Cilostazol PK/PD model

2003. 4.

1. : K-Betest AUCt, Cmax, Tmax2. PK parameter : WinNonlin AUCinf(CLtotal), Kel(t1/2), Ka, Vd/F, AUCt/AUCinf3. Population PK analysis : NONMEM Factors : Sex, Weight(height), Alcohol, Caffeine etc.4. PK/PD modeling : ADAPT PK data PD data ( ) .

PK/PD Effect vs. time

Time(hr)PharmacokineticsPlasma Concentration vs. time

Time(hr)PharmacodynamicsEffect vs. Concentration

ConcentrationConcentrationeffecteffectPharmacokinetic/pharmacodynamic modeling

pharmacokinetic and pharmacodynamic HomogenecityConcentrationCp PK

tissue concentration A.effect PD

tissue concentration B.effect

CpA: PK Homogenecity: Predictabe relationship between Cp and Creceptor

PK model Non compartment model : AUC, AUMC, Cl=dose/AUC 2. Compartment model : I.V., oral One, two, three Compartment Models. Kel(t1/2), Vd, ClMRT =AUMC AUC

PD model Fixed effect model : All or None responseLinear model : E = S x CEmax model :

Sigmoid Emax model :

E =EmaxCEC50 + CE =Emax CrECr50 + Cr

PK/PD-models to be considered during model selectionDirect LinkVs.Indirect LinkDirect ResponseVs.Indirect ResponseTime-invariantVs.Time-variantClassification of PK/PD-modelsSelected PK/PD ModelDose Concentration - Effect Relationship to be modeled

1

2 Central

3 Peripheral

DoseeffectClassification of PK/PD models

1. Direct link model KaKcpKpcKel

Dose12Central3Peripheral Effect compartmentKeoEffectPD compartmentMass balance First order processClassification of PK/PD models

1. Indirect link modelKaKcpKpcKel

Classification of PK/PD models

2. Direct response vs. indirect response models (I)2. Indirect response models - - - endogenous substance - - counterclock-wise hysteresis loop1. Direct response models - - - - direct link model - indirect link model

Example of Indirect response model 1

2 Central3 PeripheralDose4. Effect compartmentKinPK model : two compartment model. The model input is via single oral bolus.PD model : Indirect response model with production of the response variable inhibited by the concentration of the drug in the plasmaKaKcpKpcKel

Pharmacokinetics Dose

KelClassification of PK/PD models

2. Indirect response modelsCentralPharmacodynamic Kin

KoutResponseI. Kin : zero-order production rate constantII. Kout : first-order degradation rate constant

I. INHIBITION-KinII. INHIBITION-KoutResponse(R)kinkoutIC50

Ro

R Tmax Time

R Tmax Ro TimedRdt=kin (1-CpIC50 +Cp ) Kout RResponse(R)kinkoutIC50dRdt= kin kout(1-CpIC50 +Cp ) RClassification of PK/PD models 1. Indirect response models

III. STIMULATION-KinIV. STIMULATION-KoutResponse(R)kinkoutEC50

Ro

R Tmax Time

R Tmax Ro TimedRdt=kin (1+EmaxCpEC50 +Cp ) - kout RResponse(R)kinkoutEC50dRdt=kin kout(1+EC50 +Cp ) REmaxCpKEY :EC50StimulationIC50InhibitionClassification of PK/PD models 2. Indirect response models

Classification of PK/PD models 3. Time invariant vs. time variant models Time-invariant model - PD parameter - 2 - Direct response model Time-variant model - Emax EC50 PD parameter - (tolerance) : - Clock-wise Hysteresis - (sensitization) : Counterclock-wise Hysteresis loop

Summaryeffect counter clock-wise

clock-wise Cp

No hysteresis - Direct link Model

HysteresisClock-wise hysteresis - Time-variant PD model(Tolerance)Counterclock-wise hysteresis - Indirect link model( ) - Indirect response model - Time-variant PD model (Sensitization)

Cilostazol Phosphodiesterase(PDE) III inhibitor 1. 2. 3. , , 1983 - - : ,

In vitro cilostazol cilostazol PK dataCilostazol PD data : PK/PD model

Blood : Sod. Citrate (9 : 1)Platelet rich plasma (PRP)Platelet poor plasma (PPP)Centrifuge (160g/10min )Centrifuge (2000g/10min )Plasma sample or Cilostazol 40 ulAggregation inducer 40 ul (ADP or epinephrine)Method

Cilostazol 37C, 3 minAggregation 5 min

Aggregation % (Extent) : Slope (Rate) : Inhibition % =(AB)/A 100 A : control maximum aggregation % B : maximum aggregation %

PK/PD data designVolunteers 10ml 3ml Citrated (9:1)1) 7ml heparinizedCilostazol 100mg HPLC 2)

Data analysis1. In vitro PD analysis WinNonlin ADP epinephrine inhibition % Sigmoid Emax model fitting PD parameter(Emax, EC50, )

2. PK analysis Two compartment model fitting PK parameter

3. PK/PD analysis ADAPT II program (, slope) : Indirect response model (, ) : Direct response model

4. Effect compartmentKeoDirect response model1

2 Central3 PeripheralDose PK model : two compartment model. The model input is via single oral bolus PD model : Direct response model. Drug response is related via the Hill equation (Sigmoid Emax model) to drug concentration in an effect compartmentKcpKpcKaKel

Indirect response model1

2 Central3 PeripheralDose4. Effect compartmentKinPK model : two compartment model. The model input is via single oral bolus.PD model : Indirect response model with production of the response variable inhibited by the concentration of the drug in the plasmaKaKcpKpcKel

Differential equations for indirect response modeldx 1(t)dt= -Ka x 1 (t)=-(Kel + Kcp)x2 (t) + Ka x1 (t) + Kpcx3(t)dx 2(t)dt= Kcpx2 (t) - Kpcx3(t)dx 3(t)dt= Kin ( 1- ) - x4(t)dx 4(t)dt x 2(t)IC50 +x 2(t)KinIC(4)Kout =Kin/IC(4)

Model SDRSS (the standardized residual sum-of-squares) = (residual2/variance)AIC (Akaike information criterion) = m ln (OWLS) + 2 p or m ln (ONLL) + 2 (p+q)ECV (the estimator criterion value)SC (Schwartz criterion)Visual inspection SDRSS, ECV, AIC SC

model 1. parameter confidence interval -50% < C.I. < +50%

2. Parameter Correlation Coefficient 80%

3. Visual inspection

1. In vitro cilostazol Inhibition %Slope Inducer Emax (%) EC50 (M) ADP 98.11 14.40 2.28 Epinephrine 100.6 15.10 1.69 - ADP- Epinephrine

Open circles are observed values and solid line is the result of Weighted least squares(WLS) method in ADAPT II program.Parameter (unit) value . Non-compartmental analysis AUC(ng*hr/ml) 10379.59 584.33 Cmax(ng/ml) 775.10 45.33 Tmax(hr) 3.65 0.20 CLt(L/hr) 10.47 0.83 V/F(L) 14.4Compartmental analysis Kel(hr-1) 0.1405 Ka(hr-1) 0.3928 Kcp(hr-1) 0.1937 Kpc(hr-1) 0.0194 t 1/2-alpha(hr) 1.77 t 1/2-beta(hr) 21.222. PK analysis

3. PK/PD analysis Plot of cilostazol concentration versus effect. Platelet Aggregation Inhibition %Diastolic pressureHeart rate

PK/PD modeling

1) Cilostazol model

Direct response model [ Indirect link model ]Indirect response modelModel A[direct link]Model B[Indirect link]parameter Model A Model B Kin 69.82 69.80 IC50 2422 2418IC(4) or IC(5) 99.11 99.12Keo - 8263 Criterion Model A Model B SDRSS 137.036 137.044 AIC 92.029 94.029 SC 95.686 98.905 ECV 31.223 31.223 Time delay parameter

t 1/2-Keo= 0.693/ Keo

8.4 10-5 (hr)

Plots of aggregation % and time course. Data points are observed values. The solid lines are the fittings from Model APlots of slope and time course. Data points are observed values. The solid lines are the fittings from Model A.PK/PD modeling 1) Cilostazol Best fitted

PK/PD modeling

2) Cilostazol model Direct response model [Indirect link model]Model ILinked Peripheral compartmentModel IILinked effect compartmentCriterion Diastolic pressure Heart rate SDRSS 146.528 32.275 AIC 90.661 -125.81 SC 95.373 -116.05 ECV 31.318 -70.903

PK/PD modeling 2) Cilostazol Best fittedDiastolic pressureDiastolic pressureHeart rate Diastolic pressurePD parameter DBP Heart rate Keo (hr-1) 0.7713 0.3876 Emax 20500 28600 EC50(ng/ml) 2039 1509 7.060 7.919

In vitro ADP epinephrine cilostazol Sigmoid Emax model .Cilostazol 8 . cilostazol PK/PD model PD model input function indirect response model . cilostazol two compartment model .Cilostazol , 6 . PK/PD model effect compartment Hill equation (Sigmoid Emax model) direct response model .