Oral Abuse Potential of Benzhydrocodone, a Novel Prodrug of

198
Oral Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone
Presented at the
American Academy of Pain Medicine (AAPM)
February 18–21, 2016 • Palm Springs, CA
Sven Guenther, PhD1; Travis Mickle, PhD1; Nelson Meléndez, BS1; Leone Kirk, BS1; Michael Smith, PharmD2; Rosemary Ndolo, PhD2; Kathryn Roupe, PhD3; Jing Zhou, MS3; Daniel Dickerson, MD, PhD, FAAFP2
1
KemPharm, Inc., Coralville, IA, USA; 2PRA Health Sciences, Raleigh, NC, USA; 3Worldwide Clinical Trials, King of Prussia, PA, USA
Figure 1. Past 30-Day Abuse Per 100 Assessments
(A) and Frequency of Routes of Administrationa Over
the 1/1/2014–6/30/2015 Period (B) for Hydrocodone
IR Combination Products and Comparator Opioids
Within the ASI-MV® Networkb,6
A.
12.0
Rate Per 100 Assessments
10.0
8.0
6.0
• Study KP201.A01 was conducted to assess the abuse
liability, relative bioavailability, and safety of KP201/APAP,
compared with that of HB/APAP (Norco®), when administered at supratherapeutic oral doses to non-dependent,
recreational opioid users
2.0
Hydrocodone Oxycodone Oxycodone All Other IR All ER/LA
IR
IR
IR Single- Prescription Opioids
Combination Combination entity
Opioids
Products Products
(SE)
All ADF All Non-ADF
ER/LA
ER/LA
Opioids
Opioids
B.
Methods
Study Design
m Hydrocodone IR combination products
m Oxycodone IR combination products
m Oxycodone IR single-entity (SE)
m All other IR prescription opioids
m All ER/LA opioids
m All ADF ER/LA opioids
m All Non-ADF ER/LA opioids
9,000
8,000
Frequency (Number of Individuals)
• KP201/APAP tablet 6.67 mg/325 mg is an IR combination
product of KP201 (benzhydrocodone HCl) and APAP.
KP201 is a prodrug of hydrocodone chemically bound to
benzoic acid, which may have abuse-deterrent properties
at the molecular level, rather than through formulation
—Breaking of the covalent bond between benzoic acid
and hydrocodone is required for the release of hydrocodone, which occurs most rapidly and efficiently in
the intestinal tract (ie, after oral administration)
• KP201 has shown decreased bioavailability at high oral
doses (ie, above therapeutic use) and when snorted
—KP201 has demonstrated high tamper resistance and
its physicochemical properties may deter IV abuse
—Overall, the data show that KP201/APAP provides
equivalent hydrocodone exposure and thus the same
efficacy as hydrocodone IR combination products
when taken as indicated, but reduces exposure at
supratherapeutic oral doses and when snorted
Objectives
4.0
0.0
A Novel IR Opioid Product with
Abuse-Deterrent Properties
7,000
6,000
5,000
4,000
3,000
• This was a single-center, randomized, double-blind, activeand placebo-controlled, 7-period, crossover study consisting
of Screening, Qualification, Treatment, and Follow-Up phases
• During the Qualification phase, subjects underwent a
Naloxone Challenge Test to confirm that they were not
physically dependent on opioids. Those who passed this
test were administered a Drug Discrimination Test to
ensure that subjects could differentiate between effects
of HB/APAP and placebo
• Each of the 7 double-blind treatment periods were
separated by a minimum 72-hour washout period
2,000
Study Population
1,000
0
Oral
Snorted
Injection
Smoked
Other
a
Routes of administration were not mutually exclusive; bASI-MV® is a proprietary and validated7 data stream of the National Addictions
Vigilance Intervention and Prevention Program (NAVIPPRO®). Data for the ASI-MV are collected via a self-administered and structured
computerized interview from adults within a network of substance abuse treatment centers and other assessment settings, currently drawn
from 44 states in the US. NAVIPPRO is a scientifically developed risk management program for prescription opioids and other Schedule II or
III therapeutic agents, which provides real-time, product specific surveillance information from proprietary and public data sources to
monitor patterns and trends in abuse of prescription medications and illegal drugs.
IR, immediate release; ASI-MV®, Addiction Severity Index—Multimedia Version; ER, extended release; LA, long acting;
ADF, abuse-deterrent formulation.
• Eligible subjects were healthy men and women aged
18 to 55 years old at the time of screening and engaged
in recreational opioid use without opioid dependency, as
determined by the Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition13
—Subjects were also required to have experience with
nontherapeutic (ie, recreational) opioid use on at least
10 occasions within the preceding year and at least
once within the 12 weeks prior to screening
Study Treatments
• All subjects were to receive 7 oral treatments including
a placebo dose alone and active treatments KP201/APAP,
6.67 mg/325 mg (test drug) and HB/APAP, 7.5 mg/
325 mg (comparator) at low (4 tablets), mid (8 tablets),
or high (12 tablets) doses in a computer-generated
randomized sequence (Table 1). KP201, 6.67 mg is
equivalent to HB, 7.5 mg.
—All KP201/APAP and HB/APAP tablets were overencapsulated and placebo was administered in
capsules to maintain blinding
Table 1. Oral Treatments Administered in Crossover
Fashion to All Subjectsa
Treatment
KP201/APAP, 6.67/325 mg
High-dose
Mid-dose
Low-dose
HB/APAP, 7.5/325 mg
High-dose
Mid-dose
Low-dose
Placebo
• Pharmacodynamic assessment of abuse potential was
conducted using a mixed-effects model of analysis of
variance (ANOVA) for the completer population
—Study completers were subjects who completed all 7
dosing periods of the Treatment Phase, and completed
≥1 postdose assessment of the DL-VAS and ≥1 postdose
drug concentration assessment from each dosing period
• Based on the ANOVA, pairwise comparisons of leastsquare (LS) means between individual treatments were
conducted at the significance level of 0.05 (2-sided) for
consistency with the 95% confidence interval (CI), using
a model-based t-test
• A linear mixed-effects model was used to analyze the
natural log-transformed PK parameters
12/0
8/4
4/8
0/12
Study Population
• Of 151 enrolled subjects, 71 entered and 62 completed
the Treatment Phase and were included in the analyses
(Figure 2)
Figure 2. Disposition of All Enrolled Subjects
Number of Subjects Enrolled
N=151
Received Naloxone Challenge
n=125
90/3900
60/2600
30/1300
0
Received Drug Discrimination Test
n=119
Subjects received each oral treatment once, each separated by a ≥72-hour washout, in a computer-generated randomized sequence
based on a Williams’pair design; bAll tablets of active drugs were over-encapsulated.
APAP, acetaminophen; HB, hydrocodone bitartrate.
Entered Treatment Phase
n=71a
Pharmacokinetic (PK) Sample Collection
• Pharmacodynamic (PD) analysis
—Maximum, or peak, effect (Emax) of subject-rated Drug
Liking (DL-VAS) in study completers, assessed on a
bipolar 100-point Visual Analogue Scale after each
dose was administered during the Treatment Phase
• PK parameters
—Area under the plasma concentration versus time curve
(AUC) from 0 hour to 0.5, 1, 2, 4, 8, and 24 hours; to the
last quantifiable sample (AUClast); and extrapolated to
infinity (AUCinf)
—Maximum observed plasma concentration (Cmax)
—Time at which Cmax occurs (Tmax)
• Safety measures included
—Incidence, type, severity, and relation to treatment of
adverse events (AEs)
—Physical examination, vital signs, electrocardiograms,
laboratory testing
Figure 5. Cumulative Percent Reduction in Cmax
and AUC0-1 of Hydrocodone at Mid- Doses (A) and
High-Doses (B) of KP201/APAPa Versus HB/APAPb
Not eligible for Naloxone Challenge, n=26
• Washout criteria, n=1
• Positive UDS, n=1
• Withdrew consent, n=2
• Inclusion/exclusion critiera, n=22
200
A.
Completed Treatment Phase
n=62
Withdrew prior to Treatment Phase, n=48
• Adverse events, n=1
• Failed Drug Discrimination, n=37
• Labs, n=1
• Positive UDS, n=4
• Investigator termination, n=2
• Withdrew consent, n=3
Withdrew During Treatment Phase, n=9
• Investigator termination, n=2
• Withdrew consent, n=3
• Adverse events, n=2
• Not qualified after check-in, n=1
• Lost to follow-up, n=1
a
One additional subject failed the Drug Discrimination Test but was re-enrolled and completed the study.
UDS, urine drug screen.
• Among treatment completers (n=62), approximately 82%
of subjects were male, 50% were Black and 38.7% White,
and 90.3% were not Hispanic or Latino
• Mean age (range) was 29.1 (19–54) years
PD Parameters
• The mean (standard deviation) Emax scores on the DL-VAS
among completers (n=62) were similar for KP201/APAP
and HB/APAP at high-, mid-, and low-doses:
—Emax scores were 87.8 (14.8), 82.4 (16.4), and 72.6 (17.2)
for KP201/APAP versus 87.4 (15.6), 83.4 (16.4), and
72.5 (16.5) for HB/APAP at high-, mid-, and low-doses,
respectively, and 51.5 (3.4) for placebo
• The statistical analysis for the DL-VAS results revealed
no significant LS mean differences in Emax of Drug Liking
between KP201/APAP and HB/APAP at high-, mid-, or
low-doses
• Therefore, the DL-VAS results did not demonstrate a
decreased liking for KP201/APAP versus HB/APAP
—Interpretation of these results is complicated by the
presence of high doses of APAP in both comparator
medications because APAP may potentially confound
PD measurements due to its indirect activation of
cannabinoid CB1 receptors15
100
Cmax
AUC0-1
150
80
100
50
0
0.0
Not eligible for Drug Discrimination Phase, n=6
a
Study Endpoints
Figure 3. Mean Plasma Hydrocodone ConcentrationTime Profiles Following Single Oral Doses of
KP201/APAPa and HB/APAPb
Results
80.04/3900
53.36/2600
26.68/1300
• Serial blood samples were collected during the Treatment
Phase for PK analysis before each dose and up to
24 hours after each dosing for the measurement of
KP201 and hydrocodone in plasma
• Blood samples were also collected before each dose
and at 0.5, 2, and 8 hours after each dosing for the
measurement of APAP in plasma
• All blood samples were analyzed using validated liquid
chromatography with tandem mass spectrometry
methods
• Systemic exposure to hydrocodone as measured by
Cmax and total (AUClast) as well as partial (AUC0-1 through
AUC0-24) was statistically lower for KP201/APAP at the
high- (12 tablets) and mid- (8 tablets) doses
—Cmax was 10.0% and 11.5% lower at the mid- and
high-doses of KP201/APAP, respectively, versus the
corresponding HB/APAP doses (Figure 3)
250
No. Tabletsb (Active Drug)/ Total Dose
Capsules (Placebo)
Active Drug (mg)
12/0
8/4
4/8
PK Parameters
• Systemic exposure was similar at the low 4-tablet doses
of KP201/APAP and HB/APAP
• No statistically significant differences in Tmax of hydrocodone, as reflected in P values from the Wilcoxon signed
rank test, were observed for any comparison between
corresponding doses of KP201/APAP and HB/APAP
• At mid-dose (8 tablets), approximately 39% and 38%
of subjects had ≥20% cumulative reductions in Cmax and
AUC0-1 measures of exposure to hydrocodone, respectively,
with KP201/APAP versus HB/APAP (Figure 5A)
• At high-dose (12 tablets), approximately 25% and 34%
of subjects had ≥20% cumulative reductions in Cmax and
AUC0-1 measures of exposure to hydrocodone, respectively,
with KP201/APAP versus HB/APAP (Figure 5B)
Percentage of Subjects
• Opioid combination products containing hydrocodone
bitartrate (HB) are the second most commonly prescribed drugs in the US1
• However, misuse and abuse of prescription opioids,
including the use of alternate routes of administration to
achieve the desired effects more quickly or intensely, is
an ongoing public health concern2-4
—Immediate-release (IR) hydrocodone combination
products, typically including acetaminophen (APAP),
are the most commonly abused opioids5,6 (Figure 1A)
—While opioids are most frequently abused via oral
administration, recent survey data indicate that
approximately 23% of hydrocodone IR combination
product abusers use an intranasal (snorting), and 1%
use an intravenous (IV), route of administration6
• Although the percentage of respondents who have
snorted hydrocodone IR combination products was
lower versus other opioids, the absolute number was
similar to other opioid categories due to high usage
of hydrocodone IR combinations (Figure 1B)
—However, the potential influence of APAP on the present
Drug Liking results was not assessed
Statistical Analysis
0.25
0.5
0.75
1.0
Time (h)
4 Tablets of KP201/APAP
8 Tablets of KP201/APAP
12 Tablets of KP201/APAP
1.25
1.5
1.75
2.0
60
4 Tablets of HB/APAP
8 Tablets of HB/APAP
12 Tablets of HB/APAP
0
>0
Each tablet of KP201/APAP contains 6.67 mg benzhydrocodone HCl/325 mg acetaminophen; bEach tablet of HB/APAP contains 7.5 mg
hydrocodone bitartrate/325 mg acetaminophen.
APAP, acetaminophen; HB, hydrocodone bitartrate; HCl, hydrochloride.
a
B.
—AUC0-0.5 through AUC0-24 percent differentials ranged
from approximately –18% to –4% with KP201/APAP
versus HB/APAP at the high-doses (12-tablets) of each
(Figure 4), and from –14% to –5% at the mid-doses
(8 tablets), with the exception of AUC0-1 at mid-dose,
at which exposure was similar
≥10 ≥20 ≥30 ≥40 ≥50 ≥60 ≥70 ≥80 ≥90 ≥100
Percent Reduction in Cmax and AUC0-1 of Hydrocodone for
Single Oral Doses of 8 Tablets of KP201/APAP vs HB/APAP
100
Cmax
AUC0-1
80
Figure 4. Forest Plot of Geometric Mean Ratiosa
and 90% Confidence Intervals of the Pharmacokinetic
Parameters of Hydrocodone Following Oral Administration of High- (12-Tablet) Doses of KP201/APAPb
and HB/APAPc
60
40
20
Cmax
0
>0
AUC0-0.5
AUC0-1
AUC0-2
≥10 ≥20 ≥30 ≥40 ≥50 ≥60 ≥70 ≥80 ≥90 ≥100
Percent Reduction in Cmax and AUC0-1 of Hydrocodone for
Single Oral Doses of 12 Tablets of KP201/APAP vs HB/APAP
a
Each tablet of KP201/APAP contains 6.67 mg benzhydrocodone HCl/325 mg acetaminophen; bEach tablet of HB/APAP contains 7.5 mg
hydrocodone bitartrate/325 mg acetaminophen.
APAP, acetaminophen; AUC0-1, area under the plasma concentration versus time curve from 0 hour to 1 hour; Cmax, maximum observed
plasma concentration; HB, hydrocodone bitartrate; HCl, hydrochloride.
AUC0-4
AUC0-8
AUC0-24
References
AUClast
AUCinf
60
70
80
90
100
110
120
Percent Ratio and 90% Confidence Interval of PK Paramenters
of Hydrocodone for KP201/APAP vs HB/APAP Following
Oral Administration of 12 Tablets
a
Geometric means based on least squares mean of log-transformed parameter values; bEach tablet of KP201/APAP contains 6.67 mg
benzhydrocodone HCl/325 mg acetaminophen; cEach tablet of HB/APAP contains 7.5 mg hydrocodone bitartrate/325 mg acetaminophen.
APAP, acetaminophen; AUCinf, area under the plasma concentration versus time curve from 0 to infinity; AUClast, area under the plasma
concentration versus time curve from 0 to the last quantifiable sample; AUC0-x, area under the plasma concentration versus time curve from
0 hour to time x (hours); Cmax, maximum observed plasma concentration; HB, hydrocodone bitartrate; HCl, hydrochloride.
Safety Assessment
• Exposure
—A total of 119 subjects received ≥1 dose of study drug,
including placebo; this cohort comprised the safety
population
—During the Treatment Phase, 69 subjects received a
total of 197 single doses of HB/APAP and 67 subjects
received a total of 194 single doses of KP201/APAP
• AEs
—A total of 117 of 119 treated subjects (98.3%) experienced ≥1 treatment-emergent AE (TEAE); no serious
AEs were reported
—All 62 completers of the Treatment Phase (100%)
experienced ≥1 AE; the most common were euphoric
mood (97.2%) and somnolence (90.1%)
—TEAE rates during the Treatment Phase were similar
overall for KP201/APAP treatment (98.5%) and HB/APAP
treatment (98.6%), and higher for both versus placebo
(26.2%)
—However, overall rates of hypoxia were lower with
KP201/APAP (23.9%) versus HB/APAP (36.2%), due to
differences at the mid-and high-doses
—TEAEs were considered possibly or probably related to
study treatment in 115 treated subjects overall (96.6%)
Conclusions
40
20
Percentage of Subjects
Background
• Subjects were excluded who had
—Received or sought treatment for substance-related
disorders within the previous 5 years, or a history
of/current dependency on drugs or alcohol
—A recent history of suicidal ideation or suicidal behavior
as assessed by the Columbia-Suicide Severity Rating
Scale14
—Failed to pass either the Naloxone Challenge Test or
Drug Discrimination Test
Plasma Concentration (ng/mL)
Introduction
• Due to concerns over abuse risk, hydrocodone IR combination products were changed from Schedule III to the
more restricted Schedule II classification by the US Drug
Enforcement Administration in October 20148
—Although the number of prescriptions of these products
decreased following the rescheduling,1 survey data suggest the absolute prevalence of abuse of hydrocodone
IR combination products increased, via all routes of
administration, in the first half of 20156
• In addition, a final US Food and Drug Administration
(FDA) Guidance for Industry was issued in April 2015 to
provide a framework for evaluating and obtaining label
claims for abuse-deterrent formulations of opioids9
• Although 2 extended-release (ER), stand-alone HB products with abuse-deterrent reformulations have recently
gained FDA approval, Hysingla® ER10 and Zohydro® ER11
no hydrocodone IR products with abuse-deterrent
properties have been marketed12
•Statistically significant reductions in peak
exposure (Cmax) and cumulative systemic
exposure (AUC) to hydrocodone were
observed for KP201/APAP versus HB/APAP
at oral doses of 8 and 12 tablets, while Drug
Liking scores were similar for both treatments
at equivalent dose levels
•Both KP201/APAP and HB/APAP were
generally well tolerated, with primarily mild
AEs reported that were typical of opioids
•Considering the large patient and abuser
populations that take hydrocodone IR combinations, the lower exposure to hydrocodone
along with the lower incidence of hypoxia
reported for KP201/APAP versus HB/APAP
may decrease the overall risk of oral overdose
and as a result the risk for morbidity and
mortality following overdosage of KP201/APAP
compared to currently marketed hydrocodone IR combination products
Disclosures
Sven Guenther, Travis Mickle, Nelson Meléndez, and Leone Kirk
are employees of KemPharm, Inc. Daniel Dickerson, Jing Zhou, Kathryn Roupe, Rosemary
Ndolo, and Michael Smith have no conflicts of interest to declare. Funding for editorial,
design, and production support was provided by KemPharm, Inc., Coralville, IA, USA, to
The Curry Rockefeller Group, LLC, Tarrytown, New York, USA.
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