Transcript A New Once-Daily Formulation of Isotretinoin Accutane NF John McLane, PhD

A New Once-Daily
Formulation of Isotretinoin
Accutane NF
John McLane, PhD
Roche Medical Science and Safety
David Young, PharmD, PhD
GloboMax LLC

Rationale for New Formulation of Isotretinoin

New Formulation Development Program

Dose/Exposure Response Relationship

Risk Management of Two Formulations

Benefit of New Formulation
Accutane Dose Efficacy Studies
Publication
Farrell 1980
Jones 1981
Plewig 1981
Strauss 1984
Peck 1979
N
Dose
Efficacy
Rank (mg/kg)
Conditions
14
22
127
150
14
1.0  0.5  0.1
1.0 = 0.5 > 0.1
1.0 > 0.5 > 0.2
1.0  0.5  0.1
2.0 = 1.0
Fed
Fed
Fed
Fed
Fasted
Variability in Accutane Exposure

Dosing without food results in a significant reduction in
exposure

Physician Survey
– 68% of patients instructed to take Accutane with food
– 21% of patients instructed to take Accutane once a day
(approximately 1 mg/kg)
– Prescribers report that 33% of patients do not take Accutane
consistently with food
– Prescribers report that 22% of patients do not consistently take
the second dose in a BID regimen
Overall Effect: significant patient variability in exposure
Accutane Dosing Issues

Inconsistency in dosing recommendations
– once a day or twice a day
– with or without food

Individual tolerability
Prescriber survey shows that the principal reasons for
patients withdrawing from therapy are:
– mucocutaneous effects (19%)
– triglyceride elevations (17%)

Compliance
– Noncompliance would result in under/over dosing
which may affect efficacy and safety
The New Formulation (NF) of Isotretinoin
is as Safe and Efficacious as Accutane

Simplifying dosing recommendations
– The NF can be given with or without food
– The NF can be given QD

Individual tolerability
– The NF has fewer and less intense mucocutaneous events
– The NF has fewer patients with elevated triglycerides

Compliance with dosing regimen
– More predictable exposure from NF decreases the impact of
individual noncompliance

Rationale for New Formulation of Isotretinoin

New Formulation Development Program

Dose/Exposure Response Relationship

Risk Management of Two Formulations

Benefit of New Formulation
Clinical Development Program for NF

Pivotal Clinical Program
– efficacy and safety trial

Pharmacokinetic Program
– food effect on bioavailability
– bioequivalence
– dose proportionality

Hormonal Contraceptive Interaction Program
– in vitro studies
– clinical evaluations
Clinical Study Objective
Compare the efficacy and safety:
New Formulation
vs.
Accutane
Once per day
Twice per day
No Food
Food
Lower Exposure
Labeled Exposure
182M / 118 F
174M / 126F
Daily Dosing Regimen
Accutane Group 1 mg/kg
Active
Active
12 AM
Breakfast
Placebo
12 Noon
Placebo
12 AM
Dinner
Placebo
Active
New Formulation Group 0.4 mg/kg
Inclusion Criteria

Male or non-pregnant and non-nursing female
patients, 12 years of age or older

Diagnosed with severe recalcitrant nodular
acne, with 10 or more nodular lesions at least
5 mm in diameter
Clinical Efficacy Endpoints

Primary
– number of patients with 90% reduction in nodules
– reduction in total number of nodules from baseline

Secondary
– global evaluations by both patients and physicians
– reduction in total number of papules and pustules
Safety Evaluations During Trial

Laboratory
– CBC, blood lipids, liver enzymes

Psychiatric evaluations
– Mood/Depression Questionnaire
– Beck Depression Inventory

Mucocutaneous adverse events
–
–
–
–
–
Dry or peeling skin
Dry or bleeding nose
Dry or irritated eyes
Chapped lips
Rash or erythema of face
Additional Evaluations

Objective measurements of inflammatory
lesions at 8 week and 16 week evaluation
points

Subjective measurement of need for
retreatment
– phone call to patients 16 weeks post therapy
Results - STD Efficacy Analyses
Efficacy
Parameter
New Formulation
Baseline
Total nodules
Total papules
and pustules
Patients with
>90% clearing
Accutane
Outcome
20
20
Baseline
weeks
weeks
20.6
2.4
18.7
1.8
26.1
3.5
26.1
2.6
70.9%
Equivalent
Equivalent
78.4%
Equivalent
Physician
1
Global
70%
74%
Not
Statistically
Different
Need for
Retreatment at
2
16 wk post
18.3%
13.4%
Not
Analyzed
1. Categorized as “cleared” or “excellent response”
2. Subjective evaluation
Overall Comparison of Safety
Variable
Accutane NF
Accutane
296
293
1362
1450
16
16
Serious adverse events
2
4
Withdrawals (non AEs)
22
30
Patients with adverse event
Total adverse events
Adverse events leading to
treatment discontinuation
Adverse Events Leading to Treatment
Discontinuation
Accutane (16)
Appendicitis
Chapped lips, dry skin
Headache (3)
Irritated eyes
LFT (3)
Low white cell count
Triglyceride elev (6)
New Formulation (16)
Depression (3)
Dizziness/Blurred vision
General body weakness
Hair loss
Headache
LFT (3)
Mood swings
Pregnancy
Pustular eruption
Triglyceride elev (3)
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Number of Events
Comparison of Total Adverse Events (>5%)
300
NF
Accutane
150
100
50
0
Lipid Profile During Treatment

Abnormal triglyceride levels were observed in
– 48/300 patients on Accutane NF
– 75/300 patients on Accutane

Mean triglyceride levels increased by
– 0.57 ± 0.87 mmol/L for Accutane NF
– 0.99 ± 1.44 mmol/L for Accutane

Mean cholesterol levels increased by
– 0.4 ± 0.56 mmol/L for Accutane NF
– 0.6 ± 0.69 mmol/L for Accutane
Comparison of Psychiatric Events
Treatment Group
Accutane NF
Accutane
N = 300
N =300
Patients reporting AEs
11
1
Positive Mood Assessments
37
38
Patients with BDI >13 (not BL)
9
10
Pts with Baseline BDI131
6
7
13
15
2
2
Prior history (medications)
Additional BDI1
1. Subgroup of prior category
Mucocutaneous Adverse Events (MAEs)

MAEs were fewer and less intense in Accutane
NF-treated patients

At several time points, differences were
statistically significant

Subgroup analysis showed no imbalance among
age, sex, race, or body weight categories
Mucocutaneous Event:
Dry or Bleeding Nose
*
Percent of Patients
50%
*
*
40%
*
*
30%
20%
Accutane NF
Accutane
10%
0%
0
5
10
Weeks
15
20
Mucocutaneous Event: Dry or Irritated Eyes
Percent of Patients
50%
40%
*
30%
*
*
*
*
20%
Accutane NF
Accutane
10%
0%
0
5
10
Weeks
15
20
Isotretinoin / Hormonal Contraceptives
Program

To assure that isotretinoin does not alter the
clinical pharmacology of hormonal
contraceptives

Two components of program:
– in vitro studies with hepatocytes and
microsomes
– clinical program
In Vitro Human Hepatocytes Experiments
Experiment Completion Dates
Progestin
Inhibition
Compound
Study*
Medroxyprogesterone No inhibition
Progesterone
No inhibition
Norethindrone
Oct 2000
Norgestimate
Jan 2001
Levonorgestrel
Mar 2001
Induction
Study†
Dec 2000
Jan 2001
Apr 2001
May 2001
Aug 2001
*Initiated January 2000: 5-6 months to complete each study
†Initiated January 2000: 11 months to complete each study
Oral Contraceptive Clinical Studies

Two studies to determine if isotretinoin affects oral
contraceptives (Ortho-Novum 7/7/7)
– pharmacokinetics (ethinyl estradiol and
norethindrone)
– pharmacodynamics (LH/FSH/progesterone)

Females with severe recalcitrant nodular acne

Accutane 1.0 mg/kg/day in two divided doses
with food

Accutane NF 0.4 mg/kg/day as a single daily
dose fasted
Oral Contraceptive Studies: Pharmacokinetic (PK)
and Pharmacodynamic (PD) Assessments
Study Month 1
OC Stabilization
Isotretinoin
Initiated
Study Month 2
OC Pill Cycle 2
Day 6
Day 20
PK and PD
Assessments
Day 6
Study Month 3
OC Pill Cycle 3 + Isotretinoin
Day 20
Study Month 4
OC Pill Cycle 4 + Isotretinoin
Oral Contraceptive Studies
Current Status

No pregnancies

No serious or unexpected adverse events
Timelines:

September 2000: last patient visit scheduled
for both studies

1st Quarter 2001: final study reports to FDA

Rationale for New Formulation of Isotretinoin

New Formulation Development Program

Dose/Exposure Response Relationship

Risk Management of Two Formulations

Benefit of New Formulation
Isotretinoin Dose Efficacy Studies
Publication
Farrell 1980
Jones 1981
Plewig 1981
Strauss 1984
Peck 1979
NF Study
N
Dose
Efficacy
Rank (mg/kg)
Conditions
14
22
127
150
14
600
1.0  0.5 0.1
1.0=0.5>0.1
1.0>0.5>0.2
1.00.50.1
2.0=1.0
1.0  0.4 NF
Fed
Fed
Fed
Fed
Fasted
Fed/Fasted
Plasma Concentrations of Isotretinoin After Single Dose of
Accutane (80 mg), Accutane NF (30 mg) Under Fed or
Fasted Conditions (n=74)
700
Accutane, 80 mg, Fasted
600
Accutane, 80 mg, Fed
500
Accutane NF, 30 mg, Fasted
Accutane NF, 30 mg, Fed
Isotretinoin
ng/mL
400
300
200
100
0
0
6
12
Time, (hrs)
18
24
Effect of Food on Exposure

Accutane has a significant food effect:
– 2.5 : 1 ratio between Accutane (fed) and Accutane
(fasted)
– inconsistent eating habits lead to large within
subject variability
– between subject variability is less when
administered with food

Taking Accutane without food significantly
increases the risk of under exposure to
isotretinoin, which could result in sub-optimal
therapy (decreased efficacy)
Effect of Food on Exposure (cont’d)

Accutane NF has minimal food effect
– 30% greater exposure when administered with food
– between subject variability is similar when
administered with or without food
– reduced within subject variability (versus Accutane)
even with inconsistent eating habits

Risk of sub-optimal therapy is minimized with
Accutane NF
Method for Simulating the Steady State
Plasma Concentrations of Isotretinoin

Data from the Fed/Fasted PK Accutane - NF
study were used

Principle of superpositioning for linear
pharmacokinetics was used to simulate
plasma concentrations of isotretinoin for
different dosage regimens of NF and Accutane
under fed or fasted conditions
Figure 1 - Simulated Steady-State Exposure to Isotretinoin
Following Administration of Accutane* & Accutane NF†
Accutane, 35 mg BID, Fed (545, 9209)
Accutane, 17.5 mg BID, Fed (272, 4605)
Accutane NF, 28 mg QD, Fasted (332, 4161)
600
500
400
Isotretinoin
300
ng/mL
200
100
0
0
*1.0 mg/kg and 0.5 mg/kg
†0.4 mg/kg
4
8
12
Nominal
Nominal Time,
Time, hr
hr
16
20
24
NF 414, 9/17/00
Simulated Steady State Exposure to Isotretinoin Following the
Administration of Accutane and Accutane NF under Fed and
Fasted Conditions
Accutane, 35 mg BID
(1.0 mg/kg), Fed
Accutane NF, 28 mg QD
(0.4 mg/kg), Fed
Accutane NF, 28 mg QD
(0.4 mg/kg), Fasted
Accutane, 35 mg BID
(1.0 mg/kg), Fasted
AUC (ng*hr/mL)
9209
5461
4161
3655
Isotretinoin Dose Efficacy Studies
Publication
Farrell 1980
Jones 1981
Plewig 1981
Strauss 1984
Peck 1979
NF Study
N
Dose
Efficacy
Rank (mg/kg)
Condition
14
22
127
150
14
600
1.0  0.5 0.1
1.0=0.5>0.1
1.0>0.5>0.2
1.00.50.1
2.0=1.0
1.0  0.4 NF
Fed
Fed
Fed
Fed
Fasted
Fed/Fasted
AUC Exposure to Isotretinoin for
Accutane and Accutane NF
Dose
AUC
Condition
0.1
921
Fed
0.2
1,842
Fed
0.4NF
4,161
Fasted
0.5
4,605
Fed
1.0
9,209
Fed
2.0
7,310
Fasted

Rationale for New Formulation of Isotretinoin

New Formulation Development Program

Dose/Exposure Response Relationship

Risk Management of Two Formulations

Benefit of New Formulation
Risk of Confusion with Two Formulations

Taking Accutane with or without food

Misunderstanding about QD administration for
NF and BID for Accutane

Concurrent administration of NF and Accutane

Potential for substitution at the pharmacy
Simulated Steady State Exposure to Isotretinoin
Following Administration of Accutane and Accutane NF
Under Fed and Fasted Conditions
Accutane, 35 mg BID
(1.0 mg/kg), Fed
Accutane NF, 28 mg QD
(0.4 mg/kg), Fed
Accutane NF, 28 mg QD
(0.4 mg/kg), Fasted
Accutane, 35 mg BID
(1.0 mg/kg), Fasted
AUC (ng*hr/mL)
9209
5461
4161
3655
Simulated Steady State Exposure to Isotretinoin
Following Administration of Accutane and Accutane NF
Under Fed and Fasted Conditions
Accutane, 35 mg BID
(1.0 mg/kg), Fed
Accutane, 17.5 mg BID
(0.5 mg/kg), Fed
Accutane NF, 28 mg QD
(0.4 mg/kg), Fasted
Accutane, 17.5 mg BID
(0.5 mg/kg), Fasted
AUC (ng*hr/mL)
9209
4605
4161
1828
Simulated Steady-State Exposure to Isotretinoin Following
Administration of Accutane (1.0 mg/kg) Given As Divided Doses &
As a Single Daily Dose Compared With Accutane NF (0.4 mg/kg)
Accutane, 70 mg QD, Fed, (777, 9210)
900
Accutane, 35 mg BID, Fed (545, 9209)
800
Accutane, 70 mg QD, Fasted (281, 3655)
700
600
Isotretinoin
ng/mL 500
400
300
200
100
0
0
4
8
12
Time, hr
16
20
24
New Formulation Product Differentiation

Differences in dosing
– once per day vs twice per day
– taken with or without food

Unique packaging
– pouches versus prescription packs
– packaging shape and color

Capsule appearance
– contrasting capsule color schemes
– different identification marks on capsules
– different capsules strengths (7.5, 15, 22.5 mg for Accutane NF)

Distinct, unique brand name for NF
– trade name submitted to FDA July 2000
The New Formulation of Isotretinoin is
as Safe and Efficacious as Accutane

Simplifying dosing recommendations
– The NF can be given with or without food
– The NF can be given QD

Individual tolerability
– The NF has fewer and less intense mucocutaneous events
– The NF has fewer patients with elevated triglycerides

Compliance with dosing regimen
– More predictable exposure from NF decreases the impact of
individual noncompliance
Labeling for the New Formulation

Once per day

Can be taken with or without food

All safety issues and programs carried over
from Accutane

Indication remains the same