衔接性试验评估与药动学之应用

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 Extrinsic factors Intrinsic factorsRaceGenderGeneticHepaticDiseaseRenalDiseaseAgeClimateMedical PracticeCultureRegulatory practiceGCP Drug-drug interactionWhich way ?ICH E5More or Less Likely AnalysisSensitivity to ethnic factors銜接性試驗評估銜接性試驗評估 Study of the rate processes th

2、at are responsible for the time course of the level of an exogenous compound in the body.PHARMACOKINETICS PHARMACOKINETICS Pharmacokinetics involves the kinetics of drug absorption, distribution, and elimination (ie, excretion and metabolism). The description of drug distribution and elimination is

3、often termed drug disposition. 探討藥物吸收、分佈、代謝、排除之動力學。探討藥物吸收、分佈、代謝、排除之動力學。 Linear dose range. How much times higher than therapeutic dose. PK parameters proportional with dose.A flat pharmacodynamic (PD) (Effect-concentration) curvew For both efficacy and safety.w In the range of the recommended dosage

4、 and dose regimen. Wide or narrow Dose regimen range Highest dose / therapeutic dose In terms of safety and tolerabilityLabeled dose, AUC, oreffective concentration (100%)Safety (Adverse Effect) CurveEfficacy Curve80%170%Response (PD)Dose, AUC, or Concentration (PK)ExposureHuang SM, Lesko, LJ, Willi

5、ams RL, J Clin Pharmacol, 39 :1006-1014, 1999Wide Therapeutic RangeLabeled dose, AUC, oreffective concentration (100%)Safety (Adverse Effect) CurveEfficacy Curve80%Response (PD)Dose, AUC, or Concentration (PK)Exposure125%Narrow Therapeutic RangeMetabolism Extensive or poor ( % of dose) How many meta

6、bolites ? (% for each Met.) Single or multiple pathway ? What kind of enzyme involved ? Genetic polymorphism enzyme ? Potential for drug-drug interactions ? Prodrug ?Inter-subject Variability High, moderate, or low ? Mean SD; CV=(SD/Mean)*100 Bioavailability Protein binding Food effectsPlasma Protei

7、n BindingMultiple co-medicationor inappropriate use Judge by the property of the drug , indications. CustomsPopulation pharmacokineticPopulation pharmacokinetic methodspopulation-based evaluation of measurements of systemic drug concentrations, usually two or more per patient under steady state cond

8、itions, from all, or a defined subset of, patients who participate in clinical trials.ASIANS DATA JAPAN data Comparison The same study design PK or Dose finding Safety or efficacy, side effects.Predictability No one property of the medicine is predictive of the compounds relative sensitivity to ethn

9、ic factors. Clinical pharmacology therapeutics; 2005:78(2)102-13 JapanUS/EUDose2.5 mg/d5 mg/dAUC0-24hr (ng.hr/mL)2.90 1.54 2.52 1.23Bone mineral densityRisedronate NaDifferences in PharmacokineticsOthers include: Alendronate NaOmeprazole + clarithromycin + amoxicillinClinical pharmacology therapeuti

10、cs; 2005:78(2)102-13 Pharmacokinetic differences w May not always create that necessity : dosage adjustments in some cases might be made without new trials. However w any substantial difference in metabolic pattern : may often indicate a need for a controlled clinical trial. Differences in adverse r

11、eactionsJapanUS/EUDose10-40 mg10-40 mgAUC and Cmax1 1.3-1.4 Dose 80 mg/day80 mg /dayNausea10.4%5.7%Somnolence16.9%6.6%Eletriptan HBrClinical pharmacology therapeutics; 2005:78(2)102-13 Different dosing recommendations Simply reflected different dose setting in the bridging study. Pramipexole dihydro

12、chloride: smaller initial dose; same maintenance dose Donepezil HCl Leucovorin Ca + tegafur/uracilClinical pharmacology therapeutics; 2005:78(2)102-13 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。 銜接性試驗銜接性試驗 (Bridging study)What type of bridging study neede

13、d ?A matter of judgment.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.Hints

14、 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.Request for Bridging study data onl

15、y 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. The ICH E5 guideline suggests that in many cases a bridging study shou

16、ld 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.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 possibil