1 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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3 Extrinsic factors Intrinsic factors Race Gender Genetic Hepatic Disease Renal Disease Age ClimateMedical Practice CultureRegulatory practice GCP Drug-drug interaction

4 Which way ?

5 ICH E5 More or Less Likely Analysis Sensitivity to ethnic factors 銜接性試驗評估

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8 Study of the rate processes that are responsible for the time course of the level of an exogenous compound in the body. PHARMACOKINETICS

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11 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。

12 Linear Pharmacokinetics Linear dose range. How much times higher than therapeutic dose. PK parameters proportional with dose.

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14 A flat pharmacodynamic (PD) (Effect-concentration) curve  For both efficacy and safety.  In the range of the recommended dosage and dose regimen.

15 Therapeutic dose range Wide or narrow Dose regimen range Highest dose / therapeutic dose In terms of safety and tolerability

16 Huang SM, Lesko, LJ, Williams RL, J Clin Pharmacol, 39 : , 1999 Wide Therapeutic Range

17 Narrow Therapeutic Range

18 Metabolism 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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20 Inter-subject Variability High, moderate, or low ? Mean  SD; CV=(SD/Mean)*100 Bioavailability Protein binding Food effects

21 Plasma Protein Binding

22 Multiple co-medication or inappropriate use Judge by the property of the drug, indications. Customs

23 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.

24 ASIANS DATA JAPAN data Comparison The same study design PK or Dose finding Safety or efficacy, side effects.

25 Predictability No one property of the medicine is predictive of the compound ’ s relative sensitivity to ethnic factors.

26 Clinical pharmacology therapeutics; 2005:78(2)102-13

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31 JapanUS/EU Dose2.5 mg/d5 mg/d AUC 0-24hr (ng.hr/mL) 2.90   1.23 Bone mineral density √√ Risedronate Na Differences in Pharmacokinetics Others include: Alendronate Na Omeprazole + clarithromycin + amoxicillin Clinical pharmacology therapeutics; 2005:78(2)102-13

32 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.

33 Differences in adverse reactions JapanUS/EU Dose10-40 mg AUC and Cmax Dose 80 mg/day Nausea10.4%5.7% Somnolence16.9%6.6% Eletriptan HBr Clinical pharmacology therapeutics; 2005:78(2)102-13

34 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

35 「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。 銜接性試驗 (Bridging study)

36 What type of bridging study needed ? A matter of judgment.

37 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.

38 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.

39 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.

40 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.

41 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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