Clinical Pharmacology 2: - PowerPoint Presentation

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Clinical Pharmacology 2: Clinical Pharmacology Considerations During Phase 2 and Phase 3 of Drug Development

Su-Young Choi, Pharm.D., Ph.DDivision of Clinical Pharmacology IVOffice of Clinical PharmacologyOffice of Translational SciencesCDER, 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.

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Objectives

Understand the role of clinical pharmacology throughout drug developmentUnderstand 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 barriersUnderstand the impact of complete and incomplete clinical pharmacology programs on information available to health care providersSlide3

Phases of Drug Development

Phase 1 Investigate the safety, tolerability, and pharmacokinetics of the drugAllow selection of an appropriate dose range for Phase 2-3Phase 2 Provide preliminary data on the safety and effectiveness of the drugAllow selection of appropriate doses for evaluation in Phase 3Phase 3 Provide pivotal information about effectiveness and safetyAllow evaluation of the overall benefit-risk relationship of the drugSlide4

Examples of Phase 1-3 Trials

Selected examples of dolutegravir Phase 1-3 trialsPhase 1 trial Effects of low, moderate, or high fat meals on the pharmacokinetics of dolutegravir in 24 healthy volunteersEffects of dolutegravir on the pharmacokinetics of ethinylestradiol in 16 healthy female volunteersPhase 2 trial278 HIV patients were randomly assigned to one of the following groupsDolutegravir 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 studyPhase 3 trial844 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.Slide5

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 trialsTypically in a sparse manner in Phase 2-3 trialsThe sample collection schedule varies depending on PK characteristics, feasibility, and specific questions that you want to address.Example Dolutegravir Phase 3 trialDosing regimen: 50 mg once daily for > 48 weeksPatients 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.Slide6

Clinical Pharmacology Evaluation during Phase 2-3 TrialsWhy 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 relationshipSlide7

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,

etcSlide8

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]Slide9

The Value of E-R Information

Help design well-controlled studies (e.g., from Phase 2 to Phase 3) and select adequate doses for approvalDoes 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 effectivenessDo 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

registrationSlide10

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 medicationsSlide11

The Value of E-R Information Support new target populations, use in subpopulations, new doses/dosing regimens, dosage forms and route of administrationSlide12

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.pdfSlide13

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.htmSlide14

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 Slide15

Example 3- Interpretation of Drug Interaction Results

Interacting drugChanges in grazoprevir AUC Ritonavir 2.0-foldKetoconazole3.0-foldDarunavir/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.pdf

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?Slide16

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. Slide17

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?)

ConcentrationSlide18

Time

ConcentrationThe exposure-response relationship analysis can answer!Slide19

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 hormoneStudy design flawsStudy conduct flawslack of validated bioanalytical assay lack of documentation (dosing times not captured, sampling times not captured)Slide20

Overcoming the BarrierGood Practice for Exposure-Response Evaluation

Identification of key questionsDetails of some analyses can be defined beforehand. Design and interpretation based on pharmacology and physiological principlesExample: 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 lifeActive metabolites in immune cells: longer half life  a better marker for the adherence

Modified from

CPT

pharmacometrics

Syst.

Pharmacol

(2015) 4, 565-575Slide21

Good Practice for Exposure-Response Evaluation

Good understanding of the assumptions and limitationsAppropriate choice of analysis methods and datasetsVarious statistical models are availableWhich clinical trial results should be/should not be used?Appropriate handling of dropouts and covariatesModified from CPT pharmacometrics Syst. Pharmacol (2015) 4, 565-575Slide22

Summary and Conclusion

Without exposure-response informationDose selection may not be optimalWe cannot interpret the significance of exposure changesResult: Lack of dosing instructions for certain groupsThey are deprived of therapyOr, they risk suboptimal safety and efficacySlide23

RIGHT

DRUG

GOAL

RIGHT

DOSE

RIGHT

TIME

RIGHT

PATIENTSlide24