Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics
Cardiac Electrophysiology
Concentration-dependent QTc prolongation was observed for EPIDIOLEX. At exposures obtained when administered as monotherapy at recommended doses with a high fat meal, EPIDIOLEX did not prolong the QTc interval greater than 10 msec.
Other factors such as food intake, certain concomitant medications (e.g., clobazam), and alcohol consumption may increase the exposure of EPIDIOLEX and the potential effect on QTc prolongation in this scenario is not known.

Pharmacokinetic Properties

11.3 Pharmacokinetics
Cannabidiol demonstrated an increase in exposure that was less than dose-proportional over the range of 5 to 25 mg/kg/day in patients.
Absorption
Cannabidiol has a time to maximum plasma concentration (Tmax) of 2.5 to 5 hours at steady state (Css).

Effect of Food
Coadministration of EPIDIOLEX (750 or 1500 mg) with a high-fat/high-calorie meal increased Cmax by 5-fold, AUC by 4-fold, and reduced the total variability, compared with the fasted state in healthy volunteers [see Dosage and Administration (3.4)]. Coadministration of EPIDIOLEX with a low-fat/low-calorie meal increased
Cmax and AUC by 4-fold and 3-fold, respectively. Furthermore, coadministration of EPIDIOLEX with bovine milk increased exposure by approximately 3-fold for Cmax and 2.5-fold for AUC. Coadministration of EPIDIOLEX with alcohol also caused increased exposure to cannabidiol, with 93% increased Cmax and 63% greater AUC.
Distribution
The apparent volume of distribution in healthy volunteers was 20963 L to 42849 L. Protein binding of the cannabidiol and its metabolites was > 94% in vitro.
Elimination
The half-life of cannabidiol in plasma was 56 to 61 hours after twice-daily dosing for 7 days in healthy volunteers. The plasma clearance of cannabidiol following a single EPIDIOLEX 1500 mg dose (approximately equal to the 20 mg/kg/day dosage) is 1111 L/h.

Metabolism
Cannabidiol is metabolized in the liver and the gut (primarily in the liver) by CYP2C19 and CYP3A4 enzymes, and UGT1A7, UGT1A9, and UGT2B7 isoforms.

After repeat dosing, the active metabolite of cannabidiol, 7-OH-CBD, has a 38% lower AUC than the parent drug. The 7-OH-CBD metabolite is converted to 7-COOH-CBD, which has an approximately 40-fold higher AUC than the parent drug. Based on preclinical models of seizure, the 7-OH-CBD metabolite is active; however, the 7-COOH-CBD metabolite is not active.

Excretion
EPIDIOLEX is excreted in feces, with minor renal clearance.

Specific Populations
Patients with Hepatic Impairment
No effects on the exposures of cannabidiol or metabolite exposures were observed following administration of a single dose of EPIDIOLEX 200 mg in patients with mild (Child-Pugh A) hepatic impairment. Patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment had an approximately 2.5 to 5.2-fold higher AUC, compared with healthy volunteers with normal hepatic function [see Dosage and Administration (3.6), Warnings and Precautions (5.1), Use in Specific Populations (8.5)].

Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Drug Metabolizing Enzymes [see Drug Interactions (7.1, 7.2)]
Cannabidiol is a substrate for CYP3A4 and CYP2C19. Cannabidiol has the potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 at clinically relevant concentrations.
Cannabidiol may induce or inhibit CYP2B6 at clinically relevant concentrations.
Cannabidiol inhibits uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7, but does not inhibit the UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B17 isoforms.
Transporters
Cannabidiol and the cannabidiol metabolite, 7-OH-CBD, are not anticipated to interact with BCRP, BSEP, MDR1/P-gp, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1B1, or OATP1B3. However, due to limitations of the in vitro testing procedure, inhibition of P-gp mediated efflux by cannabidiol in the intestine could not be excluded. In vivo data show that CBD can affect P-gp efflux activity in the intestine [see In Vivo Assessment of Drug Interactions].

The cannabidiol metabolite, 7-COOH-CBD, is not a substrate of BCRP, OATP1B1, OATP1B3, or OCT1.
However, 7-COOH-CBD is a substrate for P-gp. 7-COOH-CBD is an inhibitor of transport mediated via BCRP and BSEP at clinically relevant concentrations.

In Vivo Assessment of Drug Interactions
Drug Interaction Studies with AEDs
Clobazam and Valproate
The interaction potential with other AEDs (clobazam and valproate) was evaluated in dedicated clinical studies following coadministration of EPIDIOLEX (750 mg twice daily in healthy volunteers and 20 mg/kg/day in patients).
Coadministration with clobazam in healthy volunteers increased the cannabidiol active metabolite 7-OH-CBD mean Cmax by 73% and AUC by 47%; and increased the clobazam active metabolite, N-desmethylclobazam, Cmax and AUC by approximately 3-fold, with no effect on clobazam levels [see Drug Interactions (7.2)].
When EPIDIOLEX was coadministered with valproate in a healthy-volunteer trial, there was no effect on the systemic exposure to valproate. In a separate study in epilepsy patients investigating the effect of EPIDIOLEX on valproate exposure, there were decreases in both the plasma Cmax and AUC of valproate, which were not clinically relevant (approximately 17% and 21%, respectively), and a decrease in exposure of the putative hepatotoxic metabolite of valproate, 2-propyl-4-pentanoic acid (approximately 28% and 33%, respectively).
In the healthy-volunteer trial, coadministration with valproate resulted in no clinically relevant changes in exposure to cannabidiol or its major metabolites (cannabidiol Cmax decreased by 26%; 6-OH-CBD AUC increased by 27%; 7-OH-CBD AUC increased by 22%; 7-COOH-CBD Cmax and AUC increased by 25% and 32%, respectively).

Effect of EPIDIOLEX on Midazolam
Coadministration of EPIDIOLEX with midazolam (a sensitive CYP3A4 substrate) did not result in changes in plasma concentrations of midazolam compared to midazolam administered alone.

Effect of EPIDIOLEX on Stiripentol
When EPIDIOLEX was coadministered with stiripentol in a healthy volunteer trial, Cmax and AUC of stiripentol increased 28% and 55%, respectively. In patients with epilepsy, Cmax and AUC of stiripentol increased 17% and 30%, respectively [see Drug Interactions (7.2)].
Effect of EPIDIOLEX on Caffeine
In vivo data from steady-state dosing with cannabidiol (750 mg twice daily) when coadministered with a single dose of caffeine (200 mg), a sensitive CYP1A2 substrate, showed increased caffeine exposure by 15% for Cmax and 95% for AUC compared to when caffeine was administered alone [see Drug Interactions (7.2)].

Effect of CYP3A4 and CYP2C19 Inducers and Inhibitors Coadministered with EPIDIOLEX on Exposure to Cannabidiol.
Coadministration of EPIDIOLEX with potent inhibitors of CYP3A4 and CYP2C19 had the following effects on exposure to cannabidiol and its metabolites. The potent CYP3A4 inhibitor, itraconazole, increased exposure by < 10% for cannabidiol and < 20% for 7-OH-CBD and 7-COOH-CBD for both AUC and Cmax. Although the effects of the potent CYP2C19 inhibitor fluconazole were slightly more marked, they are still considered not to be clinically meaningful (cannabidiol increased by 22% and 24% for AUC and Cmax, respectively; 7-OH-CBD decreased by 28% and 41% for AUC and Cmax; 7-COOH-CBD decreased by 33% and 48% for AUC and Cmax).

Coadministration with the potent CYP3A4 and CYP2C19 inducing agent rifampin caused a decrease in cannabidiol exposure of 32% and 34% for AUC and Cmax [see Drug Interactions (7.1)]. There were moderate changes in exposure to the active metabolite (7-OH-CBD decreased by 63% and 67% for AUC and Cmax, 7-COOH-CBD decreased by 48% for AUC, whereas there was no change in Cmax).

Effect of EPIDIOLEX on Everolimus
Coadministration of EPIDIOLEX (12.5 mg/kg twice daily) with the P-gp and CYP3A4 substrate everolimus (5 mg) in healthy volunteers led to an approximately 2.5-fold increase in everolimus mean Cmax and AUC [see Drug Interactions (7.2)].