Clinical pharmacology 2

1. Clinical Pharmacology 2:
Clinical Pharmacology Considerations
During Phase 2 and Phase 3 of Drug
Development
Su-Young Choi, Pharm.D., Ph.D
Division of Clinical Pharmacology IV
Office of Clinical Pharmacology
Office of Translational Sciences
CDER, FDA
The views expressed in this presentation are that of the author and do not reflect the official
policy of the FDA. No official endorsement by the FDA is intended nor should be inferred.

2. 2
Objectives
• Understand the role of clinical pharmacology throughout
drug development
• Understand the importance of analysis of exposure-
response (E-R) relationship
• Describe the utility of E-R analysis throughout clinical
development
• Understand barriers to informative E-R evaluation and
key steps to the overcome the barriers
• Understand the impact of complete and incomplete
clinical pharmacology programs on information available
to health care providers

3. 3
Phases of Drug Development
• Phase 1
– Investigate the safety, tolerability, and pharmacokinetics of the
drug
– Allow selection of an appropriate dose range for Phase 2-3
• Phase 2
– Provide preliminary data on the safety and effectiveness of the
drug
– Allow selection of appropriate doses for evaluation in Phase 3
• Phase 3
– Provide pivotal information about effectiveness and safety
– Allow evaluation of the overall benefit-risk relationship of the drug

4. 4
Examples of Phase 1-3 Trials
• Selected examples of dolutegravir Phase 1-3 trials
• Phase 1 trial
– Effects of low, moderate, or high fat meals on the
pharmacokinetics of dolutegravir in 24 healthy volunteers
– Effects of dolutegravir on the pharmacokinetics of ethinylestradiol
in 16 healthy female volunteers
• Phase 2 trial
– 278 HIV patients were randomly assigned to one of the following
groups
• Dolutegravir 10 mg, 25 mg, 50 mg or standard of care (active control)
• Based on the safety and efficacy data collected in this trial, 50 mg was
selected for the Phase 3 study
• Phase 3 trial
– 844 HIV patients were randomly assigned to dolutegravir 50 mg or
standard of care (active control)
Ann Pharmacother. 2015 Jul;49(7):784-9.
Lancet Infect Dis. 2012 Feb;12(2):111-8.
N Engl J Med 2013; 369:1807-1818
Antimicrob Agents Chemother. 2012 Mar; 56(3): 1627–1629.

5. 5
Pharmacokinetic Assessments during
Phase 2-3 Trials
• While the primary goal of Phase 2-3 trials is to determine the
safety and efficacy of a drug, blood (or target tissue) samples
can be collected to determine the concentrations of the drug
in Phase 2-3 trials
– Typically in a sparse manner in Phase 2-3 trials
– The sample collection schedule varies depending on PK
characteristics, feasibility, and specific questions that you want to
address.
– Example
• Dolutegravir Phase 3 trial
• Dosing regimen: 50 mg once daily for > 48 weeks
• Patients provided blood samples for pharmacokinetic analysis at the 4th,
24th, and 48th week of the treatment (at pre-dose or 1-3 hour post dose).
Br J Clin Pharmacol. 2015 Sep;80(3):502-14.

6. 6
Clinical Pharmacology Evaluation during
Phase 2-3 Trials
• Why do we collect drug concentration data
during Phase 2-3 trials?
– i.e. what valuable information can we obtain,
especially information that cannot be obtained from
healthy volunteers
“To link exposure (drug concentration) to safety
and efficacy data”
 Exposure-response relationship

7. 7
Exposure-Response Relationship
Drug concentration
Response
Efficacy
Toxicity
B C
A
Which is the optimal “target” concentration?
A vs. B
A vs. C
Cmin, Cmax, AUC, Css, Log
transformed concentrations,
etc

8. 8
Examples of Exposure-Response Relationships
Diastolic
blood
pressure
Probability
of
AST/ALT
elevation
Journal of Clinical Pharmacology, 2008;48:823-836, The AAPS Journal 2004; 6 (4) Article 28, http://regist2.virology-
education.com/2013/8hepcam/docs/12_Caro.pdf, Clin Pharmacokinet. 2016 May 18. [Epub ahead of print]

9. 9
The Value of E-R Information
• Help design well-controlled studies (e.g., from Phase 2
to Phase 3) and select adequate doses for approval
– Does treatment effect/adverse event increase with
dose/exposures?
– A dose may be selected for Phase 3 or approval even if it was
not evaluated in previous trials.
• Contribute to substantial evidence of effectiveness
– Do data indicate a treatment effect?
– It may support approval when there are not two adequate
and well controlled studies.
ICH E4 dose-response information to support drug registration

10. 10
The Value of E-R Information
• Allow a better understanding of the clinical trial data
– What is the minimal effective concentration?
– What is the therapeutic window?
– Why do certain groups of people have lower efficacy or increased
adverse events?
• Is it due to exposure differences?
– Adherence
– Patient factors (race/ethnicity, sex, hepatic/renal
impairment)
– Concomitant medications

11. 11
The Value of E-R Information
• Support new target populations, use in
subpopulations, new doses/dosing regimens, dosage
forms and route of administration

12. 12
Example 1 – Dose selection for Phase 3
Dolutegravir --Integrase strand transfer inhibitor (INSTI) indicated
for the treatment of HIV-1 infection
Patients Treatment-naïve INSTI-resistance
Issue No resistance Possible resistance to the study drug  May
require higher exposures
Phase 2 10, 25, and 50 mg QD 50 mg QD or BID
Phase 3 50 mg QD 50 mg BID
Treatment-naive INSTI-resistance
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790Orig1s000ClinPharmR.pdf

13. 13
Example 2 –Different Doses in Women
• Zolpidem: approved for the treatment of insomnia
• Zolpidem blood levels above 50 ng/mL  impairs driving to a
degree that increases the risk of a motor vehicle accident
• Women appear to be more susceptible to this risk
– It is because they eliminate zolpidem from their bodies more
slowly than men.
• After administering 10 mg zolpidem, about 15% of women and 3%
of men had zolpidem concentrations that exceeded 50 ng/mL
approximately 8 hours post-dosing.
– 15% women who take zolpidem at midnight may have impaired
driving during their morning commute!
http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm

14. 14
Example 2 –Different Doses in Women
• Current dosing recommendations for zoplidem
(immediate release)
– The recommended initial dose is 5 mg for women and either
5 or 10 mg for men, taken only once per night immediately
before bedtime with at least 7-8 hours remaining before the
planned time of awakening.
http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm
Higher exposure (concentration) in women  more adverse events
(response) in women  lower doses used in women

15. 15
Example 3- Interpretation of Drug Interaction
Results
Interacting drug Changes in grazoprevir
AUC
Ritonavir 2.0-fold
Ketoconazole 3.0-fold
Darunavir/ritonavir 7.5-fold
Lopinavir/ritonavir 12.9-fold
Cyclosporine 15.2-fold
The use of these drugs with
grazoprevir is contraindicated
based on the exposure-
response relationship for safety
(ALT elevation) of grazoprevir
ZEPATIER™ USPI
http://regist2.virology-education.com/2013/8hepcam/docs/12_Caro.pdf
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208261Orig1s000ClinPharmR.pd
• Grazoprevir is approved for the treatment of chronic hepatitis C infection
• The drug is associated with ALT elevation
• The concentrations of grazoprevir are increased when it is co-administered
with various drugs as follows. Which ones can be used with grazoprevir and
which ones should not be?

16. 16
Example 4 – To Support the Approval of New
Formulations and New Dosing Regimens
• A tablet formulation of drug X was evaluated in Phase 1-3
trials and approved. The current dosing regimen is 300 mg
twice daily.
• After the approval, the company decided to develop a
solution formulation for patients who cannot swallow
tablets.
• After the approval, the company wanted to change the
dosing regimen to 600 mg once daily to improve
adherence.

17. 17
Time
The new formulation (solution)
↑ Cmax, ↓ Cmin, ↔ AUC (area under the curve)
Question: Do you expect changes in efficacy/safety of drug
X? (i.e. are PK differences clinically relevant?)
Concentration

18. 18
Time
Concentration
The exposure-response relationship analysis can answer!

19. 19
Barriers to Informative Exposure-Response
Evaluation
• Data not collected or collected too late
– “…the general belief that the company conducted its
pharmacokinetic/pharmacodynamic study too late in the game, leading to
less than adequate dosing being brought forward in Phase III and for
approval” – Pinksheet (9/16/2014) summarizing advisory committee meeting
for parathyroid hormone
• Study design flaws
• Study conduct flaws
– lack of validated bioanalytical assay
– lack of documentation (dosing times not captured, sampling times not
captured)

20. 20
Overcoming the Barrier
Good Practice for Exposure-Response Evaluation
– Identification of key questions
• Details of some analyses can be defined beforehand.
– Design and interpretation based on pharmacology and
physiological principles
• Example: tenofovir for the prevention of HIV transmission
– Adherence to the therapy is the key for the efficacy (prevention)
– Plasma concentration of tenofovir or emtricitabine: short half life
– Active metabolites in immune cells: longer half life  a better
marker for the adherence
Modified from CPT pharmacometrics Syst. Pharmacol (2015) 4, 565-575

21. 21
Good Practice for Exposure-Response Evaluation
– Good understanding of the assumptions and limitations
– Appropriate choice of analysis methods and datasets
• Various statistical models are available
• Which clinical trial results should be/should not be used?
– Appropriate handling of dropouts and covariates
Modified from CPT pharmacometrics Syst. Pharmacol (2015) 4, 565-575

22. 22
Summary and Conclusion
• Without exposure-response information
– Dose selection may not be optimal
– We cannot interpret the significance of exposure changes
• Result: Lack of dosing instructions for certain groups
– They are deprived of therapy
– Or, they risk suboptimal safety and efficacy

23. 23
RIGHT
DRUG
GOAL
RIGHT
DOSE
RIGHT
TIME
RIGHT
PATIENT