Poster Number-70 - A Pilot Clinical and Pharmacokinetic Study of Δ9-Tetrahydrocannabinol (THC) / Cannabidiol (CBD) Nanoparticle Oro-Buccal Spray in Patients with Advanced Cancer Experiencing Uncontrolled Pain.

A Pilot Clinical and Pharmacokinetic Study of Δ⁹-Tetrahydrocannabinol (THC) / Cannabidiol (CBD) Nanoparticle Oro-Buccal Spray in Patients with Advanced Cancer Experiencing Uncontrolled Pain

Purpose:

Relief from chronic pain (cancer or non-cancer related) is a common condition cited by patients for the medical use of cannabis [1-3].  A recent systematic review and meta-analysis of randomized controlled trials suggests that cannabis-based-medicines could be effective for chronic pain treatment and primarily for neuropathic pain [4]. Others have reported that cannabinoid-based pharmacotherapies may serve as an effective replacement analgesic option that delays the use of opioid medications [5]. Alternatively, cannabis-based medicines may be administered as an adjunctive medicine. This pilot study aimed to assess the safety, tolerability, pharmacokinetics (PK) and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle suspension spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesics.

 

Methods:

The study was a non-blinded single arm 2-stage investigation that describes a pilot preliminary safety, tolerability, and PK exploratory endpoint to obtain a possible signal for efficacy of future robust studies.  In the first instance, eligible patients completed the EORTC-QLQ-30 questionnaire [6] at the induction visit and subsequent visits to the hospital and the treating clinician was blinded to this process.  The study consisted of two stages, namely, Stage I which was a two-day single ascending dose (SAD) and a multiple ascending dose (MAD) simple pharmacokinetic investigation of the nanoparticle Δ9-THC/CBD formulation. Five participants diagnosed with advanced incurable cancer as confirmed by the treating clinician and with controlled pain was deemed suitable for a preliminary PK assessment of the cannabis-based medicine. On day 1 all participants were administered 2.5 mg THC and 2.5 mg of CBD in 300 mL (two actuations of the pump) to the oro-buccal mucosa.  On day 2 all patients administered 7.5 mg of Δ9-THC and 7.5 mg of CBD in 900 mL (six actuations of the pump [3 doses]). Blood samples were collected at 0, 30, 60, 90, 120, 150, 180, 240, 360 min and 24 h after dose administration via indwelling cannula.  Stage II was the up-titrated pilot study with n=25 eligible participants diagnosed with advanced incurable cancer and uncontrolled pain as confirmed by the treating clinician while currently being treated with opioid analgesics. The stages of malignancy were verified but related on investigator assessment. Eligible participants were invited to participate over the three phases in a 30-day period. The three phases in Stage II were divided into a dose escalation phase over days 1 to 9; a treatment phase over days 10 to 15; and a follow-up phase over days 16 to 30. Prospective participants for all Stage II phases of this pilot study attended the Royal North Shore Hospital Medical Oncology unit, in Sydney for follow-up with the study’s principal investigator.


 


Results:

There was an overall improvement from baseline for global health status; physical functioning; emotional functioning; cognitive functioning; fatigue; pain; dyspnoea and insomnia.   Given the complex presentation of the cohort of patients under investigation the EORTC-QLQ-30 scores were reported for those patients with established preliminary thresholds for clinical importance. Namely, this was for patients that presented with breast and prostate cancers and diagnosed with bone metastasis as compared to the total cohort of patients in the study.   During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of D9-THC than CBD (AUC from 2.5 mg each of D9-THC and CBD, was 1.71 ng mL.h^-1 (1.1, 6.6) and 0.65 ng mL.h^-1 (0.49, 4.1), respectively).   During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastasis, had the highest mean pain score improvement on a numeric pain rating scale from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use).  For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients.

 

Conclusion:

This study demonstrated that the administration of the investigative cannabis-based medicine (MDCNB-01) was generally safe and tolerated in a short-term exposure study in a cohort of patients with advanced incurable cancers with controlled pain (Stage I) or intractable pain (Stage II) despite opioid treatment. Moreover, results from patient-reported outcome questionnaires suggested that patient functioning improved clinically for emotional functioning, fatigue, dyspnoea, insomnia, and appetite loss, especially in those patients with improved pain management with the cannabis-based medicine (i.e., breast and prostate cancers with bone metastasis) [7].   The water-soluble nanoparticle cannabis-based medicine formulation demonstrated acceptable pharmacokinetic behavior for cannabinoids consistent with safety and tolerability and preliminary analgesic benefit. There was a peak plasma concentration of less than an hour and adequate concentration to support multiple dosing every four to eight hours.  The water-soluble cannabis-based medicine suspension provided acceptable bioavailability for D9-THC/CBD in advanced incurable cancers with uncontrolled pain. Furthermore, according to the prescribing oncologist in a sub-group of patients diagnosed with breast and prostate cancers with bone metastasis there was preliminary evidence of analgesic efficacy, above what the maximal pain management was already providing ([8] unpublished data currently under review). 

 

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Patients with Advanced Cancer Experiencing Uncontrolled Pain. PLOS One 2022; [Under Review].