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CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT. Ramana S. Uppoor, R.Ph., Ph.D. Division of Clinical Pharmacology-1 Office of Clinical Pharmacology, CDER, FDA. ASENT meeting, March 6, 2008. Disclaimer. Views expressed are mine and do not necessarily reflect official FDA Policy.

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clinical pharmacology in drug development

CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT

Ramana S. Uppoor, R.Ph., Ph.D.

Division of Clinical Pharmacology-1

Office of Clinical Pharmacology, CDER, FDA

ASENT meeting, March 6, 2008

disclaimer
Disclaimer

Views expressed are mine and do not necessarily reflect official FDA Policy.

high attrition rate even in late development
High attrition rate even in late development

Kola I, Landis J.Can the pharmaceutical industry reduce attrition rates? Nat.Rev.Drug.Disc. Aug 2004.

need opportunities for innovative methods in drug development
Need/Opportunities for Innovative Methods in Drug Development

Decrease

avoidable

trial failures

Assess

useful

Biomarkers

e.g. imaging

Individualization

of

dosing

Evaluate

rational

trial

designs,

endpoints

Providing solutions for these issues calls

for optimal early trials and efficient use of prior knowledge

outline
OUTLINE
  • Definitions
  • Clinical Pharmacology domain
  • Clinical Pharmacology studies
  • Biopharmaceutics studies
  • Value
  • Case examples
  • Conclusions
clinical pharmacology is
Clinical Pharmacology is…

Translational science in which basic information about the relationship between dose, exposure and response (efficacy or safety) is applied in the context of patient care

Major contribution of Clinical Pharmacology: Knowledge of E-R relationship (key to successful therapeutics) and how it is altered by intrinsic (age, gender, renal function etc.) and extrinsic (diet, drugs, life-style) factors of an individual patient

definitions
Definitions
  • Clinical Pharmacology:
    • Pharmacokinetics (PK): What the body does to the drug (Absorption, Distribution, Metabolism, Excretion). For drug review purpose, PK also covers extrinsic and intrinsic factors like drug interactions, effect of age, gender, race, organ dysfunction, etc. PK gives you Exposure.
    • Pharmacodynamics (PM): What the drug does to the body. PD covers desirable and undesirable effects, from biomarkers to surrogates to clinical endpoints. PD gives you Response.
first principles why drugs work in vivo

Dose

Pharmacokinetics

Pharmacodynamics

Effect

Concentration

MEC

Free

Total

Time

FIRST PRINCIPLESWhy Drugs Work In Vivo
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
pk pd measures relationships between exposure response
PK-PD MEASURESRelationships Between Exposure & Response

Serum Drug Concentration

Emax

Peak conc. (Cmax)

Effect (e.g., Survival, % change in seizure frequency

AUC

EC50

PK-PD Measure

(e.g., AUC)

Time

clinical trials spectrum
Clinical Trials Spectrum
  • Phase I, II,III and IV clinical trials
  • Early and Late phase clinical trials
  • Learn and Confirm trials
  • Clinical Pharmacology (= Learn; phase 1 and 2) including dose response trials and Efficacy (= Confirm; phase 3) trials
  • Safety Trials: All phases
  • Bioequivalence Trials
clinical pharmacology biopharmaceutics studies
Clinical Pharmacology & Biopharmaceutics Studies

Pharmacokinetics/Biopharmaceutics:

  • Mass Balance studies with radiolabelled drug
  • Single and multiple dose pharmacokinetics
  • Absolute bioavailability
  • Dose proportionality
  • Food effects studies
  • Bioequivalence studies to establish the link between the market and clinical formulations
  • Metabolism and drug interactions
clinical pharmacology biopharmaceutics studies contd
Clinical Pharmacology & Biopharmaceutics Studies .. contd.

Clinical Pharmacology:

  • Pharmacokinetics in the target population
  • Special population studies
    • Age, Gender, Race, etc.
    • Disease states such as renal and liver impairment
  • Establishment of pharmacokinetic pharmacodynamic correlations
bioavailability and bioequivalence definitions
Bioavailability and Bioequivalence - Definitions

Bioavailabilitymeans the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

Bioequivalencemeans the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

bioavailability measurement
BIOAVAILABILITY MEASUREMENT

MONITORING PARAMETERS

  • Peak Concentration: Cmax
  • Time to Peak Concentration: Tmax
  • Area Under the Drug Concentration-Time Curve: AUC
food effect study
Food effect study

High fat meal:

  • 2 eggs fried in butter
  • 2 strips of bacon
  • 2 slices of toast with butter
  • 4 ounces of hash brown potatoes
  • 8 ounces of whole milk
  • 1000 calories, 50 % derived from fat

Evaluate the food effect by comparing the PK parameters obtained in fed vs. fasted state

bioequivalence measurement
SINGLE DOSE

AUC0-Tlast

AUC 0-Tinf

Cmax

Tmax

MULTIPLE DOSE

AUCss

Cmax

Cmin

Tmax

BIOEQUIVALENCE MEASUREMENT

PHARMACOKINETIC PARAMETERS

slide20

STATISTICAL REQUIREMENTS FOR Bioequivalence

Current Decision Rule:

  • Two one-sided test procedure:
  • (ALSO CALLED THE 90% CONFIDENCE INTERVAL APPROACH)
      • Recognizes that there will be a difference in mean values between treatments
      • Provides reasonable assurance that mean treatment differences are acceptable

General Requirement:

  • 90% confidence intervals for AUC and Cmax have to be within the range of: 80 – 125% (based on log transformed data)
common cpr encounters
Common CPR Encounters

Exposure-Response

Pater Current Controlled Trials in Cardiovascular Medicine 2004 5:7

general thoughts values
GENERAL THOUGHTS/VALUES
  • OCP:

The Right Dose of the Right Drug at the Right Time

for the Right Patient

  • Optimal bioavailability
  • Dose selection
  • Dosing regimen selection
  • Dose adjustment for special populations
  • Dose adjustment in presence of intrinsic and extrinsic factors
slide23

GOAL: To develop good drugs/drug products with adequate information to improve therapeutics (with an ultimate goal of optimal treatment for a patient)

slide24

Efficacy

Percentage of Response

Window of

Opportunity

Toxicity

Exposure

Exposure Response Relationship Selection of appropriate dose/regimen

case example 1 dosing regimen

Case example 1 – Dosing regimen

FDA’s proactive model-based analysis identified that the proposed dosing is sub-optimal. Simulations suggested alternatives. Development cycle extended.

regulatory issue
Regulatory Issue
  • Short t1/2 drug for lowering BP
  • Sustained effect desired
  • Proposed dosing - QD
  • Very large trial conducted
    • Typically pivotal trials are not large for hypertension
  • Exposure-Response analyses conducted
    • Effectiveness and Safety
  • Is this really a once-day-drug?
er analysis
Clear concentration-effect relationship

No delay between PK and PD

Nonlinear concentration-effect relationship

FDA performed the analysis during NDA review

ER Analysis

X mg daily

EC50

Cp

Time, h

  • Modeling demonstrated inadequacy of once a day regimen
value delivered by the exposure response analysis
Value Delivered by the Exposure Response Analysis
  • Supported evidence for effectiveness
  • Aided in judging that QD dosing is sub-optimal
  • Provided alternatives for future development
  • Prospective modeling of early PK/PD data could have (and an EOP2A meeting)
    • Avoided lengthening drug development time
    • Been more economical
case example 2 use of exposure response for pediatric approval

Case example 2 - Use of exposure response for pediatric approval

FDA’s proactive model-based analysis alleviated the need to conduct additional clinical trial for the approval of Trileptal monotherapy in pediatrics

regulatory issue1
Regulatory Issue

FDA/Sponsor pursued approaches to best utilize knowledge from the positive trials to assess if monotherapy in pediatrics can be approved without new controlled trials

motivation
Motivation
  • Monotherapy of anticonvulsants is important
    • Better safety, Ease of Rx mgmt
    • Avoid unnecessary costs
  • Monotherapy trials are challenging
  • Reasonable ER knowledge available
    • Integration of knowledge across trials and populations is needed
  • Law supports model based thinking
value of this type of analysis
Value of this type of analysis
  • Modeling and simulation aided in utilizing all previous data to justify approval without additional controlled clinical trials
  • Allowed selection of dosing guidelines in pediatrics
  • The presented approach has a greater global impact
    • Precedent was set
conclusions
Conclusions
  • PK and Exposure-Response analysis can help select suitable dose/dosing regimen and identify optimal drug products.
  • PK from early trials will help optimize the dosing conditions for pivotal trials.
  • Facilitate dosing in special populations and also provide dose adjustment guidelines in the presence of intrinsic (age, gender, renal function etc.) or extrinsic factors (concomitant drugs, food etc.).
conclusions contd
Conclusions …. contd.
  • Facilitate findings of effectiveness as well as help resolve safety concerns.
  • E-R frame created in the approved setting can be a powerful source for approval consideration for additional settings (e.g. pediatrics).
need opportunities for innovative methods in drug development1
Need/Opportunities for Innovative Methods in Drug Development

Decrease

avoidable

trial failures

Assess

useful

Biomarkers

e.g. imaging

Individualization

of

dosing

Evaluate

rational

trial

designs,

endpoints

Providing solutions for these issues calls

for optimal early trials and efficient use of prior knowledge

slide37

ACKNOWLEDGEMENTS

Dr. Mehul Mehta

Dr. Patrick Marroum

Dr. Robert Kumi

That’s all folks!