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211321orig1s000: Clinical Pharmacology and Biopharmaceutics Review (S)
211321orig1s000: Clinical Pharmacology and Biopharmaceutics Review (S)
RESEARCH
APPLICATION NUMBER:
211321Orig1s000
1
1. EXECUTIVE SUMMARY ................................................................................................................. 4
1.1 Recommendations .......................................................................................................................... 4
2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT .................................................. 5
2.1 Pharmacology and Clinical Pharmacokinetics ............................................................................... 5
2.1.1 Pharmacokinetic Comparison of Midazolam between Nayzilam and IV Administration ...... 5
2.1.2 Effect of Food on the Pharmacokinetics of Midazolam ......................................................... 5
2.2 Dosing and Therapeutic Individualization ..................................................................................... 6
2.2.1 General dosing ........................................................................................................................ 6
2.2.2 Therapeutic individualization ................................................................................................. 6
2.4 Summary of Labeling Recommendations ...................................................................................... 6
3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW ..................................................... 6
3.1 Overview of the Product and Regulatory Background .................................................................. 6
3.2 General Pharmacology and Pharmacokinetic Characteristics ........................................................ 7
3.3 Clinical Pharmacology Review Questions ..................................................................................... 7
3.3.1 Is there a significant pharmacokinetic difference of Midazolam between Nayzilam and IV
Administration? ............................................................................................................................... 8
3.3.2 To what extent does the available clinical pharmacology information provide pivotal or
supportive evidence of effectiveness? ............................................................................................. 8
3.3.3 Is the proposed dosing regimen appropriate for the general patient population for which the
indication is being sought? .............................................................................................................. 9
3.3.4 Is an alternative dosing regimen and/or management strategy required for subpopulations
based on intrinsic factors? ................................................................................................................ 9
3.3.5 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate
management strategy? .................................................................................................................... 10
3.3.6 Based on PK parameters, what is the degree of linearity or nonlinearity in the dose-
concentration relationship? ............................................................................................................ 12
4. APPENDICES ................................................................................................................................... 15
4.1: Summary of Bioanalytical Method Validation and Performance .............................................. 15
4.2 Clinical Pharmacokinetics............................................................................................................ 18
2
3
The clinical development program includes efficacy and safety studies, one in emergency
medical unit (EMU) subjects and another study in adolescent and adult outpatients. Clinical
pharmacology studies included an absolute and relative bioavailability (BA) study, two
ascending single and repeat-dose pharmacokinetic (PK)-pharmacodynamic (PD) studies in adults
and adolescents with epilepsy, a PK-PD study in healthy adult and geriatric subjects and a PK
study in pediatric subjects (age 2 to 13 years) with epilepsy.
1.1 Recommendations
The office of Clinical Pharmacology (OCP) has reviewed the information contained in NDA
211321. The information provided supports the approval of Nayzilam™ for acute treatment of
seizures in patients 12 years of age or older who require control of intermittent episodes of
increased seizure activity. Key review issues with specific recommendations and comments are
summarized below:
Pivotal or supportive evidence of The supportive evidence of effectiveness and safety comes from (b) (4)
effectiveness and safety randomized, placebo-controlled (b) (4)
4
Bridge between the to-be- The to-be-marketed formulation and delivery device, referred to as
marketed and clinical trial MDZ NS in this submission, was used in all clinical studies,
formulations including the phase 3 studies. The bridge between the proposed to-
be-marketed formulation and the approved midazolam IV
formulation was provided using population pharmacokinetic
analysis. At a dose of 5 mg, the absolute bioavailability of the to-be-
marketed formulation was predicted to be 44% compared to the
approved IV formulation (see section 3.3.1).
The absolute bioavailability (BA) was approximately 67% for an early formulation of MDZ NS.
In an ascending dose PK study in adults and adolescent epilepsy patients, midazolam AUC was
34 % lower and 1-hydroxymidazolam AUC was 4.5-fold higher in subjects taking enzyme
inducers compared to subjects not taking enzyme inducers. Dose proportionality was
inconclusive due to large intra-subject variability. In another PK-PD study in adult subjects with
epilepsy, either single dose or repeat dose administration of midazolam nasal spray, PK
parameters for both MZ and 1- OH MZ were similar across cohorts and did not exhibit dose
dependent changes. In a PK-PD study in healthy adult and geriatric subjects, midazolam PK
parameters were approximately 21% to 45% higher in geriatric subjects compared to non-
geriatric subjects.
2.1.1 Pharmacokinetic Comparison of Midazolam between Nayzilam and IV
Administration
The PK comparison between the proposed to-be-marketed formulation and the approved
midazolam IV formulation was conducted using population pharmacokinetic analysis. At a dose
of 5 mg, the absolute bioavailability of the to-be-marketed formulation was predicted to be 44%
compared to the approved IV formulation (see section 3.3.1).
5
for the treatment of intermittent bouts of increased seizure activity. The Agency
also recommended the sponsor to conduct a study in elderly population and abuse potential
assessment.
6
General Information
Bioanalysis Plasma midazolam and its active metabolite 1-hydroxymidazolam
concentrations were measured by a validated liquid chromatographic-
tandem mass spectrometric (LC/MS/MS) bioanalytical methods.
Midazolam-d4 and 1-Hydroxymidazolam-d4 were used as the internal
standards. The lower limit of quantitation was 100 pg/mL for both analytes.
Healthy Volunteers vs There were no studies compa1ing head-to- head exposure of midazolam in
Patients healthy subjects and epilepsy patients. However, based on the cross-study
comparison, the overall exposure (AUCinf) appeared to be approximately
12% lower in patients at 5 mg dose.
Dose Propo1t ionality The PK parameters following midazolam nasal spray administration were
found to be less than propo1t ional (Study P261-201) for both MZ and 1- OH
MZ. All PK parameters were similar across coho1ts and did not exhibit dose
dependent changes (see section 3.3.6).
ADME
Absorption Median time to maximum concentration (Tmax) following nasal
administration of midazolam was approximately 15 minutes. The mean
absolute bioavailability is approximately 44.4%.
The PK comparison between the proposed to-be-marketed formulation and the approved
midazolam IV formulation was conducted using population pharmacokinetic analysis, since the
to-be-marketed formulation was not used in study MZ0714. At a dose of 5 mg, the
bioavailability of the to-be-marketed formulation was predicted to be 32% lower compared to the
ITI formulation. In several studies including P261-201, increase in midazolam concentration was
less than dose proportional with increasing dose from 10 mg to 20 mg using the to-be-marketed
formulation (see section 3.3.6). The dose of 5 mg/10 mg was selected based on the literature and
PK studies conducted for intranasal midazolam.
3.3.2 To what extent does the available clinical pharmacology information provide pivotal
or supportive evidence of effectiveness?
This is a 505(b)(2) application for midazolam nasal spray using Hospira’s midazolam
(midazolam i.m or i.v injection) and Seizalam (midazolam i.m injection) as LDs. The efficacy
and safety of midazolam nasal spray were demonstrated in the following pivotal studies:
1)
(b) (4)
In P26-401, a statistically significantly higher percentage of treated patients met the primary
efficacy endpoint (53.7% vs. 34.3%, p=0.011). In addition, a statistically significant relationship
was observed (p=0.0226) between midazolam exposure (AUC0-6) and response, but treatment
success across the range of AUC0-6 were similar across the 1st, 2nd, 3rd, and 4th quartiles
(57.6%, 46.9%, 56.2% and 51.5%, respectively). The number of subjects included in the final
analysis of this study were 201.
(b) (4)
8
The applicant also provided an absolute and relative BA study comparing an early formulation of
midazolam NS to IV midazolam administered both IV and IN (MZ0714), two ascending single
and repeat-dose PK-PD studies in adults and adolescents with epilepsy (MZ0815 and P261-201),
a PK-PD study in healthy adult (aged 18-40 years, n=12) and geriatric (aged ≥65 years) subjects
(P261-102, n=18) and a PK study in pediatric subjects (aged 2-13 years) with epilepsy (P261-
202) to support the application.
3.3.3 Is the proposed dosing regimen appropriate for the general patient population for
which the indication is being sought?
Yes, the proposed dosage is acceptable. The proposed initial dose is a single 5 mg dose into one
nostril and an additional 5 mg dose may be administered after 10 minutes if the patient has not
responded to the initial dose. The proposed dose was found to be safe and effective in Phase 3
registration trials.
There were no differences in midazolam overall exposures (AUC) observed between male and
female subjects following nasal administration. However, there were relatively small increase
(~25%) in Cmax of midazolam in males due to higher relative bioavailability, but incidence of
somnolence was slightly higher in females compared to males. Sensitivity analysis of efficacy
using treatment as the fixed effect, and age, sex, BMI, geographic region, and AED-inducer
status as covariates did not show an any effect of covariates tested. No dosage adjustment is
necessary based on gender and these co-variates.
9
proposed nasal formulation because of the route of administration and the proposed indication,
acute treatment of seizures in patients who require control of intermittent episodes of increased
seizure activity.
No new drug-drug interaction studies were conducted for this application. The sponsor relies on
LDs for appropriate management strategy. However, the applicant collected PK data from
subjects taking concomitant anti-epileptic drugs (CYP3A-inducers).
10
Note: Midazolam fo1mulations for intramuscular, intravenous or by oral route are indicated
for preoperative sedation/anxiolysis/amnesia prior to diagnostic, th erapeutic or endoscopic
procedures or before induction of anesthesia and for status epilepticus. CmTently midazolam
is intended for use in monitored settings only and not for chronic or home use. The approved
midazolam products include black box warnings indicating respirato1y depression and
respirato1y anest, especially when used for sedation in noncritical care settings. However, the
proposed use of nayzilam is in an outpatient setting. When midazolam was concomitantly
with dmgs that are known to strongly inhibit the CYP3A4 enzyme resulted in more than 7-
fold increase in midazolam AUC (table below). However, the prescribing infon nation
indicates that caution should be advised, (bll' should be considered.
Since Nayzilam is indicated for an out-patient setting, 1nidazolam nasal spray should not be
administered concomitantly with diugs that are known to strongly inhibit the CYP3A4
enzyme. Nayzilam is not recommended with moderate inhibitors of CYP3A4 enzyme.
Nayzilam should be used with caution when co-adininistered with 1nild inhibitors of
CYP3A4.
Following table represents SUllllllaIY of midazolam AUC changes when concomitantly
adininistered in the presence of CYP3A4 inhibitors or CYP3A4 inducers from the literature
and previously approved midazolam products.
Summary of the changes in the AUC of midazolam when CYP3A4 inhibitors or CYP3A4
inducers were concurrently administered with oral or intravenous midazolam in adult
subjects
11
3.3.6 Based on PK parameters, what is the degree of linearity or nonlinearity in the dose-
concentration relationship?
Midazolam exposure increased proportionally with increasing midazolam nasal spray dose from
2.5 mg to 5.0 mg. However, a greater than dose proportional increase in metabolite exposure was
1
https://www.drugs.com/pro/midazolam-syrup.html#ID_d83b65e4-2f5d-4502-ac54-6f56a1245eeb
12
In studies P261-201, increase in midazolam concentration was less than dose proportional at
higher doses for Cmax and AUC in adult patients for midazolam and 1-hydroxymidazolam with
increasing dose 10 mg to 20 mg as shown in the box plots below. In visit 2 midazolam dose was
administered as a single dose whereas in visit 3 (Repeat Dose) midazolam dose was split and
administered 10 min apart.
13
14
4. APPENDICES
4.1.1 How are the active moieties identified and measured in the clinical pharmacology and
biopharmaceutics studies?
A: Midazolam
B: 1-Hydroxymidazolam
A: r2 t 0.9903
Linearity:
B: r2 t 0.9893
A: 100.00 to 100000.00 pg/mL
Calibration Curve Ranges:
B: 100.00 to 50000.00 pg/mL
A: Biases: -0.66 to 5.79% CV: 5.47 to 8.45%
B: Biases: -0.40 to 2.46% CV: 4.99 to 7.91%
Between-Run Accuracy and Precision:
16
122h27 at 4°C
Reinjection Reproducibility:
24h00 at 4°C
Pre-Automated Extraction Stability
142h58 at 4°C
Post-Preparative Stability:
A: 24h10 at RmT
Short-Term Stability of Analytes in
Solution (High Concentration): B: 24h00 at RmT
A: 24h10 at RmT
Short-Term Stability of IS in Solution
(High Concentration): B: 24h00 at RmT
Note: The applicant also submitted a cross-validation report evaluating the equivalence between
two assays for the determination of midazolam and 1-hydroxymidazolam in human EDTA K2
plasma; the analytical method related to 9916.081 and the one related to 10615.022.
(b) (4) (b) (4)
The equivalence of both methods was assessed by analyzing pools of study samples.
17
Objectives:
The objectives of this study were (1) to evaluate midazolam bioavailability, pharmacokinetics
(PK), and safety for the intranasal (IN) route of administration using ITI’s 2.5, 5.0, and 7.5 mg
dose nasal spray (NS), and (2) to compare PK and pharmacodynamic (PD) parameters following
2.5, 5.0, and 7.5 mg IN administration (ITI’s midazolam NS) with administration of the currently
marketed injection product (2.5 mg intravenous [IV] administration) and 5.0 mg of the IV
solution (marketed injection product) administered intranasally via a needleless syringe
Study Design This study was a randomized, five-way crossover, open-label, single-center
study in 25 normal, healthy male and female volunteers. Subjects received
one of the following five doses at each treatment period. Each period was
separated by at least a 3-day washout period. Midazolam PK and PD were
measured after each of the five isolated single doses.
Study Population Healthy Subjects (males and female)
Age: 18-45 years
BMI: 18 to 29.9 kg/m2.
25 subjects were enrolled and 25 completed the study
Treatments Dose A - 2.5 mg midazolam NS administered IN
Dose B - 5.0 mg midazolam NS administered IN
Dose C - 7.5 mg midazolam NS administered IN
Dose D - 2.5 mg midazolam HCl sterile injection infused IV over 15
minutes
Dose E - 5.0 mg midazolam HCl sterile injection administered IN with a
needleless syringe.
18
Midazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 1.5, 3.0, 28 and 192 0.5, 1.0, 8.0, 32,
Curve Concentration (ng/mL) ng/mL 64, 128, 224 and
256 ng/mL
Between Batch Precision 4.1 to 7.8% 2.9 to 9.0%
(%CV)
Between Batch Accuracy -1.8 to 4.2% -3.9 to 1.8%
(%RE)
Linearity Weighted linear equation (1/X2), mean r=
0.99579
Linear Range (ng/mL) 0.5 to 500 ng/mL
Sensitivity (LLOQ, ng/mL) 0.5 ng/mL
1-Hydroxymidazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 1.5, 3.0, 28 and 192 0.5, 1.0, 8.0, 32,
Curve Concentration (ng/mL) ng/mL 64, 128, 224 and
256 ng/mL
Between Batch Precision 3.0 to 5.3% 2.4 to 8.7%
(%CV)
Between Batch Accuracy -0.5 to 0.7% -2.1 to 2.5%
(%RE)
Linearity Weighted linear equation (1/X2), mean r=
0.99723
Linear Range (ng/mL) 0.5 to 500 ng/mL
Sensitivity (LLOQ, ng/mL) 0.5 ng/mL
Pharmacokinetic Pharmacokinetic evaluations: Blood samples were collected pre-dose (0
and minutes) and at the following timepoints post-dose for measurements of
Pharmacodynamic plasma midazolam and 1-hydroxymidazolam: 5, 10, 15, 20, 30, 45, 60, and
Assessments 90 minutes; and 2, 3, 4, 6, and 12 hours. Plasma concentrations were used
to calculate PK parameters.
Pharmacodynamic evaluations: The following evaluations were performed
at pre-determined timepoints on the day of dosing: Stanford Sleepiness
Scale (SSS), Digit-Symbol Substitution Task (DSST), and Observer’s
Assessment of Alertness/Sedation (OAA/S).
Safety Adverse events (AEs), standard laboratory assessments, vital signs,
Assessments electrocardiograms and physical examination.
19
RESULTS:
Following figure represents mean plasma midazolam concentration-time profiles per dosing
group on linear scale.
Following tables represents midazolam pharmacokinetic parameters for each dose group.
20
21
Following figure represents mean DSST completion rate from baseline per dosing group.
22
Pharmacokinetic parameters following increasing nasal doses (2.5, 5 and 7.5 mg) were
essentially dose proportional.
Maximum plasma midazolam concentrations were achieved within 10 to 15 minutes in
all dose groups
Peak midazolam plasma concentrations of all three doses of the NS formulation were
well within those achieved following IV administration of the IV formulation.
The PK of the NS formulation showed increasing concentrations with increasing dose,
with wide inter-individual variability.
The mean (± SD) absolute bioavailability of the NS regimens of 2.5, 5.0, and 7.5 mg
were 73% (± 28), 65% (± 22), and 62% (± 23), respectively.
The PD measures returned to baseline approximately 4 to 5 hours in all subjects.
23
Objectives:
Primary:
To determine the safety, tolerability, and PK of single doses and 2-doses of 2.5 mg, 5.0 mg, and
7.5 mg of USL261administered to adult and adolescent subjects with epilepsy on stable AED
regimens.
Secondary:
To evaluate PD measures following single doses and 2-doses of 2.5 mg, 5.0 mg, and 7.5 mg of
USL261.
Study Design This was a randomized, open-label, inpatient study of ascending single-
dose and 2 dose regimens (2-doses) of USL261 conducted in 60 adults and
30 adolescent subjects receiving stable AED regimens. As seen in the table
below, at Visit 1, subjects were administered a single intranasal dose of 2.5
mg to 7.5 mg of USL261. At Visit 2, which occurred at least 3 days
following Visit 1, subjects were administered 2 intranasal doses of 2.5 mg
to 7.5 mg separated by 15 minutes (total dose: 5 mg to 15 mg). All adult
dose cohorts were completed before any adolescent subjects were
administered single doses of USL261.
Study Population Epilepsy patients, 60 adults and 30 adolescent subjects receiving stable
AED regimens. Age: 18-65 years and 12 -17 years
Treatments Dose Cohort Designations for Adult and Adolescent Subjects
Midazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 1.5, 28 and 192 ng/mL 0.5, 1.0, 8.0, 32,
Curve Concentration (ng/mL) 64, 128, 224 and
256 ng/mL
Between Batch Precision 4.8 to 7.2% 4.1 to 8.5%
(%CV)
Between Batch Accuracy -5.3 to 2.3% -7.2 to 3.8%
(%RE)
24
1-Hydroxymidazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 1.5, 28 and 192 ng/mL 0.5, 1.0, 8.0, 32,
Curve Concentration (ng/mL) 64, 128, 224 and
256 ng/mL
Between Batch Precision 4.3 to 6.2% 3.0 to 7.0%
(%CV)
Between Batch Accuracy -1.6 to 1.0% -1.6 to 2.1%
(%RE)
Linearity Weighted linear equation (1/X2), mean r=
0.99668
Linear Range (ng/mL) 0.5 to 500 ng/mL
Sensitivity (LLOQ, ng/mL) 0.5 ng/mL
Pharmacokinetic Pharmacokinetic assessments: The following PK parameters for MZ and 1-
and OH MZ were calculated: maximum observed drug concentration (Cmax),
Pharmacodynamic time to reach Cmax (Tmax), area under the plasma concentration-time
assessments and curve (AUC) from time zero to the last non-zero concentration (AUC(0-
sampling last)), AUC from time zero to Hour 6 (for use in PD analysis) (AUC(0-
6hr)), AUC from time zero to Hour 10 (for use in PD analysis) (AUC(0-
10hr)), AUC from time zero extrapolated to infinity (AUC(0-inf)), AUC
extrapolated from the last drug concentration to infinity in percent of the
total AUC (fext), apparent total plasma clearance after extravascular
administration (CL/F), apparent volume of distribution based on terminal
phase (Vz/F), apparent first-order terminal elimination rate constant (kel),
and terminal elimination phase half-life (T1/2). The Cmax was the
maximum observed drug concentration without interpolation and Tmax
was the elapsed time at which Cmax was observed.
Blood samples At Visit 1, blood samples were collected prior to and at 5,
10, 15, 20, 30, 45, and 60 minutes, and 2, 4, 6, and 12 hours after
administration of study drug. At Visit 2, blood samples were collected
prior to and at 5, 10, 15, 20, 25, 30, 45, and 60 minutes, and 2, 4, 6, and 12
hours after administration of the first dose of study drug. Plasma samples
containing heparin as an anticoagulant were analyzed for midazolam (MZ)
and 1-hydroxymidazolam metabolite (1-OH MZ) using liquid
chromatography with tandem mass spectrometry. The assay range for MZ
and for 1-OH MZ was 0.5 to 500 ng/mL.
25
RESULTS:
Pharmacokinetic results:
Midazolam PK parameters following intranasal administration included a peak plasma
concentration occurring approximately 13 to 19 minutes post-administration of a single dose.
The mean (SD) MZ T1/2 (range) was 3.6 (1.7) hours for a single dose and 3.9 (1.7) hours for 2-
doses with all age and dose groups combined. The mean T1/2 for each dose group at Visit 1
(single dose) and at Visit 2 (2 doses) ranged from 2.75 to 4.39 hours. Systemic exposure
parameters for MZ following intranasal dosing are summarized by dose and visit in the following
table.
26
Systemic exposure parameters for 1-OH MZ following intranasal dosing are summarized by dose
and visit in the following table.
27
The PK parameters were further stratified by adolescent versus adult subjects, and subjects
taking enzyme inducers or not. For MZ, Cmax was 34% lower in adolescent compared to adult
subjects and similar in subjects taking enzyme inducers versus subjects who did not take enzyme
inducers. For all subjects, MZ AUC(0-inf) was similar for adolescent and adult subjects, and was
34% lower in subjects taking enzyme inducers compared to subjects not taking enzyme inducers
and to a higher degree in adult subjects.
For 1-OH MZ, Cmax was approximately 3-fold higher in subjects taking enzyme inducers and
approximately 2-fold higher in adolescent subjects. Additionally for 1-OH MZ, AUC(0-inf) was
approximately 4.5-fold higher in adolescent subjects taking enzyme inducers compared
28
Pharmacodynamic results:
Stanford Sleepiness Scale (SSS)
In a graphical evaluation across all cohorts, there was an increase from baseline in mean SSS
score at each time point from 10 minutes through 2 hours post-dose at Visit 1 and from 10
minutes through 4 hours at Visit 2. In adults, mean SSS scores peaked between 1 and 2 hours
post-dose, and the average peak SSS score was between 3 and 4 at Visit 1 and between a score of
4 and 5 at Visit 2. In adolescent subjects, the mean peak SSS effects at both visits was larger than
that in adults (i.e., mean score was approximately 1 point higher in adolescent compared to adult
subjects), and occurred earlier (i.e., less than 1 hour post-dose). At Visit 1, on average subjects
returned to near baseline function by 4 hours post-dose. At Visit 2, subjects tended to return to
baseline more than 4 hours post-dose.
29
30
CONCLUSIONS
Pharmacokinetic conclusions
The Cmax, AUC(0-last), and AUC(0-inf) of 1-hydroxymidazolam were highest in
adolescent subjects taking enzyme inducers.
Midazolam Cmax, AUC(0-last), and AUC(0-inf) generally increased with increasing
total dose; however, Cmax was significantly less than dose proportional for adolescent
subjects taking or not taking enzyme inducers and for adult subjects taking enzyme
inducers. Dose proportionality of AUC(0-last) and AUC(0-inf) was inconclusive due to
large intra-subject variability.
For 1-hydroxymidazolam, systemic exposures also increased with total dose, but dose
proportionality was generally inconclusive over the dose range of 2.5 mg to 15 mg.
Midazolam Cmax was 34% lower in adolescent as compared to adult subjects while1-
hydroxymidazolam Cmax was 2-fold higher in adolescent as compared to adult subjects.
Midazolam AUC(0-last) and AUC(0-inf) were similar between adolescent and adult
subjects, while 1 - hydroxymidazolam AUC(0-last) and AUC(0-inf) were generally 3-
fold higher in adolescent compared to adult subjects.
Midazolam Cmax was generally similar in subjects taking enzyme inducers compared to
subjects not taking enzyme inducers; while 1-hydroxymidazolam Cmax for all subjects
was approximately 3-fold higher in subjects taking enzyme inducers with adolescent
subjects taking enzyme inducers having a 5- fold higher Cmax compared to adolescent
subjects not taking enzyme inducers.
Midazolam AUC(0-last) and AUC(0-inf) were lower in subjects taking enzyme inducers
compared to subjects not taking enzyme inducers and to a greater degree in adult
subjects; while 1-hydroxymidazolam AUC(0-last) and AUC(0-inf) were higher in
subjects taking enzyme inducers compared to subjects not taking enzyme inducers and to
a much greater degree in adolescent subjects.
Pharmacodynamic Conclusions
The PD endpoints over time and irrespective of USL261 AUCC exposure, adolescent
subjects typically had greater impairment than adult subjects. Generally, the SSS peak
score peaked earlier for adolescent subjects and had a longer duration of effect.
All the PD measures reached baseline function by the time the next assessment was
performed at 10 hours post-dose.
31
Objectives:
Primary Objective(s):
The primary objective of this study was to evaluate the safety and tolerability of single and two-
dose regimens of USL261 compared with that of placebo in adult subjects with epilepsy on
stable antiepileptic drug (AED) regimens.
Secondary Objective(s):
The secondary objectives of this study were to evaluate pharmacokinetic (PK) and
pharmacodynamic (PD) of USL261 following single and two-dose regimens of USL261
compared with that of placebo in adult subjects with epilepsy on stable AED regimens.
32
Midazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 300, 5000, 50000 and 100, 200, 2000,
Curve Concentration (pg/mL) 75000 pg/mL 4000, 10000,
20000, 40000,
80,000 and 100000
pg/mL
Between Batch Precision 3.71 to 4.18% 3.91 to 9.47
(%CV)
Between Batch Accuracy -3.13 to 0.96% -11.19 to 10.86
(%RE)
Linearity Weighted linear equation (1/X2), mean r=
0.99761
Linear Range (pg/mL) 100 to 100000 pg/mL
Sensitivity (LLOQ, pg/mL) 100 pg/mL
1-Hydroxymidazolam
RESULTS:
Following figure represents mean plasma midazolam concentration-time profiles during visit 2.
34
Following figure represents mean plasma midazolam concentration-time profiles during visit 3.
35
36
37
38
CONCLUSIONS:
PHARMACOKINETIC CONCLUSIONS:
Midazolam NS was absorbed with a range of median MZ Tmax values from 0.150 –
0.317 hours and 0.317 – 0.359 hrs following single and repeat dose administration,
respectively.
Following either single dose or repeat dose administration, PK parameters for both MZ
and 1- OH MZ were similar across cohorts and did not exhibit dose dependent changes.
Exposure to MZ and 1-OH MZ (as indicated by Cmax and AUC parameters) was not
dose proportional following single dose or repeat dose administration of 10.0 mg to 20.0
mg USL261. The lack of dose proportionality remained even after normalization for
subject weight and accounting for AED inducer status as a covariate.
39
PHARMACODYNAMIC CONCLUSIONS:
Compared to subjects receiving placebo, PD assessments indicated that subjects receiving
USL261 exhibited mild sedation (SSS and OAA/S) and decreases in psychomotor
performance (WAIS-IV Coding Subtest).
Effects of USL261 on sedation and psychomotor performance were transient following
single and repeat dose administration and were consistent across USL261 doses. Peak
effects occurred rapidly within 1hour post dose and return to baseline was generally
observed within 4 hours for the majority of subjects.
P261-102: A Randomized, Investigator and Subject Blind, Sponsor Open, Phase 1 Study of the
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intranasal Midazolam
(USL261) in Healthy Geriatric and Non-Geriatric Subjects
Objectives:
To evaluate the safety and pharmacokinetics (PK) and pharmacodynamics (PD) of single 2.5 mg
and 5.0 mg doses of USL261 in generally healthy geriatric and non-geriatric subjects.
Study Design This was a Phase 1, randomized, Investigator and subject blind, Sponsor
open, safety, tolerability, PK, and PD study in generally healthy geriatric
and non-geriatric subjects (12 non-geriatric subjects in the 18 - 40 years
old age range and 18 geriatric subjects in the ≥ 65 years old age range).
40
Midazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 300, 5000, 50000 and 100, 200, 2000,
Curve Concentration (pg/mL) 75000 pg/mL 4000, 10000,
20000, 40000,
80,000 and 100000
pg/mL
Between Batch Precision 3.71 to 4.69% 2.27 to 5.31%
(%CV)
Between Batch Accuracy -3.13 to 0.96% -1.57 to 2.55%
(%RE)
Linearity Weighted linear equation (1/X2), mean r=
0.9989
Linear Range (pg/mL) 100 to 100000 pg/mL
Sensitivity (LLOQ, pg/mL) 100 pg/mL
1-Hydroxymidazolam
41
42
RESULTS:
Mean Plasma Midazolam Concentrations Versus Time in Healthy Geriatric and Non-
Geriatric Subjects - (Semi-log Scale)
43
44
45
Mean maximum midazolam and 1-OH MZ exposures (Cmax) were higher in geriatric subjects
(ranging from approximately 20% to 27% higher) than non-geriatric subjects. The higher
midazolam exposure in geriatric subjects was associated with longer t½ values secondary to
decreased midazolam clearance (CL/F) in geriatric subjects compared to non-geriatric subjects.
Similar metabolite to parent ratios (based on mean MR AUC0-∞ and MR Cmax) were seen
across age groups suggesting that geriatric subjects clear the parent and metabolite more slowly
than non-geriatric subjects. A 2-fold increase in USL261 dose from 2.5 mg to 5.0 mg resulted in
increased mean maximum (Cmax) and overall (AUC0-t and AUC0-∞) midazolam exposure
(including MZ+1-OH MZ AUC0-∞) by approximately 2-fold. Based on the statistical analysis,
midazolam exposure increased proportionately with increasing USL261 dose from 2.5 mg to 5.0
mg; however, a greater than dose proportional increase in metabolite exposure was observed. For
1-OH MZ, sequence effect was marginally significant for ANOVA and ANCOVA. Due to the
limitation of a 2-sequence, 2-period crossover design, the cause of this could not be determined,
but is not considered to affect the interpretability of the results.
46
Pharmacodynamic Results:
Following a single intranasal dose of 2.5 mg or 5.0 mg USL261 in geriatric and non-geriatric
subjects, the PD effects were analyzed through SSS Scores (higher SSS values indicate increased
sedation), OAA/S Composite and Sum Scores (lower OAA/S values indicate increased sedation),
and unadjusted and baseline-adjusted DSST Trial Completion Rate and Percent Correct (lower
DSST values indicate greater effects on cognition). These endpoints were selected because they
are measures of PD effects associated with this class of drugs (sedation and cognitive effects are
known to reflect benzodiazepine pharmacology).
Sedation
The following table summarizes the main PD outcome of sedation as assessed by the SSS and
OAA/S (Composite Score; consistent results were observed with the Sum Score).
Summary of Maximum Observed PD Effect on Sedation and Time to Peak Effect Following
Administration of Intranasal 2.5 mg and 5.0 mg USL261 in Healthy Geriatric and Non-Geriatric
Subjects
47
Pharmacokinetic/Pharmacodynamic Results:
By comparing individual PD scores versus time matched individual plasma midazolam
concentrations, it appears that there is no clear relationship observed between sedation scores
(OAA/S or SSS) and time-matched midazolam or 1-OH MZ concentrations.
48
Consistent trends were observed between increasing sedation as measured by SSS and OAA/S
PD parameters and midazolam PK parameters (Cmax and AUCs) suggesting increased sedation
with increasing exposure. However, the slope of the relationship was generally small with
midazolam AUCs and usually did not achieve statistical significance. A clear relationship was
observed between increased midazolam exposure (based on midazolam AUC0-∞, MZ+1-OH
MZ AUC0-∞, and midazolam Cmax) and decreased psychomotor performance, based on Emax
of baseline-adjusted DSST Trial Completion Rate and baseline-adjusted DSST Percent Correct.
This finding is consistent with the observed relationships between individual baseline-adjusted
DSST parameters and time-matched plasma concentrations of midazolam.
CONCLUSIONS
Pharmacokinetic Conclusions:
• Midazolam was absorbed relatively quickly following single intranasal dose of either 2.5 mg or
5.0 mg USL261, with mean peak concentrations achieved at approximately 15 minutes for both
dose levels, regardless of age cohort. The metabolite 1-OH MZ achieved mean peak
concentrations at approximately 1.0 hour postdose regardless of dose level and age cohort.
• Following both dose levels, midazolam overall and maximum systemic exposures, based on
AUC0-t, AUC0-∞, and Cmax, were approximately 21% to 45% higher in geriatric subjects
compared to non-geriatric subjects.
• The higher midazolam exposure in geriatric subjects was associated with longer t½ values
secondary to decreased midazolam clearance (CL/F) in geriatric subjects compared to non-
geriatric subjects. Similar metabolite to parent ratios (based on mean MR AUC0-∞ and MR
Cmax) were seen in both age groups suggesting that geriatric subjects clear the parent and
metabolite more slowly than non-geriatric subjects.
• Midazolam exposure increased proportionally with increasing USL261 dose from 2.5 mg to 5.0
mg; however, a greater than dose proportional increase in metabolite exposure was observed.
49
• Maximum and overall sedation effects as measured by SSS and OAA/S Composite and Sum
Scores, were comparable between geriatric and non-geriatric subjects.
• Geriatric subjects exhibited greater cognitive effects than non-geriatric subjects as measured by
unadjusted DSST scores.
• No clear relationship was observed between sedation scores (OAA/S or SSS) and time matched
midazolam or 1-OH MZ concentrations.
Objectives:
To characterize the pharmacokinetics (PK) of USL261 following single-dose intranasal
administration (1.25, 2.5, or 5.0 mg) in pediatric subjects with epilepsy and to evaluate the safety
and tolerability profile.
Study Design This was a Phase I, open-label, inpatient PK study of single doses of
intranasally administered USL261. The study included a Screening Visit
(Visit 1), a Study Evaluation Visit (Visit 2; within 28 days of the Screening
Visit), and a Follow-up Visit (Visit 3; 3 to 7 days after Visit 2, or at Early
Termination). Subjects were assigned to 1 of 3 cohorts according to body
weight.
Study Population Pediatric epilepsy patients (males and female)
Age: 2-13 years
Weight: ≥10.0 kg to ≤60.0 kg
36 subjects were enrolled and 36 completed the study
Treatments USL261 (intranasal formulation of midazolam) 1.25, 2.5, or 5.0 mg
administered as a single dose (ie, each subject received 1 dose only) by the
intranasal route.
1.25 mg (12.5 mg/mL)
2.5 mg (25 mg/mL)
5.0 mg (50 mg/mL)
50
Midazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 1.5, 3.0, 28 and 192 0.5, 1.0, 8.0, 32,
Curve Concentration (ng/mL) ng/mL 64, 128, 224 and
256 ng/mL
Between Batch Precision 2.1 to 7.9% 1.8 to 8.9%
(%CV)
Between Batch Accuracy -1.5 to 5.4% -3.4 to 1.6%
(%RE)
Linearity Weighted linear equation (1/X2), mean r=
0.9968
Linear Range (ng/mL) 0.5 to 500 ng/mL
Sensitivity (LLOQ, ng/mL) 0.5 ng/mL
1-Hydroxymidazolam
Parameter Quality Control Standard Curve
Samples Samples
Quality Control or Standard 1.5, 3.0, 28 and 192 0.5, 1.0, 8.0, 32,
Curve Concentration (ng/mL) ng/mL 64, 128, 224 and
256 ng/mL
Between Batch Precision 3.8 to 4.6% 3.1 to 8.4%
(%CV)
Between Batch Accuracy -0.4 to 0.9% -2.1 to 4.8%
(%RE)
Linearity Weighted linear equation (1/X2), mean r=
0.99845
Linear Range (ng/mL) 0.5 to 500 ng/mL
Sensitivity (LLOQ, ng/mL) 0.5 ng/mL
Pharmacokinetic Pharmacokinetic evaluations: The following PK parameters were
Assessments calculated for midazolam and for the active metabolite 1-
hydroxymidazolam (1-OHmidazolam): Noncompartmental analysis Area
under the concentration-time curve AUC from time zero to the last
quantifiable concentration (AUC0-last ), AUC from time zero to 6, 8, or 10
hours postdose (AUC0-6, AUC0-8 [Cohorts 1 and 2 only], or AUC0-10
[Cohort 1 only], respectively), maximum plasma concentration (Cmax),
and time to Cmax (Tmax).
51
RESULTS:
Following figure represents mean plasma midazolam concentration-time profiles per dosing
group on linear scale.
52
53
54
55
CONCLUSIONS:
The pediatric subjects had lower clearance and volume of distribution as compared to adults,
consistent with their smaller body size.
PK parameters for both MZ and 1- OH MZ were less than dose proportionality with increasing
doses.
56
Table 1: Summary of the characteristics of the studies used for Pop PK analysis
Overa ll, the fina l dataset fo r Pop PK ana lysis consisted of 10,096 blood samples for midazolam and 1-
0 H-midazolam in 602 subjects. A total of 5.22% samples assayed for midazolam were BLQ and 14. 7%
samples assayed fo r 1-0H-midazolam were BLQ. The higher number of BLQ samples fo r 1-0H-
midazolam is attributed to early samples prior to format ion of the metabolite . Measurable
57
Two compartment models were found to best describe midazolam and 1-0H-midazolam plasma
concentration profiles. A sequential approach was used for modeling wherein a final population PK
model was established for m idazolam and then posthoc parameter estimates for that model were used
as the input for the population PK model for 1-0H-midazolam . The fraction of bioavailable midazolam
converted to 1-0H-midazolam (Fm) was fixed to 1. Allometric scaling was assumed for clearance,
volume of distribution and absorption parameters. Between-subject and intra-occasion variability (on
clearance and relative bioavailability) were modeled using a log-normal distribution. Residual variability
was described by a combined addit ive and proportiona l model. An effect of bioanalytical methods were
tested on the residual error model. Analyses were performed in NONMEM Version 7.3 w ith the FOCE
with INTERACTION option.
Covariates were included in the model using a fu ll model approach based on biological plausibility,
clinical interest or observed trend observed in exploratory analysis. A power function for continuous
covariates and a mult iplicative function for categorical covariates were used. The covariates considered
for inclusion in the model are listed in Table 2.
The distributions of categorica l and continuous covariates in the dataset are provided in Table 3 and
Table 4 .
58
Source: PROX‐CSC‐100, Table 2, Page 25.
Table 4: Summary of continuous baseline characteristics
Source: PROX‐CSC‐100, Table 3, Page 26.
59
CL/F: CYP3A inducers, age category (elderly vs. non‐elderly) and sex
Frel: body weight, age, sex, formulation and total dose
Ka: age category (children vs. older subjects)
The dose effect on relative bioavailability (Frel) was found to be formulation‐dependent. A power
model was used to describe the effect of dose on Frel for the ITI formulation and a two‐slope model was
used to describe the effect for the USL261 formulation.
The estimates of the final population PK model for midazolam are provided in Table 5. Goodness of fit
plots, including a visual predictive check demonstrated a reasonable fit to the data.
Table 5: Parameter estimates of the final PK model for midazolam
Source: PROX‐CSC‐100, Table 5, Page 34.
60
Figure 1: Covariate effects on AUC of midazolam
Source: PROX‐CSC‐100, Figure 7, Page 38
61
Source: PROX‐CSC‐100, Figure 8, Page 39.
The estimates of the final population PK model for 1‐OH‐midazolam are provided in Table 6 and basic
goodness‐of‐fit plots are presented in Figure 3.
62
Source: PROX‐CSC‐100, Table 6, Page 47.
Figure 3: Basic goodness‐of‐fit plots for final model for 1‐OH‐Midazolam
Source: PROX‐CSC‐100, Figure 13, Page 45.
63
Figure 4: Covariate effects on AUC of 1‐OH‐Midazolam
Source: PROX‐CSC‐100, Figure 15, Page 49.
64
Source: PROX‐CSC‐100, Figure 16, Page 50.
Covariate effects on the active moiety (sum of midazolam and 1‐OH‐midazolam, adjusted for molecular
weight differences) were also calculated. The results were similar in magnitude to the effects on
midazolam because midazolam is the major contributor to the active moiety (i.e., concentrations of 1‐
OH‐midazolam are significantly lower than midazolam).
The Applicant’s conclusions include the following:
The bioavailability of 5 mg midazolam is predicted to be 32% lower with the USL261 formulation
compared with the ITI formulation
65
Reviewer’s Comments:
The Applicant’s population PK model provides a reasonable description of midazolam plasma
concentrations in healthy subjects and subjects with epilepsy. The fit for 1‐OH‐midazolam is not as good,
as seen in Figure 3 with deviations in observed vs. population predictions around the line of unity. The
deterioration in fit for the metabolite is not unexpected, as a sequential approach was taken and
assumptions were made regarding the formation of the metabolite. The concentrations of the
metabolite are significantly lower than midazolam and covariate effects are similar for midazolam and
the active moiety, so the deterioration of the fit is not of critical importance.
The results indicate that the bioavailability of the to‐be‐marketed formulation is lower (approximately
32%) relative to the formulation used in the absolute bioavailability study for comparison to midazolam
injection. From a safety perspective, the lower exposure for the to‐be‐marketed formulation provides a
satisfactory bridge to the reference label. The to‐be‐marketed formulation was used in the pivotal
efficacy study, so the lower bioavailability is not of a concern in the context of efficacy. Therefore, these
analyses can be considered to provide support for a bridge to the reference product.
The covariate analysis suggests significant effects of sex and concomitant CYP3A4 inducers on exposure
of midazolam, but these are considered not to be clinically relevant and no dose adjustment for these
factors was employed in the clinical trials.
66
Exposure metrics used in the analysis were AUC0‐6, AUC0‐inf and Cmax. AUC measures were considered to
be reflective of a sustained protection against seizure occurrence, whereas Cmax may be more relevant in
terms of acute seizure abatement. Exposure metrics for the active moiety were also considered in the
analysis. The PK model described in Appendix 4.4 was used to derive rich concentration‐time profiles in
subjects based on PK data collected in the test‐dose phase of P261‐401. The response endpoint in the
analysis is consistent with the primary endpoint in the comparative phase of P261‐401, which was the
termination of seizures within 10 minutes of study drug administration and no recurrence of seizures
beginning 10 minutes after administration of study drug and up to 6 hours. The probability of treatment
success was evaluated using a time‐independent logistic regression model linking the single dose
exposure parameter with the probability of response.
A total of 292 subjects were enrolled in the test‐dose phase of P261‐401 and 201 of these subjects
proceeded to the comparative phase. There were 4 subjects evaluated in the comparative phase who
did not have PK data from the test‐dose phase and were therefore excluded from the analysis. The
relationship between AUC0‐6 of midazolam and the probability of treatment success is presented in
Figure 6.
67
Source: PROX‐CSC‐100‐2, Figure 1, Page 15.
A statistically significant relationship was observed (p=0.0226), but treatment success across the range
of AUC0‐6 were similar across the 1st, 2nd, 3rd, and 4th quartiles (57.6%, 46.9%, 56.2% and 51.5%,
respectively). The Applicant notes that a 10‐fold range of AUC0‐6 values is observed across the quartiles
(12.9 to 195 ng.h/mL) and thus changes in exposure due to concomitant administration of CYP3A4
inducers or body weight are not likely to be clinically relevant. Exposure‐response analyses using other
exposure metrics for midazolam or active moiety showed a similar trend. However, no clear relationship
was noted for 1‐OH‐midazolam exposure metrics.
A separate analysis was also performed for time to next seizure using a time‐to‐event model driven by
time‐varying concentrations of midazolam. Similar to logistic regression, this analysis suggested that the
relationship for the time to next seizure had reached a plateau at the levels of exposure observed in the
study.
Reviewer’s Comments: The Applicant’s analysis is limited by the fact that only one dose was studied in
P261‐401 and that PK samples were collected during the test‐dose phase and not during the comparative
phase. On the other hand, there was a wide spread of exposure values and the intra‐occasion variability
was found to be modest in the population PK model. The results of this analysis support the primary
efficacy results from P261‐401, including in the subpopulation of subjects receiving concomitant
administration of CYP3A inducing AEDs.
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This is a representation of an electronic record that was signed
electronically. Following this are manifestations of any and all
electronic signatures for this electronic record.
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/s/
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JIANGHONG FAN
03/11/2019 04:31:56 PM
YUCHING N YANG
03/11/2019 04:35:58 PM
KEVIN M KRUDYS
03/12/2019 08:39:05 AM
YUXIN MEN
03/13/2019 09:30:08 AM