1. 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

2. 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

3. 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

4. How do we generate dosing interval instructions? Step One Pharmacokinetics

5. 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.

6. From Exposure/Response to Dose Selection - PK Data

7. Relationship of PK to PD BloodEffect Site Central Compartment Theoretical Keo Ka Ke PK PD

8. From Exposure/Response to Dose Selection - PD Measurements

9. 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.

10. From Exposure/Response to Dose Selection

11. 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

12. Duration of Action-NSAID’s

13. 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.

14. Duration of Action-Indirect Model Predicting Duration

15. Exposure/Response in Analgesia

16. 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:

17. 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

18. 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

19. Return to baseline pain Flawed Metric

20. Pain relief

21. “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

22. 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

23. 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

24. 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

25. 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

26. Variability based on clinical setting Percent rescue Surgery > Dental > Dysmenorrhea Median time to remedication Dysmenorrhea > Dental > Surgery

27. 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

28. Metrics for Duration of Analgesia: Case studies

29. Variability based on population for analysis All subjects (ITT) Responders: (Those with onset: Stopwatch)

30. 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)

31. Variability among trials within model

32. 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 ?

33. 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 ?

34. 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

35. 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

36. 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 ?

37. 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.

38. Risk/Benefit 100% effective: No remedication!!! The “IDEAL” Analgesic ???

39. Need to balance safety with efficacy How to balance competing needs in labeling ? Increasing dose>Increasing efficacy Increasing dose> adverse events

40. Need to balance safety with efficacy Case study of labeling to optimize information on risk: benefit Tramadol

41. 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….”

42. 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”

43. 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

44. 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

45. 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

46. 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.

47. Extra-Strength Pain Relief

48. The End