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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 compoundsProvide critical data to identify safe and effective dose and dose regimens more efficient deve
2、lopment,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(therapeutic&/
3、or toxic effects)Understand complex relationshipstolerance,sensitization,mechanistic delayExplain variability in responseIdentify biomarkers and validate surrogate endpointsAid dose/dose regimen selection through simulationBridge clinical efficacy and safety results across ethnic populationsBridge c
4、linical results between adult and pediatric patients,Requirements to Characterize PK/PD Relationship,Validated biomarkers for therapeutic effects&toxicityShould be meaningful(relates to MOA),reproducible,quantitative and allows frequent sampling to characterize the time course of effectValidated Ass
5、ay(reproducible,high precision.)Exposure-response relationshipUnderstanding of pharmacologic behavior of the drug and pathophysiology of the diseasePharmacology and pharmacokinetic modeling,Modeling Direct Responses,Pharmacodynamics,Examples of direct PD effect with equilibration delay:CNS effects o
6、f benzodiazepines Muscle Relaxants of d-tubocurarine,Complexities in PK/PD Modeling,Equilibration delayMechanistic delayToleranceSensitizationActive metabolitesDrug interaction,Modeling Indirect Responses,Pharmacodynamics(mechanistic delay),Dayneka et al.,JPB,1993Jusko et al.,JPB,1995Sharma&Jusko,JP
7、B,1996Sharma&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 safety biomarker in the preclinical transgenic mice model.IL
8、5 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 in Linezolid bridging program.,IL12:An example of complex PK/PD relati
9、onship,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 activity.mIL12 has potent antitumor&antimetastatic activity in murine tumor
10、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 same dose every 3 weeks.MTD of 500 ng/kg was established in this study,Atkins et
11、 al,Clin Cancer Res.1997,1,15 16 17 18 19,Days,2 weeks washout,Repeat every 3 weeks,Phase II Study Design,Open label repeat-dose efficacy study in patients with advanced renal cell carcinoma.Cycles of 5 consecutive daily iv injection at MTD(500 ng/kg)dose every 3 weeks.,Leonard et al.,Blood,1997,27
12、28 29 30 31,Days,3 weeks washout,Repeat every 3 weeks,1 2 3 4 5,Phase II Study Results,Treatment was associated with unexpected serious adverse events.Most of the patients experienced serious AEs after 2nd and 3rd doses.Two patients died and no one entered the 2nd cycle due to drug related toxicity
13、such as GI bleeding.PK profiles for IL12 were comparable to those observed in Phase I study.,Leonard et al.,Blood,1997,Leonard et al.,Blood,1997,Reason for unexpected toxicity:,A four-fold higher trough IFNg concentrations in Phase II may have caused the serious toxicity.,Summary,If IFNg concentrati
14、ons were used as a safety biomarker,it would have been possible to avoid serious AEs by stopping after 2nd dose in Phase II study.A single dose of IL12 causes tolerance in its ability to induce IFNg production upon further dosing.IL12 produces tolerance rapidly(3-4 days)during multiple dosing which
15、lasts for a relatively long time period(14 days)in humans.PK/PD modeling to characterize schedule-dependent IL12-induced IFNg production is crucial for designing safe and effective dosing regimens.,Comparative PD of Anti-CD4 mAbs in Transgenic Mice,Sharma et al.,JPET,2000,Anti-CD4 mAbs,Mediate their
16、 immunomodulatory effects via indirect response mechanisms:removal of CD4+T cells via effector mechanism;down-modulation of cell surface CD4 via internalization or stripping and/orinhibition of CD4-MHC II interactions.Under development for autoimmune disorder such as rheumatoid arthritis.,Anti-CD4 m
17、Abs,Keliximab,Primate/human chimeric CD4 mAb of IgG1 isotype.Does not mediate complement dependent cytotoxicity.Exhibits efficient binding to human IgG Fc receptors and can cause depletion of CD4+cells.,Reddy et al.J Immun,2000,FcR and CD4 Mediated Cell Adhesion,Reddy et al.J Immun,2000,Study Design
18、,Male transgenic mice(n=10-13 per group)bearing human CD4 in place of the mouse CD4.Three dose levels(5,25 number of CD4 epitopes on the surface of T cells and CD8+T cells.,Preclinical Species,Time(hours),Plasma Keliximab Concentration(ug/mL),Davis et al.,Drug Metab Disp,1996,Target-mediated Disposi
19、tion,PK Model for Anti-CD4 mAbs,Plasma(CP),Tissue(CT),kPT,Dose,IC:Cp=Dose/Vc;CT=0,Sharma et al.,JPET,2000,Pharmacokinetics of Anti-CD4 mAbs,Parameter(unit),Estimate,Vmax(mg/mL/h),890,Km(ng/mL),5249,Vc(mL),2.5,VT(mL),25.6,kPT(day-1),0.15,Sharma et al.,JPET,2000,PD Model for Anti-CD4 mAbs,Sharma et al
20、.,JPET,2000Sharma&Jusko,Br J Clin Pharmaco,1998,IC:Ro=kin/kout,Smax=(Ro-Rmax)/Rmax,At a very high dose:,PK/PD of Anti-CD4 mAbs,Time(hour),25 mg/kg,125 mg/kg,Clenoliximab,T Cell Concentration(%Lymphocyte),Keliximab,Sharma et al.,JPET,2000,PD Parameters of Circulating CD4+T Cell Number,Summary,Clenoli
21、ximab is less potent and efficient than keliximab in causing depletion of circulating CD4+T cells.The results of this study are similar to those from clinical trials at comparable doses.This study validates the transgenic mice as an appropriate model for preclinical PK/PD evaluation of anti-CD4 mAbs.,
