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. Acute Analgesic. Ideal Once a day

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The essentials of dosing interval l.jpg
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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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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Relationship of PK to PD

PK

PD

Theoretical

Central Compartment

Ka

Blood

Effect Site

Ke

Keo



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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-NSAID’s

  • 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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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 effectand duration of effect”

Endpoints referenced in the guidance:

  • Duration of analgesia

  • Time to rescue




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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 trials?(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 trials?

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 trials?

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 trials?

  • Percent rescue

    Surgery > Dental > Dysmenorrhea

  • Median time to remedication

    Dysmenorrhea > Dental > Surgery


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Summary trials?

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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Variability based on population for analysis trials?

All subjects (ITT)

Responders:

(Those with onset: Stopwatch)


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Duration of analgesia: dental study trials?

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 >24

(stopwatch: perceptible)



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Dental Pain Studies: Summary slide trials?

Median time to remedication (hrs)

PboDrug X Drug Y

Drug T 1/2 0 hr 2 hr 17hr

Study#1 (ITT) 1.6 4.9 7.5

Study#2 (ITT) 2.4 6.1 9.5

(With onset) 6.4 9.3 >24

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 trials?

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 trials?

Median time to remedication (hrs)

Pbo Drug Z Drug Y

Drug T 1/2 0 hr 12 hr 17hr

Study #1 >24 >24 >24

Study #2 12 >24 >24

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 trials?(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 trials?

  • 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 trials?

  • 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 trials?100% effective: No remedication!!!

The “IDEAL” Analgesic ???


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Need to balance safety with trials?efficacy

How to balance competing needs in labeling ?

Increasing dose>Increasing efficacy

Increasing dose> adverse events


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Need to balance safety with trials?efficacy

Case study of labeling to optimize information on risk: benefit

Tramadol


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Clinical trials section trials?

  • “ 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 trials?

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 trials?

  • 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 trials?

  • 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 trials?

  • Analysis of time to remedication:

    -dependent on responder status:All

    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 trials?

  • 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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The End trials?