Pilot clinical and pharmacokinetic study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain

Abstract

This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg Δ9-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). 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 Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-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 metastases, had the highest mean pain score improvement 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. The water-soluble cannabis-based medicine provided acceptable bioavailability for Δ9-THC/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.

Fig 1. CONSORT diagram for Single Ascending (SAD) and Multiple Ascending Dose (MAD) Stages I and II pilot study.

In Stage I (pharmacokinetics) eligible patients administered one dose (2 sprays) on day 1 and three doses (6 sprays) on day 2. In Stage II after baseline assessments, patients commenced with one spray of the cannabis-based medicine (1.25 mg each of Δ9-THC and CBD in 0.15 mL) every 4 to 8 hours while awake for 3 days, then dose escalated to two sprays every 4–8 hours while awake for 3 days, and finally dose escalated to three sprays every 4–8 hours while awake for 3 days.

Fig 2. EORTC-QLQ-30 scores relevant to improvement or deterioration of global functioning and symptoms between patients that demonstrated improvement in pain from those patients with breast and prostate cancers and bone metastasis compared to patients from the remainder of the cohort.

Error bars represent STD.

Fig 3. PK of Stage I SAD.

Individual and median plasma concentration over time for Δ9-THC (squares) and CBD (circles) on Day 1 (single dose of 2.5 mg Δ9-THC/2.5 mg CBD) and Day 2 (3-fold dose of 7.5 mg Δ9-THC/7.5 mg CBD).

Fig 4. Change in morphine milligram equivalent dose prescribed from day 1.

Note, one patient reported highly variable changes in MMeq over the time course of the study (Day 4, -240 MMeq; Day 7–330 MMeq; Day 10–90 MMeq; Day 13 +210 MMeq; Day 16 +30 MMeq; Day 30 +1170 MMeq. Day 7 and Day 30 changes are not depicted on this figure for this patient).

Fig 5. Average daily dose of daily Δ9-THC doses administered every 4–8 hours unless asleep from day 1 to day 15.

[Day 1–3, Day 4–6, Day 7–9 = dose escalation phase; Day 10–15 = treatment phase]. Two and a half times the median amount of Δ9-THC was co-administered as CBD.

Fig 6. Median change from baseline NPRS scores for all patients, those with bone metastases, those with breast/prostate cancer and those with bone pain.

Dots represent individual patient data; the line is median change.