1. PK/PD analysis in assessment
of abuse deterrence
Megan J. Shram, PhD
Director and Principal, Altreos Research Partners Inc.
Adjunct Professor and Lecturer, Department of Pharmacology, University of Toronto
INC Research Consultant
ADF Science Meeting
October 30 – September 1, 2013
Bethesda, MD
2. Acknowledgments
• Consultant to pharmaceutical and biotech
companies
• Thank you to Purdue Pharma, LP for
permission to present data on reformulated
OxyContin® and OXN
3. Outline
• Background on PK/PD in abuse potential
• What is PK/PD relationship of opioids?
– Determinants of variation
• Application of PK/PD analysis in development
of abuse-deterrent formulations (ADF)
4. Introduction
• Draft Guidance on Assessment of Abuse Potential of
Drugs (January 2010):
– “Characterization of the PK/PD properties of a…product is
important for determining the abuse potential of
a…product.”
• Draft ADF guidance (January 2013):
– “PK data should be collected to correlate with the PD
outcomes.”
– “The rate of rise of drug onset for the intact and
manipulated potentially abuse-deterrent formulation
should be given appropriate weight in the overall analysis
of the abuse deterrent properties.”
5. Introduction
• Goal of PK/PD analysis is to assist in predicting the effect of a
drug over time, in relation to exposure
• In terms of abuse, the relationship between rate of rise of
[drug] and effect is considered important
– Fast onset, short duration of action favors repeated self-administration
– Delaying onset, extending duration of action can reduce immediate
reinforcing effect and need to take more drug
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6. Questions
• Can PK assist in predicting subjective response
to opioid?
• How can one assess if change in PK profile will
be enough to affect PD response?
• eg, partial defeat of the AD mechanism
7. PK/PD: Determinants of Variation
System
•
•
•
•
•
•
Pharmacokinetics
Age
Gender
Opioid experience
Tolerance/Dependence
Expectations
Genetic variations
??
Endpoints
Analysis
Interpretation
Pharmacodynamics
•
•
•
•
•
•
CV=coefficient of variation
(CV ≈50- >100%)
Subjective effects
Miosis
Analgesia
Respiratory depression
Adverse events
Behavior
•
•
•
•
•
•
•
(CV ≈30%)
Opioid, Dose
Formulation, Route
BBB permeability
ADME, protein binding
Active metabolites
Plasma vs. Effect site
Arterial v venous
sampling/timing
8. Assessing the link between opioid exposure
and results of a clinical abuse potential study
Recent ADF Examples
9. When PK/PD relationship might exist
• Physicochemical barrier
– Resistance to manipulation for oral, IN and IV*
administration
• Prodrug
– Must be cleaved systemically to liberate active moiety
– Deterrence from IN and IV administration, and
possibly oral if limited by saturable process
• Delivery System
– Modified drug delivery to reduce diversion via
multiple routes
*not generally feasible to administer manipulated product IV
10. PK/PD of intranasally administered
Reformulated OxyContin®
• 5-way crossover study in recreational opioid
users with intranasal experience
– Coarse and fine ground OTR (30 mg)
– Positive controls: Oxy API and fine ground original
OC (30 mg)
– Placebo control: lactose powder
11. Time course of effects
Oxycodone concentration
Drug Liking VAS
50
100
OTR fine
90
40
OTR coarse
80
35
OC
Drug Liking VAS (0-100)
Plasma oxycodone (ng/mL)
45
30
25
20
15
70
60
50
40
30
10
20
5
10
0
0
0
4
8
12
16
Time post-dose (hr)
20
24
OTR fine
0
4
OTR coarse
8
12
16
Time post-dose (hr)
OC
20
24
Effects unrelated to drug exposure can impact experience (at the moment and
overall)
Courtesy of Purdue Pharma; Perrino et al., 2012 CPDD; Harris et al., submitted
12. Rate of Rise: “Abuse quotient”
• Lower Cmax and longer Tmax lower Abuse Quotient
200
180
200
OTR fine
180
OTR coarse
160
140
OTR fine
OTR coarse
160
OC
Oxy API
140
120
100
80
80
60
60
40
40
20
20
0
Oxy API
120
100
OC
0
Cmax/Tmax
Oxycodone Pharmacokinetics
Emax/TEmax
Drug Liking Visual Analog Scale
Data courtesy of Purdue Pharma
13. Exposure-Response Relationship
• For reformulated OxyContin®, delaying and
lowering Cmax had significant impact on liking
• But if PK “drives” PD, what is concentrationeffect relationship?
14. PK/PD Correlations: Subjective Effects
By Timepoint
Derived Parameters
100
OC fine
100
80
90
70
80
Drug Liking VAS (0-100)
Emax of Drug Liking VAS (0-100)
90
60
50
40
30
Overall
20
R2=0.12
70
60
50
40
30
y = 0.2782x + 72.519
R² = 0.0602
20
10
10
0
0
0
20
40
60
80
100
0
Cmax of oxycodone (ng/mL)
20
60
100
y = 0.6612x + 44.435
R² = 0.1077
100
100
y = 0.5386x + 54.143
R² = 0.0518
90
80
OTR coarse
OTR fine
90
80
Drug Liking VAS (0-100)
80
Drug Liking VAS (0-100)
40
Plasma oxycodone concentration (ng/mL)
70
60
50
40
30
70
60
50
40
30
20
20
10
10
0
0
0
20
40
60
80
Plasma oxycodone concentration (ng/mL)
100
0
20
40
60
80
100
Plasma oxycodone concentration (ng/mL)
Data courtesy of Purdue Pharma
16. When PK/PD might matter less
• Opioid agonist-antagonist combinations
– Antagonist attenuates/reverses effect of opioid
– Does PK of antagonist help predict response to
agonist?
• Aversion
– Aversive agent not intended to impact exposure to
agonist
– PK would NOT predict overall response to ADF
– Might still experience high from opioid; however,
product not liked
17. PK/PD of intranasally administered OXN
• 3-way crossover study in recreational opioid
users with intranasal experience
– Crushed OXN 40/20 mg (oxycodone/naloxone)
– Positive control: Oxy API 40 mg
– Placebo control: lactose powder
18. Time course of effects
100
100
Plasma Concentration
90
90
80
80
Naloxone (ng/mL)
Oxy API - Oxycodone
70
OXN
Oxy API
70
Drug Liking VAS (0-100)
Plasma oxycodone (ng/mL)
Drug Liking VAS
OXN - Oxycodone
60
50
40
Placebo
60
50
40
30
30
20
20
10
10
0
0
0
4
8
12
16
Time post-dose (hours)
20
24
0
4
8
12
16
Time post-dose (hours)
20
24
• At 2:1 ratio, OXN significantly reduces Drug Liking to placebo-like
levels
• Rate of rise: “Abuse Quotient” (Cmax/Tmax) not applicable to
opioid agonist-antagonist combinations, such as OXN
Data courtesy of Purdue Pharma
19. Antagonist PK – Agonist PD
100
90
y = 0.15x + 47.987
R² = 0.008
Drug Liking VAS (0-100)
80
70
60
50
40
30
20
10
0
0
5
10
15
20
25
Plasma naloxone concentration (ng/mL)
30
35
• Highly variable concentrations and lack of concentration-effect
relationship of to-be-marketed formulation
• Relationship between antagonist PK and agonist PD typically evaluated
earlier in development in dose-ranging trials – ie, dose-effect
Data courtesy of Purdue Pharma
20. Conclusions
• Relationship between PK and PD of abuse
potential is weak and highly variable
• Effects unrelated to opioid exposure impact
subject’s experience
• Clinical PD study necessary to determine
potential for abuse (or its deterrence)
• PK alone cannot be used as substitute in
abuse potential assessment
