Transcript 銜接性試驗評估與藥動學之應用講義下載

銜接性試驗評估與藥動學之應用
鮑力恒
國防醫學院藥學系
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Climate
Culture
GCP
Medical Practice
Regulatory practice
Drug-drug interaction
Extrinsic factors
Intrinsic factors
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Which way ?
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銜接性試驗評估
ICH E5
More or Less Likely Analysis
Sensitivity to ethnic factors
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PHARMACOKINETICS
• Study of the rate processes that are
responsible for the time course of the
level of an exogenous compound in
the body.
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PHARMACOKINETICS
• Pharmacokinetics involves the kinetics of drug
absorption, distribution, and elimination (ie,
excretion and metabolism). The description of
drug distribution and elimination is often termed
drug disposition.
• 探討藥物吸收、分佈、代謝、排除之動力學。
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Linear Pharmacokinetics
• Linear dose range.
• How much times higher than therapeutic
dose.
• PK parameters proportional with dose.
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A flat pharmacodynamic (PD)
(Effect-concentration) curve
 For both efficacy and safety.
 In the range of the recommended
dosage and dose regimen.
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Therapeutic dose range
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Wide or narrow
Dose regimen range
Highest dose / therapeutic dose
In terms of safety and tolerability
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Labeled dose, AUC, or
effective concentration (100%)
80%
170%
Response (PD)
Efficacy Curve
Wide Therapeutic Range
Safety (Adverse Effect) Curve
Dose, AUC, or Concentration (PK)
[Exposure]
Huang SM, Lesko, LJ, Williams RL, J Clin Pharmacol, 39 :1006-1014, 1999
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Labeled dose, AUC, or
effective concentration (100%)
80%
125%
Response (PD)
Efficacy Curve
Narrow Therapeutic Range
Safety (Adverse Effect) Curve
Dose, AUC, or Concentration (PK)
[Exposure]
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Metabolism
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Extensive or poor ( % of dose)
How many metabolites ? (% for each Met.)
Single or multiple pathway ?
What kind of enzyme involved ?
Genetic polymorphism enzyme ?
Potential for drug-drug interactions ?
Prodrug ?
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Inter-subject Variability
• High, moderate, or low ?
• Mean  SD;
CV=(SD/Mean)*100
• Bioavailability
• Protein binding
• Food effects
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Plasma Protein Binding
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Multiple co-medication
or inappropriate use
Judge by the
• property of the drug ,
• indications.
• Customs
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Population pharmacokinetic
Population pharmacokinetic methods
– population-based evaluation of measurements
of systemic drug concentrations,
– usually two or more per patient under steady
state conditions, from all, or a defined subset
of, patients who participate in clinical trials.
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ASIANS DATA
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JAPAN data
Comparison
The same study design
PK or Dose finding
Safety or efficacy, side effects.
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Predictability
• No one property of the medicine is
predictive of the compound’s
relative sensitivity to ethnic factors.
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Clinical pharmacology therapeutics; 2005:78(2)102-13
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Differences in Pharmacokinetics
Risedronate Na
Japan
US/EU
Dose
2.5 mg/d
5 mg/d
AUC0-24hr (ng.hr/mL)
2.90  1.54
2.52  1.23
Bone mineral density
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Others include:
Alendronate Na
Omeprazole + clarithromycin + amoxicillin
Clinical pharmacology therapeutics; 2005:78(2)102-13
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Pharmacokinetic differences
 May not always create that necessity :
– dosage adjustments in some cases might be made
without new trials.
However
 any substantial difference in metabolic pattern :
– may often indicate a need for a controlled clinical trial.
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Differences in adverse reactions
Eletriptan HBr
Japan
US/EU
Dose
10-40 mg
10-40 mg
AUC and Cmax
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1.3-1.4
Dose
80 mg/day
80 mg /day
Nausea
10.4%
5.7%
Somnolence
16.9%
6.6%
Clinical pharmacology therapeutics; 2005:78(2)102-13
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Different dosing recommendations
• Simply reflected different dose setting in the
bridging study.
– Pramipexole dihydrochloride:
smaller initial dose; same maintenance dose
– Donepezil HCl
– Leucovorin Ca + tegafur/uracil
Clinical pharmacology therapeutics; 2005:78(2)102-13
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銜接性試驗 (Bridging study)
•「銜接性試驗」為可提供與國人相關之
• 藥動\藥效學或
• 療效、安全、用法用量等臨床試驗數據，
• 使國外臨床試驗數據能外推至本國相關
族群之試驗，
• 減少臨床試驗重複執行，以避免研
發資源之浪費。
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What type of bridging study needed ?
A matter of judgment.
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The Facts
• There are no predefined statistical criteria for
a bridging study for evaluating similarity in 2
populations.
• Criteria for a successful bridging strategy
should be set on a case by-case basis through
a consultation with the regulatory authority in
a new region.
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Hints
• According to ICH E5,
– locally relevant PK data are an expected part of a
complete clinical data package
• Locally relevant PK data are also needed
– to evaluate the similarity of PK profiles in the 2
regions and
– to help determine the appropriate dose in the
new region.
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Request for Bridging study data
only those additional data necessary
to assess the ability to extrapolate
foreign data from the complete clinical
data package to the new region.
In most cases, a single trial that successfully
provides these data in the new region.
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• The ICH E5 guideline suggests that in many
cases
– a bridging study should be a dose-response study
• not only confirms the drug effects in a new population
• but also gives information allowing dose determination
in a new population.
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Pharmacokinetic applications
• PK measurement in the new population is very
important for a successful bridging strategy
– to plan a bridging study and
– to evaluate the appropriateness of an optimal dose in a
new region.
• If differences in PK properties are observed between
populations, the possibility that these significantly
affect efficacy and safety of the drugs needs to be
considered.
• Furthermore, examining the relationships of PK
responses to clinical effects can contribute to the data
evaluation.
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Remark
• Summary
• Cite References
• Support articles or data
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