Cannabis (Cannabis sativa)
Drug Approval Package: Epidiolex (Cannabidiol)
CSV
JSON
U.S. Food and Drug Administration
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000TOC.cfm
1 . CBD effect on CLB and N-desmethylclobazam (id=NPDI-kJ7mIQ)
In Vivo Interaction Study
Increased systemic exposure was detected.
Study GWEP1543
Results
Clobazam exposure was increased slightly (~20%) by co-administration with CBD while exposure to the n-desmethylclobazam metabolite was increased by 3.4 fold as a result of concommitant CBD.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
12
Arm 1, Group 1
Drug or Natural Product Administration
Oral
Not specified
10 mg
5 mg BID
14 days
Oral
Solution
1500 mg
750 mg BID
14 days
Not specified
2 . CBD Effect on N-desmethylclobazam Concentrations (id=NPDI-_jX3DQ)
In Vivo Interaction Study
Increased systemic exposure was detected.
From page 109 of "Clinical Pharmacology Biopharmaceutics Review"
Results
From page 109
Units for these values are NOT means but are instead a ratio of day 33 values:day 1 values
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Females
Males
Patients
CYP2C19 intermediate metabolizer
CYP2C19 rapid metabolizer
CYP2C19 ultra-rapid metabolizer
20
"A total of 20 patients were randomized to receive 20 mg/kg/day of CBD or placebo on a 4:1 basis."
Predose; postdose: 15 and 30 m, 1, 1.5, 2, 4, 6, 12 and 24 h
Drug or Natural Product Administration
Oral
Not stated
Not stated
Not stated
31 d
Oral
Solution
20 mg/kg
BID
31 d
Not stated
10-day titration, 21 days at maintenance dose of 20 mg/kg/day
3 . CBD Effect on Stiripentol Concentrations (id=NPDI-8_xKYg)
In Vivo Interaction Study
Increased systemic exposure was detected.
Study GWEP1543
Results
When CBD was combined with stiripentol there was a minor increase in Cmax and AUCtau; 1.28 and 1.55-fold, respectively.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
12
Arm 1, Group 3
Drug or Natural Product Administration
Oral
Not stated
1500 mg
750 mg BID
14 days
Oral
Solution
1500 mg
750 mg BID
14 days
Not specified
4 . Clobazam Effect on 6-OH-CBD (id=NPDI-z3MwKw)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
16
Arm 2, Group 2
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
21 days
Oral
Not specified
10 mg
5 mg BID
21 days
Not specified
5 . Clobazam Effect on 7-COOH-CBD (id=NPDI-ZM5Pkw)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
16
Arm 2, Group 2
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
21 days
Oral
Not specified
10 mg
5 mg BID
21 days
Not specified
6 . Clobazam Effect on 7-OH-CBD (id=NPDI-9oyo4g)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
16
Arm 2, Group 2
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
21 days
Oral
Not specified
10 mg
5 mg BID
21 days
Not specified
7 . Clobazam Effect on CBD (id=NPDI-4EVwQw)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
16
Arm 2, Group 2
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
21 days
Oral
Not specified
10 mg
5 mg BID
21 days
Not specified
8 . Stiripentol Effect on CBD, 6-OH-CBD, and 7-COOH-CBD (id=NPDI-2TMzVA)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
12
Arm 2, Group 4
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
4 days
Oral
Not specified
1500 mg
750 mg BID
4 days
Not specified
9 . Valproic Acid Effect on Cannabidiol Metabolites (id=NPDI-AEDMtg)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
14
Arm 2, Group 6
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
9 days
Oral
Not specified
1000 mg
500 mg BID
9 days
Not specified
10 . CBD Effect on clobazam and N-desmethylclobazam (id=NPDI-Y9U8Tw)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1428 (p 106)
Results
Test ratios indicate the Day33:Day 1 ratio for individuals allocated to active drug.
Control ratios indicate the Day 33:Day ratio for individuals allocated to placebo.
CBD did not alter Cmax or AUC of clobazam but did increase exposure to the N-desmethylclobazam metabolite.
Data from page 109
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Double-blind
Placebo-controlled
Randomized crossover
Multiple dosing
Females
Males
Patients
CYP2C19 intermediate metabolizer
CYP2C19 rapid metabolizer
CYP2C19 ultra-rapid metabolizer
20
"A total of 20 patients were randomized to receive 20 mg/kg/day of CBD or placebo on a 4:1 basis."
Predose; post-dose: 15 and 30 m, 1, 1.5, 2, 4, 6, 12, 24 hr
Drug or Natural Product Administration
Oral
Not stated
Not stated
Not stated
31 d
Oral
Solution
20 mg/kg
BID
31 d
Not stated
10-day titration, 21 days maintenance of 20 mg/kg/day; CBD/placebo was taken twice daily immediately after patients' clobazam dose
11 . CBD Effect on Midazolam (id=NPDI-d2rDLg)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
midazolam 708298
Systemic exposure to midazolam was relatively unaffected by concomitant administration of CBD indicating lack of inhibition or induction of CYP3A4. The increased exposure to 1'-hydroxymidazolam may be due to downstream inhibition of glucuronidation by UGT2B7. Further details can be found in "Clinical Pharmacology Biopharmaceutics Review(s)"
Results
C estimated from Fig 8; page 111
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Single dosing
Females
Healthy volunteers
Males
16
Predose; 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 14, 18, 24 h
Drug or Natural Product Administration
Oral
Solution
2.5 mg
Once
Once
Oral
Solution
escalating dosing until 750 mg
BID
25 days
Not stated
Information from Study GWEP17028 (starting page 109)
Subjects received a single 2.5 mg oral midazolam dose on Day -1 (reference). Subjects then recieved "escalating doses of CBD from Day 1 (250 mg once daily) to Day 11 (750 mg twice daily), followed by 14 days of 750 mg CBD b.i.d. (Days 12-25). On Day 25, subjects received a 2.5 mg oral dose of midazolam concurrently with the morning dose of CBD (test)"
12 . CBD Effect on Valproic Acid Concentrations (id=NPDI-wM7_CQ)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
12
Arm 1, Group 5
Drug or Natural Product Administration
Oral
Not stated
1000 mg
500 mg BID
14 days
Oral
Solution
1500 mg
750 mg BID
14 days
Not specified
13 . Stiripentol Effect on 7-OH-CBD (id=NPDI-a9Sh7Q)
In Vivo Interaction Study
Decreased systemic exposure was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
12
Arm 2, Group 4
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
4 days
Oral
Not specified
1500 mg
750 mg BID
4 days
Not specified
14 . Valproic Acid Effect on CBD (id=NPDI-AWv-_A)
In Vivo Interaction Study
Decreased systemic exposure was detected.
Study GWEP1543
Results
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Fixed-sequence
Parallel
Multiple dosing
Females
Healthy volunteers
Males
14
Arm 2, Group 6
Drug or Natural Product Administration
Oral
Solution
1500 mg
750 mg BID
9 days
Oral
Not specified
1000 mg
500 mg BID
9 days
Not specified