APPLICATION OF PKPD MODELING IN DRUG DEVELOPMENT.ppt
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1、APPLICATION OF PK/PD MODELING IN DRUG DEVELOPMENT,Objectives of Early Drug Development,Identification of critical risk factors prior to investment in full clinical development selection of better compounds Provide critical data to identify safe and effective dose and dose regimens more efficient dev
2、elopment,New Paradigm in Drug Development,Validation,PK/PD in dose-ranging proof of efficacy study in patients (POC),Confirm PD in the pivotal studies,PK/PD in patients &/or in experimental models in healthy subjects (POM),Why Study PK/PD ?,Characterize time course of pharmacologic response (therape
3、utic &/or toxic effects) Understand complex relationships tolerance, sensitization, mechanistic delay Explain variability in response Identify biomarkers and validate surrogate endpoints Aid dose/dose regimen selection through simulation Bridge clinical efficacy and safety results across ethnic popu
4、lations Bridge clinical results between adult and pediatric patients,Requirements to Characterize PK/PD Relationship,Validated biomarkers for therapeutic effects & toxicity Should be meaningful (relates to MOA), reproducible, quantitative and allows frequent sampling to characterize the time course
5、of effect Validated Assay (reproducible, high precision.) Exposure-response relationship Understanding of pharmacologic behavior of the drug and pathophysiology of the disease Pharmacology and pharmacokinetic modeling,Modeling Direct Responses,Pharmacodynamics,Examples of direct PD effect with equil
6、ibration delay: CNS effects of benzodiazepines Muscle Relaxants of d-tubocurarine,Complexities in PK/PD Modeling,Equilibration delay Mechanistic delay Tolerance Sensitization Active metabolites Drug interaction,Modeling Indirect Responses,Pharmacodynamics (mechanistic delay),Dayneka et al., JPB, 199
7、3 Jusko et al., JPB, 1995 Sharma & Jusko, JPB, 1996 Sharma & Jusko, BJCP, 1998,Pharmacokinetics (equilibration delay),Examples: Anticoagulants effects of warfarin; Gene-mediated effects of corticosteroids,Examples,IL12: Tolerance in efficacy & safety biomarker response (IFNg). CD4 mAbs: Validate a s
8、afety biomarker in the preclinical transgenic mice model. IL5 mAb: Biomarker (eosinophil) is not a validated surrogate endpoint. P38 MAPK: Characterize an experimental model of acute inflammation for anti-TNF response. Avitriptan: Characterize safety profile (BP and heart rate). Pop PK/PD approach i
9、n Linezolid bridging program.,IL12: An example of complex PK/PD relationship,IL12,A 70 kDa heterodimer cytokine (35+40 kDa subunits). Enhances T helper 1-type immunity. Potentiates secretion of IFNg by, and the cytolytic activity of, NK cells and CTLs. IL12-induced secretion of IFNg is required for
10、activity. mIL12 has potent antitumor& antimetastatic activity in murine tumor models. Under development for cancer and infectious diseases.,Phase I Study Design,Open label dose-escalation study in cancer patients. A single dose of rhIL12 followed by cycles of 5 consecutive daily iv injection at the
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