PK/PD analysis in assessment of abuse deterrence

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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 3 September 1, 213 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4 Introduction Draft Guidance on Assessment of Abuse Potential of Drugs (January 21): Characterization of the PK/PD properties of a product is important for determining the abuse potential of a product. Draft ADF guidance (January 213): 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

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 Age Gender Opioid experience Tolerance/Dependence Expectations Genetic variations?? Endpoints Analysis Interpretation Pharmacokinetics (CV 3%) Opioid, Dose Formulation, Route BBB permeability ADME, protein binding Active metabolites Plasma vs. Effect site Arterial v venous sampling/timing CV=coefficient of variation Pharmacodynamics (CV 5- >1%) Subjective effects Miosis Analgesia Respiratory depression Adverse events Behavior

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 (3 mg) Positive controls: Oxy API and fine ground original OC (3 mg) Placebo control: lactose powder

11 Plasma oxycodone (ng/ml) Drug Liking VAS (-1) Time course of effects Oxycodone concentration Drug Liking VAS OTR fine OTR coarse OC OTR fine OTR coarse OC Time post-dose (hr) Time post-dose (hr) Effects unrelated to drug exposure can impact experience (at the moment and overall) Courtesy of Purdue Pharma; Perrino et al., 212 CPDD; Harris et al., submitted

12 Rate of Rise: Abuse quotient Lower C max and longer T max lower Abuse Quotient OTR fine OTR coarse OC OTR fine OTR coarse OC 14 Oxy API 14 Oxy API Cmax/Tmax Emax/TEmax Oxycodone Pharmacokinetics Drug Liking Visual Analog Scale Data courtesy of Purdue Pharma

13 Exposure-Response Relationship For reformulated OxyContin, delaying and lowering C max had significant impact on liking But if PK drives PD, what is concentrationeffect relationship?

14 Drug Liking VAS (-1) Drug Liking VAS (-1) PK/PD Correlations: Subjective Effects Derived Parameters By Timepoint OC fine Emax of Drug Liking VAS (-1) Overall R 2 =.12 Drug Liking VAS (-1) y =.2782x R² = Cmax of oxycodone (ng/ml) Plasma oxycodone concentration (ng/ml) OTR fine OTR coarse y =.5386x R² = y =.6612x R² = Plasma oxycodone concentration (ng/ml) Plasma oxycodone concentration (ng/ml) Data courtesy of Purdue Pharma

15 Pupil size (mm) Pupil size (mm) PK/PD Correlations: Physiological Effects y = -.249x R² =.2132 Pupil size (mm) MPC (mm) Derived Parameters By Timepoint 8 OC fine Overall R 2 = Cmax of oxycodone (ng/ml) Plasma oxycodone concentration (ng/ml) OTR fine OTR coarse y = -.59x R² = y = -.586x R² = Plasma oxycodone concentration (ng/ml) 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 4/2 mg (oxycodone/naloxone) Positive control: Oxy API 4 mg Placebo control: lactose powder

18 Plasma oxycodone (ng/ml) Time course of effects 1 Plasma Concentration 1 Drug Liking VAS Naloxone (ng/ml) Oxy API - Oxycodone OXN - Oxycodone Drug Liking VAS (-1) OXN Oxy API Placebo Time post-dose (hours) Time post-dose (hours) At 2:1 ratio, OXN significantly reduces Drug Liking to placebo-like levels Rate of rise: Abuse Quotient (C max /T max ) not applicable to opioid agonist-antagonist combinations, such as OXN Data courtesy of Purdue Pharma

19 Drug Liking VAS (-1) Antagonist PK Agonist PD y =.15x R² = Plasma naloxone concentration (ng/ml) 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

Assessing the Clinical Abuse Potential of Abuse Deterrent Opioid Formulations

Assessing the Clinical Abuse Potential of Abuse Deterrent Opioid Formulations November 16, 2016 Beatrice Setnik, PhD VP, Clinical Pharmacology, Early Phase INC Research Disclosure I am an employee of INC