2012/3/28 Outline Population PK/PD in Taiwan (from Academic Viewpoint) Brief introduction International population PK/PD groups Population PK/PD in Taiwan Population PK/PD in Taiwan Application of population PK/PD in clinical research Dosage recommendation of phenytoin 林君榮 Chun-Jung Lin Dose response of rabeprazole School of Pharmacy, College of Medicine National Taiwan University PAGANZ Population Approach Group in Australia and New Zealand (first meeting in 1999) Population Approach Group Europe (first meeting in 1992) PAGJA since 2006 Twenty ‐ first meeting Twenty first meeting Venice, Italy, 5 ‐ 8 June, 2012 http://www.page-meeting.org/default.asp The first World Conference on Pharmacometrics (WCoP) Seoul, Korea, 5-7 September, 2012. (first meeting in 2008) htt http://www.go-wcop.org/ // / Organizing Committee Marc Gastonguay, Metrum Research Group, USA Nick Holford, University of Auckland, New Zealand Mats Karlsson, Uppsala University, Sweden Holly Kimko, Janssen Research & Development, USA France Mentre, Unversite Paris Diderot, France Kyungsoo Park, Yonsei University, Korea (延世大學) Goonaseelan Colin Pillai, Novartis, Switzerland since 2008 1
2012/3/28 Population PK/PD in Taiwan Why do we want to use Academic population PK/PD approach in research? 1. 陳瑞龍教授、李勇進教授、蔡義弘教授、許明照教授、林其和教授…等 2. Population PK/PD is probably not the major research (1/3 or less) 3. Different approaches in population PK/PD studies sparse data/sample available Industry unbalanced design 1. Less experience in population PK/PD? 2. Major in BA/BE studies for local industry 3. Some phase1 , phase2 and phase 3 clinical trials Outpatients Regulatory (Center for Drug Evaluation; CDE) cancer patients PK or PK/PD 1. Based on US FDA experience neonatal patients 2. Population PK training properties ? parkinsonian patients Previous workshop Concepts, Methodologies and Applications of Population Pharmacokinetics in the Clinical Studies April 27, 2001, Tsang-Bin Tzeng ( 曾滄濱博士 ) Pharmacostatistical Modeling Fixed Effects: Genotypes, Gender, Age, Weight, BSA Concomitant drugs, Renal/Liver functions …etc Pharmacostatistical Models PK (CL/F, V/F, Ka) Structure models Structure models Statistical models Statistical models Blood Levels Bl d L l Clinical Response Fixed Interindividual Intraindividual PK(PD) Effects Variability (Residual) Model (theta; θ ) Variability Random Effects: Intersubject variation Intrasubject variation How to approach population PK ? Example 1 • The two-stage approach Dosage Recommendation of Phenytoin • Naïve pooled data (NPD) approach for Patients with Epilepsy • NONlinear Mixed Effects Modeling approach with Different CYP2C9/CYP2C19 Polymorphisms (NONMEM, Beal & Sheiner, 1982) Therapeutic Drug Monitoring 2004; 26:534-540 • Nonparametric maximum likelihood method ( 洪靚娟；劉宏輝 ) 洪靚娟 劉宏輝 (Mallet 1986) • Bayesian methods (Racine-Pion & Smith, 1990) • Variants of the NONMEM (Amisaki & Tatsuhara, 1988) (Lindstrom & Bates, 1990) 2
2012/3/28 Metabolism of phenytoin can be described by the Michaelis-Menten equation ： Therapeutic Range: 10 -20 g/ml （ Vmax ）（ Cpss ） R ＝ Km ＋ Cpss Low-extraction ratio (Clearance fu CLi) R ： daily dose (mg/day) Cpss ： concentrations at steady state ( g/mL) Nonlinear Pharmacokinetic Properties Vmax ： maximal metabolic rates (mg/day) Km ： Michaelis-Menten constant ( g/mL) CYP2C9: Phenytoin (S)-p-HPPH (70-80% of dose) EM PM CYP2C9*1 :wild type Extensive Metabolizers Poor Metabolizers CYP2C9*2 : exon 3 C430T (Arg 144 /Cys) CYP2C9*3 : exon 7 A1075C (CIle 359 /Leu) CYP2C19: Phenytoin (R)-p-HPPH (5-8% of dose) CYP2C19*1: wild type CYP2C19*2: exon 5 G681A (splicing defect in exon5) CYP2C19*3: exon 4 G636A (TGG-->TGA create a premature stop code) $SUBROUTINE Methods (define the model by ADVAN, TRANS or user PRED) The PREDPP library includes five pre-programmed subroutines: one compartment linear model ADVAN1 Patients with epilepsy (n = 169; 505 data) one compartment linear model with first order absorption ADVAN2 ADVAN3 two compartment linear model ADVAN4 two compartment linear model with first order absorption CYP2C9/CYP2C19 genotypes ADVAN10 ADVAN10 one compartment model with Michaelis Menten elimination one compartment model with Michaelis-Menten elimination Concentrations of phenytoin, (S)- p -HPPH and (R)- p -HPPH Other ADVAN routines that need additional info (e.g., differential equations) to be defined in $MODEL and/or $DES ADVAN5 general linear Data analysis by NONMEM (version V) ADVAN6 general nonlinear ADVAN7 general linear with real eigenvalues general nonlinear kinetics with stiff equations ADVAN8 nonlinear kinetics with equilibrium compartments ADVAN9 3
2012/3/28 ADVAN6 $PROB Css of phenytoin in Taiwanese (PM and EM) (MODEL and DES required) $INPUT ID AGE SEX HT WT EVID TIME AMT SS II DV MDV GT $DATA data $SUBR ADVAN6 TOL=5 $MODEL COMP=(DEPOT, DEFDOS), COMP=(CENTRAL, DEFOBS) k12 GI Body $PK $DES A(1) A(2) C2=A(2)/V2 DADT(1)=-K12*A(1) DADT(1)=-K12 A(1) DADT(2)=K12*A(1)-VM*C2/(KM+C2) V = (Vm x Cpss) / (km+Cpss) $ERROR $THETA $OMEGA dA $SIGMA 1 k A $EST 12 1 dt $TABLE dA V C $COVARIANCE 2 m ss k A $SCATTER 12 1 dt K C m ss Objective Function Value OBJ= - 2 LL = - 2 times the maximum log of the likelihood of the data To compare two models (e.g., differ in a parameter), we camper ( -2LL). Minimal value of the objective function ： The distribution of -2LL is about chi-squared distribution with n degree -2 log likelihood of freedom (n = difference in # of parameters between models (e.g., n=1 for one parameter difference in two models). Covariates inclusion ： minimal value of -2LL Difference in # of parameters (n) P=value the objective function 3.84 j 1 > 3.84 < 0.05 Covariates exclusion ： minimal value of 1 > 6.63 < 0.01 the objective function 7.88 1 > 7.88 < 0.005 2 > 5.99 < 0.05 2 > 9.21 < 0.01 2 > 10.6 < 0.005 AIC = (-2LL)+2p where p = # of parameters in model AIC = (-2LL A )-(-2LL B )+2(P A -P B ) NONMEM Model Group CYP2C9 CYP2C19 CYP2C9 and CYP2C19 phenotype Final model ： G1 *1 / *1 *1 / *1 CYP2C9EM / CYP2C19EM V’max ij = Vmax *(WTij/60) θ pw *GT ij Vmax G2 *1 / *1 *1 / *2 CYP2C9EM / CYP2C19EM K’m ij = Km * GT ij Km *1 / *3 CYP2C9EM / CYP2C19EM G3 G3 *1 / *1 1 / 1 *2 / *2 2 / 2 CYP2C9EM / CYP2C19PM CYP2C9EM / CYP2C19PM *2 / *3 CYP2C9EM / CYP2C19PM For intraindividual variation: Rij=R’ ij*(1+ ε ij ) G4 *1 / *3 *1 / *1 CYP2C9PM / CYP2C19EM *1 / *2 CYP2C9PM / CYP2C19EM For interindividual variation: *1 / *3 CYP2C9PM / CYP2C19EM Vmaxij=V’maxij*(1+ η j Vmax ) G5 *1 / *3 *2 / *3 CYP2C9PM / CYP2C19PM Kmij= K’mij*(1+ η j Km ) 4
2012/3/28 Group Group Km Km Vmax Vmax Vmax/Km Vmax /Km G1 G5 G4 ( μ g μ g/ /mL mL) ) (mg/kg/day) (mg/kg/day) (mL mL/kg/day) /kg/day) G2 G3 50 G5 G4 G3 G2 G1 concentration (mg/L) 1230 10 G1 G1 8.15 8.15 10.01 10.01 1230 10 40 (7.99 (7.99- -8.31) 8.31) (9.83- (9.83 -10.19) 10.19) 30 G2 G2 9.03 9.03 9.77 9.77 1081 1081 10 10 (8.91- (8.91 -9.15) 9.15) (9.65 (9.65- -9.89) 9.89) 20 Phenytoin c G3 G3 9.38 a 9.38 9.18 a 9.18 976 7 a 976 (9.20 (9.20- -9.56) 9.56) (9.03- (9.03 -9.33) 9.33) 10 607 6 a,b,c G4 G4 10.38 a,b 10.38 a,b 6.31 a,b,c 6.31 a,b,c 607 a,b,c 0 (10.21 (10.21- -10.55) 10.55) (6.20 (6.20- -6.42) 6.42) 0 1 2 3 4 5 6 7 8 9 Daily Dose (mg/kg/day) G5 G5 15.63 15.63 5.43 5.43 348 348 a Compared to G1, p ＜ 0.05 b Compared to G2, p ＜ 0.05 c Compared to G3, p ＜ 0.05 G5 G4 G3 G2 G1 The recommend doses of phenytoin for patients with epilepsy 50 entration (mg/L) G1 patients would be 5.5-7 mg/kg/day 40 G2 patients would be 5-7 mg/kg/day 30 phenytoin conce G3 patients would be 5-6 mg/kg/day 20 G4 patients would be 3-4 mg/kg/day 10 G5 patients would be 2-3 mg/kg/day 0 0 2 4 6 8 daily dose (mg/kg/day) Structures of proton pump inhibitors Example 2 Pharmacokinetic-Pharmacodynamic analysis of the role of CYP2C19 genotypes pyridine in rabeprazole-based triple therapy methylsulfinyl group benzimidazole against Helicobacter pylori British Journal of Clinical Pharmacology 2009; 67:503-510 ( 楊喻帆；楊智欽 ) 5
Recommend
More recommend
