The Essentials of Dosing Interval

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The Essentials of Dosing Interval

• Larry Goldkind M.D.
• Deputy Division Director, Division of
  Anti-Inflammatory, Analgesics, and Ophthalmic
  Drug Products
• Dennis Bashaw, Pharm.D.
• Team Leader, Division of Pharmaceutical
  Evaluation-III

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Acute Analgesic

• Ideal
• Once a day
• 100 pain relief in 100 of patients
• Without adverse effects
• Most drugs currently available
• Multiple doses/day
• Suboptimal relief
• Dose limiting toxicities

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Therefore..

• Majority of patients faced with questions
• 1. What to do until next dose
• 2. Do I change medication?
  
• 3. Do I redose early?
  
• 4. Do I take another drug concomitantly with
  unknown synergy and safety ?
• There is no ideal dose interval in the real
  world. The goal is to adequately characterize the
  drug effect and toxicity for prescriber and
  patient and require tolerable toxicity profile

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How do we generate dosing interval instructions?

• Step One
• Pharmacokinetics

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Role of Exposure/Response in Dose-Duration
Selection

• For single-dose analgesia studies the
  relationship between blood-level and onset of
  effect can generally be well described.

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From Exposure/Response to Dose Selection - PK Data
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Relationship of PK to PD
PK
PD
Theoretical
Central Compartment
Ka
Blood
Effect Site
Ke
Keo
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From Exposure/Response to Dose Selection - PD
Measurements
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Why is there counter-clockwise hysteresis?

• This is due to the time lag between drug entering
  the central compartment and distribution into the
  effect site.
• Formation of an active metabolite that has the
  majority of the activity.
• The observed effect is not due to direct effects
  but due to a rate-limiting transduction and
  secondary process.

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From Exposure/Response to Dose Selection
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Duration of Action

• Once a PK/PD relationship has been developed,
  ideally duration of action can be estimated by
  time above either EC50 or EC75.
• Neuromuscular Blockade-Train of 4
• pancuronium
• atracurium
• vecuronium

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Duration of Action-NSAIDs
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Duration of Action-NSAIDs

• Duration of action can be modeled using indirect
  pk/pd models that allow for down-stream activity.
• Requirements
• Understanding of the underlying physiology
• The dynamics of the response (i.e.. magnitude,
  etc.).
• A large number of both pk and pd observations,
  preferably across a number of doses.

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Duration of Action-Indirect ModelPredicting
Duration
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Exposure/Response in Analgesia
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1992 Guidance Metrics for Duration of Analgesia

• Similar to onset of analgesia, there are
  various approaches to defining the duration of
  analgesia. Examples include
• From administration of study drug or onset of
  analgesia until

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1992 Guidance Metrics for Duration of Analgesia

• - Intensity of pain returns to baseline
• - Patient indicates that analgesic effect is
  vanishing
• - Patient requests rescue time to rescue (TTR) -
  mean or median
• - Percent of patients who do not rescue during
  specific interval

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European Medicines Evaluation Agency (EMEA) Draft
Guidelines 2001

• A real effort should be made to obtain data on
  the best dose and interval regimen, time to onset
  of peak effect and duration of effect
• Endpoints referenced in the guidance
• Duration of analgesia
• Time to rescue

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Return to baseline painFlawed Metric
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Pain relief
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• Return to baseline pain
• Acute pain resolves
• in most studies no return to baseline!
• Potential bias
• repeat measurements of pain relief or pain
  intensity over time ( hourly x 6-12)
• Therefore
• Time to return of pain creates bias for longer
  dose interval
• This metric is rarely used in drug development

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How do we generate dosing interval instructions
in clinical trials?

• Dose interval ranging studies not generally done
• Metrics primarily come from single dose studies
• Qualitative data from multiple dose studies

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Metrics from single dose studies(Describe
rescue status not optimal interval)

• 1. Percent of subjects who rescue during study
  period. Results largely affected by
• Study design
• study duration
• last hourly acute pain measurement
• Study execution
• discouragement of remedication
• presence of monitor
• self dispensation of drug

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Metrics from single dose studies

• 2. Time to rescue. Varies based on
• setting (major/minor surgery, dysmenorrhea)
• time from dose or from onset of relief
• statistic used (median versus mean)
• median less susceptible to outliers
• mean shorter intervals due to very early
  
• rescues in nonresponders
  

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Analysis of data single dose studies

• Population for analysis
• All treated includes nonresponders
• - shifts towards shorter interval
• Responders
• - subjects who register
• -a time to onset of relief
  
• -perceptible, meaningful,
  adequate
• - a prespecified VAS or categorical
  
• improvement

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Variability based on clinical setting

• Percent rescue
• Surgery gt Dental gt Dysmenorrhea
• Median time to remedication
• Dysmenorrhea gt Dental gt Surgery

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Summary

• Variability based on
• Study design (period of observation)
• Study conduct (monitor behavior)
• Statistic used (mean or median TTR)
• Population analyzed ( all vs. responders)
• Definition of relief ( perceptible, meaningful,
  adequate)
• Setting (type of pain model)
• From trial to trial

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Metrics for Duration of Analgesia

• Case studies

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Variability based on population for analysis

• All subjects (ITT)
• Responders
• (Those with onset Stopwatch)

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Duration of analgesia dental study

• Median time to remedication (hrs)
• Pbo Drug X
  Drug Y
• Drug T 1/2 0hr 2 hr
  17 hr
• ITT 2.4
  6.1 9.5
• With onset 6.4 9.3
  gt24
• (stopwatch perceptible)

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Variability among trials within model
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• Dental Pain Studies Summary slide
• Median time to remedication (hrs)
• Pbo
  Drug X Drug Y
• Drug T 1/2 0 hr
  2 hr 17hr
  
• Study1 (ITT) 1.6
  4.9 7.5
• Study2 (ITT) 2.4
  6.1 9.5
• (With onset) 6.4
  9.3 gt24
• For Dental Pain Is drug X q4H, Q6H or q8H ?
• Is drug Y q8H,
  q12H or q24 H ?

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Conclusions from dental pain studies

• 1. Effect of population analysis (all treated vs.
  responders).
• 2. Limited relationship between pk and clinical
  data.
• 3. Time to rescue and rescue within an interval
  are informative but not definitive.
• 4. Would there be benefit from a formal study of
  2 dosing intervals A and B ?

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Duration of Analgesia Dysmenorrhea

• Median time to remedication (hrs)
• Pbo Drug
  Z Drug Y
• Drug T 1/2 0 hr
  12 hr 17hr
• Study 1 gt24
  gt24 gt24
• Study 2 12
  gt24 gt24
• Percent who rescue (w/i 12 hr)
• Study 1 45
  30 27
• Study 2 51
  28 20
• Dysmenorrhea not generalizable to other settings

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Duration of Analgesia Post-operative(orthopedic
first day off PCA narcotic)

• Median time to remedication (hrs)
• Pbo Drug Z
  Drug Y
• Drug T 1/2 0 hr 12 hr
  17 hr
• ITT 2.8
  5.3 5.3
• Percent rescue (96) (74)
  (67)
• in 12 hour
• For Surgical Pain Is Drug Z q4H or q6H
• Is Drug Y q4H
  or q6H

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Post-op (Orthopedic) Study

• Surgical setting different than dental or
  dysmenorrhea
• How to establish dosing interval for post-op
  pain?
• If Drugs Y and or Z cannot be safely given q6H
  should it be indicated for post-op pain ?

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Qualitative data from multidose study

• Use of supplemental/rescue medication over days
  2-5
• Patients Global evaluation
• Pain intensity scores over days 2-5
• These endpoints were not sensitive to important
  differences.

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Risk/Benefit 100 effective No remedication!!!
The IDEAL Analgesic ???
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Need to balance safety withefficacy

• How to balance competing needs in labeling ?
• Increasing dosegtIncreasing efficacy
• Increasing dosegt adverse events

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Need to balance safety withefficacy

• Case study of labeling to optimize information on
  risk benefit
• Tramadol

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• Clinical trials section
• Ultram has been given in single doses of 50,
  75, 100, 150 and 200 mg in patients with pain.
• Dosage and administration section
• For patients with moderate to moderately severe
  pain not requiring rapid onset of analgesic
  effect, the tolerability of Ultram can be
  improved with the following titration schedule.

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Balance of risk and benefit

• Dosage and administration section
• For the subset of patients for whom rapid onset
  of analgesic effect is required and for whom the
  benefits outweigh the risks of discontinuation
  due to adverse events associated with higher
  initial doses, Ultram 50-100 mg can be
  administered as needed for pain relief every four
  to six hours,
• not to exceed 400 mg per day

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Information juggling needed for optimal analgesic
management

• Starting Dose 50 -100 mg
• Interval 4-6 hours
• Titration of dose
• Maximum dose/Safety Not to exceed 400 mg/day

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Conclusions

• Duration of analgesia guided by PK
• Return to baseline pain not an adequate
  endpoint for assessment of dose interval
• Clinical setting affects apparent duration of
  analgesia and remedication use

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Conclusions

• Analysis of time to remedication
• -dependent on responder statusAll
• treated versus those registering
• meaningful analgesia/responder
• Percent who rescue
• -informative but does not define optimal
• dose interval
• Current metrics are not standardized

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Conclusions

• Additional information on dosing interval is
  needed.
• More formal study of dosing schedules may further
  characterize optimal dosing intervals..
• Different acute pain settings may need to be
  addressed in labeling.

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Extra-Strength Pain Relief
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The End