RemoxyRemoxyIn VivoIn Vivo Abuse Resistance Abuse Resistance

StudiesStudies

RemoxyRemoxyIn VivoIn Vivo Abuse Resistance Abuse Resistance

StudiesStudies

Ping Ji, PhDSenior Clinical PharmacologistOffice of Clinical Pharmacology

Center of Drug Evaluation and ResearchFood and Drug Administration

Ping Ji, PhDSenior Clinical PharmacologistOffice of Clinical Pharmacology

Center of Drug Evaluation and ResearchFood and Drug Administration

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In VivoIn Vivo Abuse Resistance Abuse Resistance StudiesStudies

In VivoIn Vivo Abuse Resistance Abuse Resistance StudiesStudies

• Physical Disruption Study

• Mastication (chewing) Study

• Buccal Absorption Study

• Physical Disruption Study

• Mastication (chewing) Study

• Buccal Absorption Study

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Dose DumpingDose DumpingDose DumpingDose Dumping

• For opioids, Cmax is a critical pharmacokinetic parameter

• For the assessment of dose dumping, it is important to examine data from both individual and group mean basis

• For opioids, Cmax is a critical pharmacokinetic parameter

• For the assessment of dose dumping, it is important to examine data from both individual and group mean basis

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Cumulative Frequency AnalysisCumulative Frequency AnalysisCumulative Frequency AnalysisCumulative Frequency Analysis

• In a data set, the ‘more than’ cumulative frequency of a value x is the total number of observations that are more than or equal to x

• Frequency counts can be measured in terms of absolute numbers or relative numbers (e.g., proportions or percentages)

• In a data set, the ‘more than’ cumulative frequency of a value x is the total number of observations that are more than or equal to x

• Frequency counts can be measured in terms of absolute numbers or relative numbers (e.g., proportions or percentages)

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X

Cu

mu

lati

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Re

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(M

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Physical Disruption StudyPhysical Disruption Study

– Treatment A: Remoxy 40 mg capsule (whole)

– Treatment B: Remoxy 40 mg capsule (crushed, extracted with solvent)

– Treatment C: OxyContin 40 mg tablet (whole)

– Treatment D: OxyContin 40 mg tablet (crushed, extracted with solvent)

– Treatment E: Oxycodone oral solution 40 mg

– Treatment A: Remoxy 40 mg capsule (whole)

– Treatment B: Remoxy 40 mg capsule (crushed, extracted with solvent)

– Treatment C: OxyContin 40 mg tablet (whole)

– Treatment D: OxyContin 40 mg tablet (crushed, extracted with solvent)

– Treatment E: Oxycodone oral solution 40 mg

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Physical Disruption Study Physical Disruption Study Mean Oxycodone Plasma Concentration-Time Profiles

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40

60

80

100

120

0 2 4 6 8 10 12

Time (h)

Oxy

cod

one

Con

c. (

ng/

mL

)

Oxycodone Oral SolutionOxyContin Crushed & ExtractedRemoxy Crushed & ExtractedOxyContin WholeRemoxy Whole

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Physical Disruption Study Physical Disruption Study

Remoxy OxyContin

Mean Oxycodone Plasma Concentration-Time Profiles

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60

80

100

120

0 2 4 6 8 10 12

Time (h)O

xyco

done

Con

c. (

ng/m

L)

OxyContin Whole

OxyContin Crush & Extracted

0

20

40

60

80

100

120

0 2 4 6 8 10 12

Time (h)O

xyco

done

Con

c. (

ng/m

L)

OxyContin Whole

OxyContin Crush & Extracted

0

20

40

60

80

100

120

0 2 4 6 8 10 12

Time (h)

Oxy

codo

ne C

onc.

(ng

/mL

)

Remoxy Whole

Remoxy Crushed & Extracted

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20

40

60

80

100

120

0 2 4 6 8 10 12

Time (h)

Oxy

codo

ne C

onc.

(ng

/mL

)

Remoxy Whole

Remoxy Crushed & Extracted

Treatment Ratio Cmax AUCRemoxy Crush /Remoxy Whole 2.07 (1.84-2.34) 1.07 (0.96-1.20)

OxyContin Crush/OxyContin Whole 2.12 (1.92-2.33) 1.01 (0.93-1.10)

Mean (90% CI)Statistical Comparison

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Physical Disruption Study Physical Disruption Study Mean Oxycodone Plasma Concentration-Time Profiles

Statistical Comparison

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80

100

120

0 2 4 6 8 10 12

Time (h)

Oxy

cod

one

Con

c. (

ng/

mL

)

Oxycodone Oral SolutionOxyContin Crushed & ExtractedRemoxy Crushed & Extracted

Treatment Ratio Cmax AUCRemoxy Crush /Oxycodone Oral Solution 0.79 (0.74-0.84) 1.24 (1.19-1.30)

OxyContin Crush/Oxycodone Oral Solution 0.97 (0.89-1.06) 1.01 (0.96-1.07)

Mean (90% CI)

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Physical Disruption StudyPhysical Disruption StudyCumulative Frequency Plots

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100

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Cmax Ratio

Cu

mu

lati

ve

Re

lati

ve

Fre

qu

en

cy

(Mo

re T

ha

n)

Remoxy Crush/Oral solution Remoxy Whole/Oral solution

OxyContin Crush/Oral solution OxyContin Whole/Oral solution

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Physical Disruption Study Physical Disruption Study ConclusionConclusion

Physical Disruption Study Physical Disruption Study ConclusionConclusion

• The extended-release characteristics appeared to be compromised when Remoxy was subjected crushing and extraction with a solvent

• The extended-release characteristics appeared to be compromised when Remoxy was subjected crushing and extraction with a solvent

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Mastication StudyMastication Study

–Treatment A: Remoxy 40 mg capsule (whole)–Treatment B: Remoxy 40 mg capsule masticated rigorously and then swallowed–Treatment C: Oxycondone oral solution 40 mg

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Mean Oxycodone Plasma Concentration-Time Profiles

Mastication StudyMastication Study

Statistical Comparison

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120

140

0 2 4 6 8 10 12

Time (h)

Oxy

codo

ne C

onc.

(ng

/mL

)

Remoxy MasticatedOxycodone Oral SolutionRemoxy Whole

Treatment Ratio Cmax AUCRemoxy Mastication/Remoxy Whole 2.20 (1.97-2.45) 1.10 (1.02-1.18)

Remoxy Mastication/Oxycodone Oral Solution 0.74 (0.70-0.79) 1.19 (1.15-1.22)

Mean (90% CI)

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Cumulative Frequency Plots Mastication StudyMastication Study

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100

0 0.2 0.4 0.6 0.8 1 1.2 1.4Cmax Ratio

Cu

mu

lati

ve

Rel

ati

ve

Fre

qu

ency

(Mo

re T

han

)Mastication/Oral Solution

Whole/Oral Solution

Cmax Ratio Whole Mastication>0.8 2 35>0.9 1 15>1 1 10

Cumulative Relative Frequency (%)

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Mastication Study ConclusionMastication Study ConclusionMastication Study ConclusionMastication Study Conclusion

• The extended-release characteristics appeared to be compromised when Remoxy was subjected to mastication

• The extended-release characteristics appeared to be compromised when Remoxy was subjected to mastication

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Buccal Absorption StudyBuccal Absorption Study

–Treatment A: Remoxy 40 mg capsule (whole)–Treatment B: Remoxy 40 mg capsule held in the buccal cavity and then swallowed–Treatment C: Oxycodone oral solution 40 mg

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Buccal Absorption StudyBuccal Absorption StudyMean Oxycodone Plasma Concentration-Time Profiles

Statistical Comparison

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80

100

120

0 2 4 6 8 10 12

Time (h)

Ox

yco

don

e C

on

c. (

ng

/mL

).Remoxy BuccalOxycodone Oral SolutionRemoxy Whole

Treatment Ratio Cmax AUCRemoxy Buccal/Remoxy Whole 1.83 (1.66-2.01) 1.11 (1.03-1.19)

Remoxy Buccal/Oxycodone Oral Solution 0.76 (0.71-0.81) 1.24 (1.20-1.29)

Mean (90% CI)

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Cumulative Frequency Plots

Buccal Absorption StudyBuccal Absorption Study

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100

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Cmax Ratio

Cu

mu

lati

ve R

ela

tive F

req

uen

cy

(Mo

re T

han

)Buccal/Oral Solution

Whole/Oral Solution

Cmax Ratio Whole Buccal>0.8 5 43>0.9 3 22>1 0 10

Cumulative Relative Frequency (%)

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Buccal Absorption Study Buccal Absorption Study ConclusionConclusion

Buccal Absorption Study Buccal Absorption Study ConclusionConclusion

• The extended-release characteristics appeared to be compromised when Remoxy was subjected to buccal absorption

• The extended-release characteristics appeared to be compromised when Remoxy was subjected to buccal absorption

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Overall SummaryOverall Summary

•The extended-release characteristics appeared to be compromised when Remoxy was subjected to crushing and extraction with ethanol, mastication, and buccal absorption