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Nabilone in C.I.N.V. August 2007. 2 Introduction Present a scientific validation for cannabinoids (CBs) asserting their therapeutic effects through Omnineuromodulation.

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Presentation on theme: "Nabilone in C.I.N.V. August 2007. 2 Introduction Present a scientific validation for cannabinoids (CBs) asserting their therapeutic effects through Omnineuromodulation."— Presentation transcript:

1 Nabilone in C.I.N.V. August 2007

2 2 Introduction Present a scientific validation for cannabinoids (CBs) asserting their therapeutic effects through Omnineuromodulation CBs activate CB1 endocannabinoid receptors, which are omnipresent throughout the Central Nervous System (CNS) Action on these receptors modulates neuronal signaling Review evidence showing how omnineuromodulation underlies the therapeutic role of CBs in the management of Chemotherapy-Induced Nausea and Vomiting (CINV)

3 3 The Ubiquitous CB1 Endogenous CBs are a major class of neuromodulators, acting through receptors, CB1 and CB2 CB1 receptors are primarily located on CNS neurons Levels exceed those of nearly all neurotransmitter receptors Exogenous CBs exert their effects by driving this innate system, often mimicking and enhancing its natural functions

4 4 The Ubiquitous CB1 The omnipresent central distribution of CB1, has led to the term, Omnineuromodulator, to describe CB action Therapeutic effects are primarily due to agonist action in brain regions that mediate nausea/vomiting, appetite, and neuropathic pain

5 5 Omnineuromodulation Nabilone acts on presynaptic CB1 receptors, similar to endocannabinoids Inhibits the release of excitatory (e.g., glutamate) and inhibitory (e.g., GABA) neurotransmitters The primary effect on neuronal signaling appears to be inhibitory, but network effects may be complex and hence modulatory in nature Endogenous CB1 ligands act “backwards” from classical neurotransmitters by serving as retrograde synaptic messengers

6 6 A Sequential Overview of Omnineuromodulation

7 7 Neurotransmitter (NT) released from vesicles within the presynaptic neuron activates the postsynaptic neuron

8 8 Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process

9 9 The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor

10 10 The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release

11 11 CB agents, acting as Omnineuromodulators, circumvent this multi- step process by directly activating CB1 receptors to stimulate the endogenous CB system, enhancing its function

12 12 Summary of Actions of the Cannabinoids Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron Endogenous and Exogenous Cannabinoids Reduce Neuronal Signaling Postsynaptic Neuron Neurotransmitter Receptor Endogenous Cannabinoid Retrograde Signaling CB1 Receptor Presynaptic Neuron Inhibition of Neurotransmitter Release Cannabinoid Therapy (nabilone) Activated postsynaptic neuron releases endocannabinoids. Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor. CB1 receptor activates a G- protein, leading to inhibition of NT release. Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids *see notes for references

13 13 Anti-emetic, Anti-nausea Effects of Cannabinoids

14 14 Causes of nausea and vomiting/emesis: Viral illness Cancer Chemotherapy Radiotherapy

15 15 The Nucleus of the Solitary Tract (NTS) in the DVC receives information about: Blood-borne emetics via the brainstem (BS) “Chemo- receptor Trigger Zone” Abdominal irritants via vagal afferents NTS neurons, in turn, project to a BS central pattern generator, which coordinates vomiting behavior Dorsal Vagal Complex (DVC) - NTS Dorsal Vagal Complex (DVC) - NTS

16 16 Higher cortical and limbic regions (governing taste, smell, sight, pain, memory and emotion) can suppress or stimulate nausea/vomiting through descending connections to the BS emetic circuitry Cortex Limbic System Brainstem Emetic Circuitry Brainstem Emetic Circuitry

17 17 Cannabinoids are thought to exert their antiemetic effects primarily via action on CB1 receptors in the NTS and higher cortical and limbic regions Indirect, partial actions on 5-HT and DA signaling via 5- HT 3 and D 2 receptors are implicated Dorsal Vagal Complex - NTS Dorsal Vagal Complex - NTS Brainstem Emetic Circuitry Cortex Limbic System

18 18 Summary CB agonists act as Omnineuromodulators —a term that describes their role in activating CB1 endocannabinoid receptors, which are omnipresent throughout the CNS and modulate neuronal signaling Evidence shows that Omnineuromodulation underlies the therapeutic role of CB agents in the treatment of CINV, Cachexia, and Neuropathic Pain

19 19 Approved License for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional anti-emetic treatments

20 20 Nabilone delivers: 1 Convenient BID dosing: The usual adult dosage is 1 or 2 mg BID Predictable pharmacokinetics: Peak plasma concentrations occur within 2 hours following oral administration Long acting: 8 to 12 hour duration of action Not detected by the EMIT test 2 In anti-emetic phase III studies, involving 316 cancer patients receiving a variety of chemotherapeutics (including cisplatin), nabilone was shown to be superior in efficacy to placebo, as well as to prochlorperazine, in: 1 Reduction of vomiting episodes Reduction of nausea severity Improvement in appetite Investigators’ global impression of efficacy 3 *see notes for references

21 Nabilone Pivotal Studies

22 22 Placebo-Controlled, Fixed-Dose Trials Primary Endpoint: Patient-Rated Efficacy Criteria Number of vomits Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

23 23 Active-Controlled, Fixed-Dose Trials Primary Endpoint: Patient-Rated Efficacy Criteria Number of vomits Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

24 24 Primary Endpoint: Investigator-Rated Efficacy and Safety Active-Controlled, Fixed-Dose Trials Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poor Safety: Based on the frequency of adverse events Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

25 25 Active-Controlled, Flexible-Dose Trial Primary Endpoint: Patient-Rated Efficacy Criteria Number of vomits Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

26 26 Patients Prefer Nabilone Preferred Nabilone Preferred Placebo No Preference Placebo-Controlled, Fixed-Dose Trials Preferred Nabilone Preferred Prochlorperazine No Preference Active-Controlled, Fixed-Dose Trials 77% 12% 73% 20% 7%

27 27 Summary: Nabilone and Reduction of Vomiting Frequency Chemotherapy InducedNausea - and Vomiting

28 28 Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America. Nabilone Reduces the Frequency of Vomiting N=75 **P < N=129 *P < 0.01 Reduction in Frequency of Vomiting Nabilone Placebo Prochlorperazine

29 29 Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S. Nabilone Significantly Reduces Vomiting Frequency

30 30 CR=complete response; PR=partial response Herman TS, et al. N Engl J Med. 1979;300: Nabilone: Superior to Prochlorperazine in Patients with Severe CINV

31 31 CINV is an established indication for Nabilone Clinical trials have confirmed the efficacy of Nabilone in reducing frequency of vomiting in cancer patients receiving chemotherapy Nabilone is an important addition to the physician’s armamentarium against the nausea and vomiting associated with chemotherapy in patients who have failed to respond adequately to conventional antiemetic therapy Summary: Nabilone and Reduction of Vomiting Frequency

32 32 Nabilone: In reduction of Nausea Chemotherapy InducedNausea -

33 33 30 randomized, comparative studies of cannabinoids with placebo or other antiemetics (oral Nabilone [nabilone]= 16 studies; oral dronabinol=11 studies; intramuscular levonatrodol=1 study) Active control= prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone, and alizapride Tramèr MR, et al. BMJ. 2001;323:1-8. Control of Nausea Cannabinoids: A Systematic Review

34 34 Comparative Efficacy of Nabilone vs. Prochlorperazine Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America. *Based on patients’ report (daily average): 0=none; 1=mild; 2=moderate; 3=severe N=129 *P < N=75 **P < 0.007

35 35 Score: 0=none; 1=mild; 2=moderate; 3=severe Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S. Nabilone Significantly Reduces Nausea Severity

36 36 Severity of Nausea Significantly Reduced with Nabilone Ahmedzai S, et al. Br J Cancer. 1983;48:

37 37 Summary: Nausea Nausea is more difficult to control than is vomiting Control of nausea remains a significant unmet need in cancer patients receiving chemotherapy Nabilone has demonstrated efficacy in reducing the severity of nausea Patients prefer Nabilone over placebo and active controls (prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride)

38 38 Several reductions in acute pain exacerbations and nighttime pain Relief within 1 week of beginning Nabilone (n=1) Patients’ testimonial Taking Nabilone at night made pain more localized, and relief lasted until the following afternoon Nabilone made pain “livable” Nabilone “takes the edge off” Other benefits: Impact of Nabilone on Pain A Retrospective Chart Review Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.

39 39 Berlach DM, et al. Am Acad Pain Med. 2006;7: Other Benefits of Nabilone Improvement in quality or duration of sleep Decreased nausea or vomiting 3 patients continued to take Nabilone for benefits other than pain relief 50% of patients 25% of patients Sleep improvements (n=1) Decreased nausea & increased appetite (n=1) Decreased nausea and vomiting and increased sleep (n=1)

40 40 Benefits of Cannabinoids in Cancer Patients: A Retrospective Case Study Methodology *Data on file

41 41 Edmonton Symptom Assessment System (ESAS)

42 42 Reasons for Cannabinoid Discontinuation 12/17 (71%) due to side effects Drowsiness Dizziness Delirium 5/17 (29%) advised by other MDs Discontinuation Rate: Overall = 20.7% Adjusted = 14.6%

43 43 Nabilone TM (nabilone) Package Insert. Valeant Pharmaceuticals North America; Marinol ® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc. Differentiating Between the Cannabinoids: Pharmacokinetics NabiloneMarinol Oral Dosing 1-2 mg 1-3 hrs before chemotherapy, and 2 times per day for up to 48 hrs afterwards 5 mg/m hrs before chemotherapy, and every 2-4 hrs afterwards for a total of 4-6 doses per day SourceSynthetic ∆ 9 -THC analogSynthetic ∆ 9 -THC FormulationCrystalline powder capsule Capsule formulated with sesame oil, among other ingredients (contraindicated in patients with a hypersensitivity to sesame oil) Onset of Action60-90 min30-60 min Peak plasma concentrations (Tmax) 2 hrs2-4 hrs Duration of Action8-12 hrs4-6 hrs for psychoactive effects Metabolites2 active metabolites 2 active metabolites and more than 20 other metabolites Clearance Major excretory pathway is the biliary system Biliary excretion is major route of elimination

44 44 CYP450 Metabolizing Enzymes CYP450 Enzyme Inhibition CYP450 Enzyme Induction Nabilone 2C9*, 3A4 (aldehyde oxygenase) None to Date Marinol 2C9*, 2C11, 3A4 (aldehyde oxygenase) 3A4None to Date Nahas GG, Surim KM, Harvet DJ, Agurell S, eds. Marihuana and Medicine. Totowa, NJ: Human Press; 1999: Metabolized principally through the CYP450 2C9 isoenzyme No inhibitory or inducing effect on any of the isoenzymes Competes with very few medications at the metabolic level, including opioids Examples of medications metabolized by CYP3A4: anti-fungals, methadone, many anti-depressants, HIV protease inhibitors * Main metabolizing isoenzyme Nabilone Cannabinoid Metabolism

45 45 Safety Overview of Cannabinoids Nabilone™MARINOL® (dronabinol) Contraindications In patients with a history of hypersensitivity to any cannabinoid In patients with a history of hypersensitivity to any cannabinoid or sesame oil Most Commonly Occurring Adverse Effects Drowsiness Vertigo Dry mouth Euphoria Ataxia Headache Concentration difficulties Asthenia Palpitations Tachycardia Vasodilatation/facial flush Abdominal pain Nausea Vomiting Amnesia Nabilone (Nabilone TM ) Package Insert; San Diego, Valeant Pharmaceuticals North America; 2006; Dronabinol (Marinol® ) Package Insert. Marietta, Ga: Solvay Pharmaceuticals, Inc.; Cannabinoids should not be taken with alcohol, sedatives, hypnotics, or other psychoticomimetic substances Ataxia Confusion Depersonalization Dizziness Euphoria Paranoid reaction Somnolence Thinking abnormal

46 46 Summary Treatment Challenges Unique MOA of Cannabinoids Clinical Trial Results CINV—a highly prevalent side effect of cancer treatment Persistent CINV is associated with several adverse sequelae Pain is often under- diagnosed and under- treated Target ubiquitous CB receptors in the CNS and periphery CINV: agonism of CB1 receptors inhibits neurotransmitters Pain: neuromodulatory effects involving both CB1 and CB2 receptors Support the use of cannabinoids to treat refractory CINV Suggest that cannabinoids may be useful adjunctive therapy for pain

47 END SLIDE QUESTIONS?

48 48

49 49 Adverse Events can be reported to the drug safety department at Valeant Pharmaceuticals at


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