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
• 100% pain relief in 100% of patients
• Without adverse effects
Most drugs currently available
• Multiple doses/day
• Suboptimal relief
• Dose limiting toxicities
 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
How do we generate dosing
interval instructions?

Step One
Pharmacokinetics
 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.
From Exposure/Response to Dose
Selection - PK Data
 Relationship of PK to PD
PK PD
Central Compartment Theoretical
Ka
Blood Effect Site

Ke
Keo
From Exposure/Response to Dose
Selection - PD Measurements
 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.
From Exposure/Response
to Dose Selection
 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
Duration of Action-NSAID’s
 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.
Duration of Action-Indirect Model
Predicting Duration
 Exposure/Response in Analgesia

Mechanism Onset of Duration

of Action Action
Opiates Direct YES YES

NSAID Indirect YES Model -

Dependent
 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:
 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
 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
Return to baseline pain

Flawed Metric
Pain relief
 “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

 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
 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
 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
 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
 Variability based on clinical setting

• Percent rescue
Surgery > Dental > Dysmenorrhea

• Median time to remedication

Dysmenorrhea > Dental > Surgery
 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
Metrics for Duration of
Analgesia:

Case studies
 Variability based on
population for analysis

All subjects (ITT)

Responders:
(Those with onset: Stopwatch)
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 >24

(stopwatch: perceptible)
Variability among trials
within model
 Dental Pain Studies: Summary slide
Median time to remedication (hrs)

Pbo Drug 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 ?
 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 ?
 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 >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

 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
 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 ?
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.
 Risk/Benefit
100% effective: No remedication!!!

The “IDEAL” Analgesic ???

Need to balance safety with
efficacy

How to balance competing needs in

labeling ?

Increasing dose>Increasing efficacy

Increasing dose> adverse events
Need to balance safety with
efficacy

Case study of labeling to optimize

information on risk: benefit

Tramadol
 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….”
 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”
 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

 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
 Conclusions
• 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
 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.
Extra-Strength Pain Relief
The End