tandem
mass spectrometry (LC-MS/MS)[5]. This assay was chosen to identify any correlation to
medicinal cannabis ratio and the individual dose. Individual tolerability was subjectively
measured via ADLs. Participants were instructed to titrate the dose of the intervention by
0.2ml/daily until an individual tolerability was reached.
The analysis for absorption includes the results of each measured cannabinoid for every
participants over the four time points using repeated measures. Difference in plasma
cannabinoids levels over time was described using multiple linear regression to predict the
value of the independent variable. Spearman’s Correlation determined the strength and
direction of a non-linear, monotonic relationship between variables. To examine the combined
and the unique influences of the independent variables of BMI, weight, gender, age and dose
a hierarchical regression over the 3 time points for each cannabinoid and cannabinoid
metabolite was conducted.
Medicinal cannabis was shown to have an individual dose tolerability, and that inter-individual
variability from the dose input is influenced by multiple dynamic pharmacokinetic variables
that also demonstrate intra-individual variance in cannabinoids and cannabinoid metabolites
over time.
There was a positive correlation between certain plasma cannabinoids and cannabinoid
metabolites and the dose of medicinal cannabis at some time points, however the known
influences of the pharmacokinetic parameters of metabolism in this population did not
significantly predict plasma cannabinoid metabolites.
There was a positive correlation between dose and plasma THC in linear regressions,
however after controlling for age, gender, weight and BMI in hierarchical regression, the effect
of dose was not significant at any time point. This finding suggests that dose is supported by
the variables of age, gender, weight and BMI, but no one was more indicative than another.
This is the first study of this type to examine the dose variability and metabolism of plasma
cannabinoids and cannabinoid metabolites of an oral cannabis based medicine in patients with
glioblastoma multiforme or high grade glioma. A secondary analysis of existing data from a Phase
II double blind randomised clinical trial assessing the tolerability of medicinal cannabis in patients
with high grade glioma or recurrent GBM (ACTRN 12617001287325) has been analysed to
measure a correlation of orally administered medicinal cannabis ratios and dosing to the
measurable levels of cannabinoids and cannabinoid metabolites.
This project provides an unique insight on the pharmacokinetics of medicinal cannabis (MC) with
respect to the absorption of two different ratios of MC and the individual dose effect variables in
oncology.
1. Russo, E.B. and J. Marcu, Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Adv Pharmacol, 2017. 80: p. 67-134.
2. Tateo, S., State of the evidence: Cannabinoids and cancer pain-A systematic review. Journal of the American Association of Nurse Practitioners, 2017. 29(2): p. 94-103.
1. MacCallum, C.A. and E.B. Russo, Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine, 2018. 49: p. 12-19.
4. Stout, S.M. and N.M. Cimino, Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metabolism Reviews, 2014. 46(1): p. 86-95.
5. Schwope, D. M., Scheidweiler, K. B., & Huestis, M. A. (2011). Direct Quantification of Cannabinoids and Cannabinoid Glucuronides in Whole Blood by Liquid Chromatography Tandem Mass Spectrometry. Analytical and bioanalytical chemistry,
401(4), 1273-1283. doi:10.1007/s00216-011-5197-7
6. Huestis, M.A., Human Cannabinoid Pharmacokinetics. Chemistry & biodiversity, 2007. 4(8): p. 1770-1804.
7. Sharma, P., P. Murthy, and M.M.S. Bharath, Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications. Iranian Journal of Psychiatry, 2012. 7(4): p. 149-156.
8. Grotenhermen, F., Pharmacokinetics and pharmacodynamics of cannabinoids. Clinical Pharmacokinetics, 2003. 42(4): p. 327-360.
9. Turgeman, I. and G. Bar-Sela, Cannabis use in palliative oncology: A review of the evidence for popular indications. Israel Medical Association Journal, 2017. 19(2): p. 85-88.
10.. Piomelli, D. and E.B. Russo, The Cannabis sativa Versus Cannabis indica Debate: An Interview with Ethan Russo, MD. Cannabis Cannabinoid Res, 2016. 1(1): p. 44-46.
19 participants (n=19) with stage 4 GBM or recurrent high grade gliomas completed the 12
week trial. All participants reached individual tolerability by week 5. All but one participant who
was withdrawn continued on the individual tolerable dose until trial conclusion.
The average dose for intervention arm A was 11.14mg/ml THC and 11.54 CBD mg/ml.
Intervention arm B was 27.6mg/ml THC and 6.99mg/ml CBD. There was a positive correlation
between dose and plasma THC in linear regressions, however after controlling for age,
gender, weight and BMI in hierarchical regression, the effect of dose was not significant at
any time point. This finding suggests that dose is supported by the variables of age, gender,
weight and BMI, but no one was more indicative than another.
A statistically significant variance in plasma cannabinoid and cannabinoid metabolites can be
attributed to the different dosage for tetrahydrocannabinolic acid (THCA) (p=0.090),
THCCOOH (p=0.032) and THCCOOH-glucuronide (p=0.001) at week 4. With CBD, 74% and
89% of the variance in plasma cannabidiol was explained by dose at weeks 8 and 12
respectively. Participants reporting raised liver enzymes at baseline had normal range or
close to normal range liver enzymes by week 12.
0.0
5.0
10.0
15.0
20.0
25.0
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention A: THCA
MC002
MC004
MC007
MC012
MC013
MC015
MC019
MC022
MC025
MC029
0.0
5.0
10.0
15.0
20.0
25.0
30.0
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention B: THCA
MC001
MC006
MC011
MC012
MC016
MC018
MC020
MC023
MC024
MC027
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
1234
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention A: THC
MC002
MC004
MC007
MC012
MC013
MC015
MC019
MC022
MC025
MC029
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention B: THC
MC001
MC006
MC011
MC014
MC016
MC018
MC020
MC023
MC024
MC027
0.0
100.0
200.0
300.0
400.0
500.0
600.0
1234
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 weeks)
Intervention A: THCCOOH
MC002
MC004
MC007
MC012
MC013
MC015
MC019
MC022
MC025
MC029
0.0
100.0
200.0
300.0
400.0
500.0
600.0
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 weeks)
Intervention B: THCCOOH
MC001
MC006
MC011
MC014
MC016
MC018
MC020
MC023
MC024
MC027
0.0
500.0
1000.0
1500.0
2000.0
2500.0
3000.0
3500.0
1234
Time Points (Initial, 4 Weeks, 8 Weeks, 12 weeks)
Intervention A: THCCOOH-glucuronide
MC002
MC004
MC007
MC012
MC013
MC015
MC019
MC022
MC025
MC029
0.0
500.0
1000.0
1500.0
2000.0
2500.0
3000.0
3500.0
4000.0
4500.0
5000.0
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 weeks)
Intervention B: THCCOOH-glucoronide
MC001
MC006
MC011
MC014
MC016
MC018
MC020
MC023
MC024
MC027
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
1234
ng/ml
Time Points (Initial, 4 weeks, 8 Weeks, 12 Weeks)
Intervention A: THC-glucuronide
MC002
MC004
MC007
MC012
MC013
MC019
MC022
MC025
MC029
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
1 2 3 4
ng/ml
Time Points (Initial, 4 weeks, 8 Weeks, 12 Weeks)
Intervention B: THC-glucuronide
MC001
MC006
MC011
MC014
MC016
MC018
MC020
MC023
MC027
MC024
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention A: CBDA
MC002
MC004
MC007
MC012
MC013
MC015
MC019
MC022
MC025
MC029
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention B: CBDA
MC001
MC006
MC011
MC014
MC016
MC018
MC020
MC023
MC024
MC027
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1234
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention A: CBD
MC002
MC004
MC007
MC012
MC013
MC015
MC019
MC022
MC025
MC029
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1 2 3 4
ng/ml
Time Points (Initial, 4 Weeks, 8 Weeks, 12 Weeks)
Intervention B: CBD
MC001
MC006
MC011
MC014
MC016
MC018
MC020
MC023
MC027
MC024
Pharmacological constituents found in Cannabis sp have demonstrated both palliative and
modulatory effects in cancer management. An understanding of the administration, dose,
absorption, metabolism and potential drug interactions of cannabis-based medicines in cancer
populations is fundamental for the assessment of efficacy, safety and therapeutic index of
medicinal cannabis.
Pharmaceutical cannabis-based medicines and single molecule cannabinoids are approved for
use in several countries despite the common conclusion within the broader medical community
that medicinal cannabis lacks adequate evidence[3]. A dose titration approach is used to identify
an individual dose effect and to navigate the therapeutic window of a liquid medicinal cannabis to
decrease the risk of an adverse events and maintain a dose for efficacy. However, this results in a
high variability of individual dosing to achieve a therapeutic outcome.
Dose (mL)
Dose (mL)
Intervention A
Week 4
Week 8
Week 12
Intervention B
Week 4
Week 8
Week 12
MC003
1
1
1
MC013
2.1
2.1
2.1
MC004
0.6
0.6
W/D
MC014
2
2
2
MC001
2.8
3
3
MC015
2.4
2.4
2.4
MC005
2.6
3
3
MC011
1.6
1.6
1.6
MC006
2.2
2.2
2.2
MC016
0.9
0.9
0.9
MC002
2
2
2
MC012
2.6
2.6
2.6
MC007
2.2
2.2
2.2
MC017
1.6
1.6
1.6
MC008
1.9
1.9
1.9
MC018
1.8
1.8
1.8
MC009
2
2
2
MC019
2
2
2
MC010
2
2
2
MC020
1.4
1.4
1.4
Individual plasma levels of cannabinoids and metabolites measured in nanograms per
millilitre (ng/ml) reported at baseline (initial) weeks 4, 8 and 12 for intervention A and B.
Reporting of dose titration (millilitres) of two ratios of medicinal cannabis (Group A, Group B)
reported at 3 times points, over 12-week trial enrolment
• Results of this study identified an increased tolerability to a higher dose of THC when in
ratio with CBD. A whole plant cannabis extract may allow for higher dosing when when
establishing a therapeutic outcome associated with THC.
• The association of raised liver enzymes and cannabis use is not well documented, however
in this cohort there is an absence of any rise in LFT markers across the 12-week period.
More research is required to measure if this observation is a direct or indirect association of
the intervention itself and/or reduced dexamethasone. Furthermore, it was identified that
participants who had raised liver enzymes at baseline had normal range or close to normal
range liver enzymes by week 12.
• A continued understanding of the role of dose within therapeutic considerations of patient
centred outcomes in this population may support improved clinical management of patient
outcomes and quality of life.
• There are multiple intersecting confounders to consider in cannabinoid metabolism
including the influence of concomitant medications and the direct influence they can have
on microsomal hepatic metabolism that can shift the parameters of individual tolerability,
and individual pharmacogenomic considerations that influence both cannabinoid
metabolism and phase I and phase II hepatic metabolism.