Prof. Yusuke Tanigawara Keio University Hospital Tokyo, Japan “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 3rd Kitasato Harvard Symposium 2 October 2002 Simultaneous/Worldwide Development Strategies : New Challenges New Approaches of Dose Range Finding Prof. Yusuke Tanigawara Keio University Hospital Tokyo, Japan

E=f(C(t), S) Drug Action > E=f(Dose, S) “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Drug Action E=f(C(t), S) > E=f(Dose, S)

Pharmacokinetics (PK) Pharmacodynamics (PD) Dose PK data PD data “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University Pharmacokinetics (PK) 3rd Kitasato Harvard Symposium 2002/10/2 Pharmacodynamics (PD) Dose & Dosage Regimen Plasma Concen- tration Site of action Response Time Concentration Dose PK data Response Concentration (Exposure) PD data Efficacy Toxicity ©Y.Tanigawara

“New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Why PK/PD are needed. 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.

Development Phases and Types of Study (ICH E8) “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Development Phases and Types of Study (ICH E8) Therapeutic Use Therapeutic Confirmatory PK or PK/PD study in Patients Therapeutic Exploratory Human Pharmacology II III IV I Phases of Development

Factors That Can Cause the Individual Variability in Drug Response “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Factors That Can Cause the Individual Variability in Drug Response Age Gender Influence by unknown factors ↓ Random effects Body weight Possible Factors ↓ Fixed effects Liver function Kidney function Genotype Population PK/PD Analysis by Mixed Effect Model Combination drugs Plasma proteins Race etc.

Population Pharmacokinetics (PK) and Pharmacodynamics (PD) “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 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.

Feasibility and Outcome “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Drug Concentration Monitoring in Patients: Sparse Sampling by Pharmacokinetic Screen Single Trough Screen Plasma Concentration Time Multiple Trough Screen Time Full Screen Time Varying the sampling timing Once per individual Multiple trough measurement Easy & Less cost More informative Feasibility and Outcome

Ph 1: Standard PK sampling Blood sampling schedule conducted in the clinical trials of Gemcitabine (in U.S. and Japan) “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 2 4 6 8 10 12 14 1 3 Time after starting infusion (hr) Plasma concentration (mg/ml) 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 18 16 14 ● ● 12 10 Plasma concentration (mg/ml) 8 Simulated curve by the Bayesian method 6 4 ● 2 day 1 day 8 day 15

Population Pharmacokinetics and Bayesian Estimation Method “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Population Pharmacokinetics and Bayesian Estimation Method Population Information Individual Feedback

PK/PD Relationship of Antibacterial Agents “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 PK/PD Relationship of Antibacterial Agents Efficacy of Aminoglycosides Peak AUC / MIC Efficacy of New Quinolones Plasma Concentration AUC Trough MIC Time above MIC Safety of Aminoglycosides 4 8 12 16 Time (hr) Efficacy of b-lactam, macrolides, glycopeptides 20

PK/PD Relationship of Grepafloxacin for Clinical Cure “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University PK/PD Relationship of Grepafloxacin for Clinical Cure 3rd Kitasato Harvard Symposium 2002/10/2 110 50 60 70 80 90 100 10 1000 10000 % Probability of Clinical Cure AUC / MIC A. Forrest et al. J. Antimicrob. Chemother. 1997.

“New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 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.

Complete Clinical Data Package with Bridging: Typical Framework “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Complete Clinical Data Package with Bridging: Typical Framework Bridging Data Package New Region Original Region PK/PD Counterparts for the Bridging Study Bridging Study Confirmatory Studies Long-term Studies Special Populations Extrapolation of the foreign clinical data

First Successful Example: Docetaxel Efficacy/Safety Profiles “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 First Successful Example: Docetaxel 60 mg/m2 100 mg/m2 Clinical Data Population PK/PD Population PK/PD PK/PD Efficacy/Safety Profiles ©Y.Tanigawara

Interpretation of PK Data (1) “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 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 … ?

Use of Population PK to determine factors affecting PK “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Use of Population PK to determine factors affecting PK Plasma concentration (ng/mL) Japan (Fed) US+EU (Fasted) Difference between Trials Time (hr) 6 12 18 24 20 40 60 Effect of Food Time (hr) 6 12 18 24 Plasma concentration (ng/mL) 20 40 60 80 100 Fasted condition Fed condition Apparent difference between Japanese and Caucasian resulted from the different food condition. Tatami et al. ISSX, JSSX 2001.

Interpretation of PK Data (2) “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 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.

Steep PD is Sensitive to PK Difference. “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Steep PD is Sensitive to PK Difference. Response 3% 30% 30% 30% Exposure (PK)

Pharmacogenomics Altered PK Altered PD “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Pharmacogenomics Genetic polymorphisms of drug metabolizing enzymes Altered PK Altered PD Altered Efficacy/Safety profiles Influences of genotype are attributed to individual variability, rather than racial difference.

“New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 Difference in Plasma Concentrations of Omeprazole between CYP2C19 Extensive and Poor Metabolizers 1500 Frequency of PM Caucasian 2～3% Poor Metabolizer (PM) Japanese 20% 1000 Plasma concentration (ng/ml) 500 Extensive Metabolizer (EM) 2 4 6 8 10 12 Time after Dose (hr) Kita et al., Pharm Res 18: 615, 2001

“New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 24-hour Intragastric pH Profile Following Morning and Evening Dose of Omeprazole(OPZ) Intragastric pH OPZ OPZ 7 6 OPZ (20mg twice a day) CYP2C19 EM 5 4 3 Basal 2 1 Meal intake Time 9:00 15:00 21:00 3:00 CYP2C19 PM 7 1 2 3 4 5 6 Time 9:00 15:00 21:00 3:00 OPZ Kita et al., Pharm Res 18: 615, 2001

H. pylori Eradication rate (%) “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 CYP2C19 genotype-related efficacy of omeprazole for the eradication of Helicobacter pylori H. pylori Eradication rate (%) Metronidazole + AMPC + Bismuth + H2 antagonists 88% (7/8) 83% (5/6) 80% (4/5) 84% (16/19) 100% (1/1) 84% (21/25) Omeprazole 40% (4/10) 44% (4/9) 33% (1/3) 41% (9/22) + AMPC 100% (2/2) 100% (4/4) 50% (13/26) 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) Regimen CYP2C19*1/*1 CYP2C19*1/*2 CYP2C19*1/*3 EM CYP2C19*2/*2 CYP2C19*2/*3 CYP2C19*3/*3 PM Total (Tanigawara et al., Clin. Pharmacol. Ther. 66,1999)

Summary PK/PD provides a scientific basis for dose range finding. “New Approaches of Dose Range Finding” Prof. Y. Tanigawara, Keio University 3rd Kitasato Harvard Symposium 2002/10/2 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.