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Simultaneous/Worldwide Development Strategies : New Challenges New Approaches of Dose Range Finding Prof. Yusuke Tanigawara Keio University Hospital Tokyo,

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Presentation on theme: "Simultaneous/Worldwide Development Strategies : New Challenges New Approaches of Dose Range Finding Prof. Yusuke Tanigawara Keio University Hospital Tokyo,"— Presentation transcript:

1 Simultaneous/Worldwide Development Strategies : New Challenges New Approaches of Dose Range Finding Prof. Yusuke Tanigawara Keio University Hospital Tokyo, Japan 3rd Kitasato Harvard Symposium 2 October 2002

2 Y.Tanigawara 2002 2 Drug Action E=f(C(t), S) > E=f(Dose, S)

3 Response Concentration (Exposure) PD data Time Concentration Dose PK data Efficacy Toxicity Response Plasma Concen- tration Site of action Dose & Dosage Regimen Pharmacokinetics (PK) Pharmacodynamics (PD) ©Y.Tanigawara

4 Y.Tanigawara 2002 4  Human PK/PD, especially in patients, are important drug information.  PK/PD provide a scientific framework for dose/dosage regimen vs concentrations vs response relationships.  Factors affecting PK/PD are considered when dose is individualized for special populations such as geriatrics and organ dysfunction.  PK/PD can be a “bridging” tool for introducing to new indications, new dosage forms, or new populations. Why PK/PD are needed.

5 Development Phases and Types of Study (ICH E8) IIIIIIVI Phases of Development Therapeutic Use Therapeutic Confirmatory Therapeutic Exploratory Human Pharmacology PK or PK/PD study in Patients

6 Y.Tanigawara 2002 6 Factors That Can Cause the Individual Variability in Drug Response Age Gender Combination drugs Liver function Kidney function Genotype Body weight Possible Factors ↓ Fixed effects Influence by unknown factors ↓ Random effects Population PK/PD Analysis by Mixed Effect Model Plasma proteins Race etc.

7 Y.Tanigawara 2002 7 Population Pharmacokinetics (PK) and Pharmacodynamics (PD) describe typical profiles of PK/PD in a target population (patients that a drug is applied). describe magnitudes of inter- and intra-individual variability. describe factors that can affect the PK/PD of a drug (genetic, physiological, pathological, environmental). provide dosing guidance for special populations such as geriatrics, pediatrics, organ dysfunction, drug interactions, genetic deficiency of a particular enzyme... etc. provide a scientific basis for individualization of dosage regimen. can be studied based upon sparsely sampled data. → Feasible method to obtain patient data.

8 Y.Tanigawara 2002 8 Full Screen Time Multiple Trough Screen Time Single Trough Screen Plasma Concentration Time Drug Concentration Monitoring in Patients: Sparse Sampling by Pharmacokinetic Screen Once per individual Multiple trough measurement Varying the sampling timing Easy & Less cost More informative Feasibility and Outcome

9 Blood sampling schedule conducted in the clinical trials of Gemcitabine (in U.S. and Japan) 0 2 4 6 8 10 12 14 16 18 Plasma concentration (  g/ml) day 1day 8day 15 ● ● ● Ph 1: Standard PK sampling Ph 2b: Pop PK sampling During infusion ( 3 ~ 15 min ) 3 ~ 45 min post infusion 45 ~ 90 min post infusion Simulated curve by the Bayesian method

10 Population Pharmacokinetics and Bayesian Estimation Method Population Information Individual Feedback

11 Y.Tanigawara 2002 11 PK/PD Relationship of Antibacterial Agents 0481216 Time (hr) Plasma Concentration AUC Time above MIC MIC Peak Trough AUC / MIC Efficacy of Aminoglycosides Safety of Aminoglycosides Efficacy of New Quinolones Efficacy of  -lactam, macrolides, glycopeptides

12 Y.Tanigawara 2002 12 A. Forrest et al. J. Antimicrob. Chemother. 1997. % Probability of Clinical Cure 110 50 60 70 80 90 100 10 100 1000 10000 AUC / MIC PK/PD Relationship of Grepafloxacin for Clinical Cure

13 Y.Tanigawara 2002 13 Bridging Study - ICH E5 - A supplemental study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data package to the new region. Such studies could include further pharmacokinetic information. Definition of not only PK but also PD and dose- response early in the development program may facilitate the determination of the need for, and nature of, any requisite bridging data.

14 Y.Tanigawara 2002 14 Complete Clinical Data Package with Bridging: Typical Framework PK/PD Bridging Data Package New RegionOriginal Region Counterparts for the Bridging Study Bridging Study Confirmatory Studies Long-term Studies Special Populations Extrapolation of the foreign clinical data

15 First Successful Example: Docetaxel 60 mg/m 2 100 mg/m 2 Clinical Data PK/PD Efficacy/Safety Profiles Population PK/PD ©Y.Tanigawara

16 Y.Tanigawara 2002 16 Interpretation of PK Data (1)  Clinical PK data in Japanese are essential for the complete clinical data package.  If there is a difference…  Conduct a population PK analysis to gain an insight into the observed ethnic difference.  It might be caused due to different body sizes between Japanese and Caucasian.  It might be caused by different enzymatic activity.  It might be a consequence of different food conditions (low fat, high fat, fasted, non-fasted).  Explainable … ?

17 Y.Tanigawara 2002 17 Use of Population PK to determine factors affecting PK Tatami et al. ISSX, JSSX 2001. Apparent difference between Japanese and Caucasian resulted from the different food condition. Plasma concentration (ng/mL) Japan (Fed) US+EU (Fasted) Difference between Trials Time (hr) 06121824 0 20 40 60 Effect of Food Time (hr) 06121824 Plasma concentration (ng/mL) 0 20 40 60 80 100 Fasted condition Fed condition

18 Y.Tanigawara 2002 18 Interpretation of PK Data (2)  Clinical PK data in Japanese are essential for the complete clinical data package.  If there is a PK difference…  How much PK difference impacts on clinical efficacy and safety. Need to modify dose?  Require a PK/PD or dose-response relationship to consider the influence of PK difference.  Secondary use of a BE criteria when PK/PD data are absent.

19 Y.Tanigawara 2002 19 Steep PD is Sensitive to PK Difference. Response Exposure (PK) 30% 3% 30%

20 Y.Tanigawara 2002 20 Pharmacogenomics Genetic polymorphisms of drug metabolizing enzymes Influences of genotype are attributed to individual variability, rather than racial difference. Altered PK Altered PD Altered Efficacy/Safety profiles

21 Y.Tanigawara 2002 21 Extensive Metabolizer (EM) Difference in Plasma Concentrations of Omeprazole between CYP2C19 Extensive and Poor Metabolizers Caucasian2 ~ 3% Japanese 20% Frequency of PM 1500 024681012 Plasma concentration (ng/ml) 1000 500 0 Time after Dose (hr) Poor Metabolizer (PM) Kita et al., Pharm Res 18: 615, 2001

22 24-hour Intragastric pH Profile Following Morning and Evening Dose of Omeprazole(OPZ) CYP2C19 EM 7 1 2 3 4 5 6 OPZ CYP2C19 PM 7 1 2 3 4 5 6 Time9:0015:0021:003:009:00 OPZ Kita et al., Pharm Res 18: 615, 2001 OPZ (20mg twice a day) Basal Meal intake Intragastric pH Time9:0015:0021:003:009:00

23 (Tanigawara et al., Clin. Pharmacol. Ther. 66,1999) H. pylori Eradication rate (%) Regimen CYP2C19*1/*1 Metronidazole + AMPC + Bismuth + H2 antagonists 88% (7/8) 83% (5/6) 80% (4/5) 84% (16/19) 100% (1/1) 80% (4/5) 83% (5/6) 84% (21/25) EM PM Total CYP2C19*1/*2 CYP2C19*1/*3 CYP2C19*2/*2 CYP2C19*2/*3 CYP2C19*3/*3 Omeprazole 40% (4/10) 44% (4/9) 33% (1/3) 41% (9/22) + AMPC 100% (2/2) 100% (4/4) 50% (13/26) CYP2C19 genotype-related efficacy of omeprazole for the eradication of Helicobacter pylori Omeprazole + CAM 75% (15/20) 90% (19/21) 80% (4/5) 83% (38/46) + AMPC 100% (5/5) 100% (1/1) 100% (11/11) 86% (49/57)

24 Y.Tanigawara 2002 24 Summary  PK/PD provides a scientific basis for dose range finding.  Population PK/PD analysis coupled with the sparse blood sampling is an important strategy for drug development.  Pharmacogenomics will be a useful approach for targeting patient population.


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