Pharmacokinetics §PK process in the body §Kinetic processes 张翔南 浙江大学药学院...

PharmacokineticsPharmacokineticsPK process in the bodyPK process in the body

Kinetic processesKinetic processes

张翔南浙江大学药学院

xiangnan_zhang@zju.edu.cn医学院科研楼 B404

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

1 Overview1 Overview

2 2 Transport of Drug in the BodyTransport of Drug in the Body

3 Pharmacokinetic Processes of the Drug3 Pharmacokinetic Processes of the Drug

in the Bodyin the Body

1.1. OverviewOverview

ADMEADMEof the drug inof the drug in

human bodyhuman body

2.2. Transport of Drug in the Body Transport of Drug in the Body

2.1 Transmembrane Transport of 2.1 Transmembrane Transport of DrugsDrugs

(1) Passive Transport(1) Passive Transport Simple diffusionSimple diffusion （简单扩散）（简单扩散） FiltrationFiltration （滤过）（滤过）

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Characteristics of Passive TransportCharacteristics of Passive Transport

not involving specific carriers not involving specific carriers Energy-independentEnergy-independent no saturabilityno saturability no competition with other drugsno competition with other drugs Concentration gradient (down-hill)Concentration gradient (down-hill)

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(2) Active Transport(2) Active Transport

Characteristics of active transportCharacteristics of active transport

Involving specific carrier Involving specific carrier Energy-dependentEnergy-dependent SaturabilitySaturability Competition at same carrierCompetition at same carrier Moving against concentration gradient (up-hill)Moving against concentration gradient (up-hill)

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(3) Others(3) Others

Filtration through poresFiltration through pores （ 膜 孔 滤（ 膜 孔 滤过）过）

Facilitated diffusionFacilitated diffusion （易化扩散）（易化扩散） EndocytosisEndocytosis （内吞）（内吞） PinocytosisPinocytosis （胞饮）（胞饮） Ion-pair transportIon-pair transport （离子对转运）（离子对转运）

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Three types of functional membrane proteins.Three types of functional membrane proteins.

Transporters Transporters of drugs in PK of drugs in PK processesprocesses

Simple diffusionSimple diffusion

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Determinants of simple diffusionDeterminants of simple diffusion

For most drugs of small molecules (usually For most drugs of small molecules (usually are weak acids or weak bases):are weak acids or weak bases):

Lipid-soluble or un-ionized formsLipid-soluble or un-ionized forms

pKa pKa of the drug andof the drug and pHpH of the body fluidof the body fluid

The The pKapKa is that pH at which the concentrations of is that pH at which the concentrations of the ionized and un-ionized forms are equal.the ionized and un-ionized forms are equal.

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Henderson-Hasselbalch equationHenderson-Hasselbalch equation

Weak acid drugs: Weak acid drugs: ppH - H - ppKa = log ( [AKa = log ( [A--] / [HA] )] / [HA] ) ppKa - Ka - ppH = log ( [HA] / [AH = log ( [HA] / [A--] )] )

Weak base drugs:Weak base drugs: ppKa - Ka - ppH = log ( [BHH = log ( [BH++] / [B] )] / [B] ) ppH - H - ppKa = log ( [B] / [BHKa = log ( [B] / [BH++] )] )

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

ppHH ppKaKaun-ionized un-ionized

formformlipid-lipid-solublesoluble

Simple Simple diffusiondiffusion

Weak Weak acidsacids

Weak Weak basesbases

And / orAnd / or

And / orAnd / or

And / orAnd / or

And / orAnd / or

pH < pKa:pH < pKa: HA and BHHA and BH+ + are predominantare predominant

pH > pKa:pH > pKa: AA － － and B are predominantand B are predominant

ImplicationsImplications

Absorption Absorption

DistributionDistribution

ExcretionExcretion

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

2.2 Free and Bound Forms2.2 Free and Bound Forms

Plasma protein bindingPlasma protein binding

Tissue / organ affinityTissue / organ affinity

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

3.3. Fate of the drug in the body Fate of the drug in the body

AbsorptionAbsorption DistributionDistribution BiotransformationBiotransformation ( metabolism)( metabolism) ExcretionExcretion － － ADMEADME

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

3.1 Absorption3.1 Absorption Absorption is the transfer of a drug from its site of Absorption is the transfer of a drug from its site of

administration to the blood stream.administration to the blood stream.

Gastrointestinal tractGastrointestinal tract Parenteral injection Parenteral injection im. sc.im. sc. InhalationInhalation Transdermal Transdermal

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(1) Gastrointestinal tract(1) Gastrointestinal tract

Route:Route: OralOral SublingualSublingual RectalRectal

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Factors influencing absorption:Factors influencing absorption:

blood flow to the absorption siteblood flow to the absorption site total surface area available for absorptiontotal surface area available for absorption contact time at the absorption surfacecontact time at the absorption surface physic-chemical properties of the drugphysic-chemical properties of the drug first-pass eliminationfirst-pass elimination

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

First-pass elimination First-pass elimination

When a drug is absorbed across the GI tract, When a drug is absorbed across the GI tract, it enters the portal circulation before entering it enters the portal circulation before entering the systemic circulation. If the drug is rapidly the systemic circulation. If the drug is rapidly metabolized by the liver, the amount of metabolized by the liver, the amount of unchanged drug that gains access to the unchanged drug that gains access to the systemic circulation is decreased.systemic circulation is decreased.

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

First-pass First-pass eliminationelimination

(2) Parenteral injection(2) Parenteral injection

intramuscular injection ( im ) intramuscular injection ( im ) subcutaneous injection ( sc )subcutaneous injection ( sc )

DeterminantsDeterminants Local blood flowLocal blood flow Solubility of the drug Solubility of the drug

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(3) Others(3) Others

InhalationInhalation IntranasalIntranasal Transdermal Transdermal Topical Topical

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

3.2 Distribution3.2 Distribution

Drug distribution is the process by which a Drug distribution is the process by which a drug reversibly leaves the blood stream and drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) enters the interstitium (extracellular fluid) and / or the cells of the tissues.and / or the cells of the tissues.

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Body fluid Body fluid volume:volume:

Sites of drug Sites of drug

distributiondistribution

(1) Binding of drug to plasma proteins(1) Binding of drug to plasma proteins

Bound drug: Bound drug: Inactive temporilyInactive temporily can not distributioncan not distribution reversible (storage form)reversible (storage form) percentage of bindingpercentage of binding competitively displacement competitively displacement

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

competitively displacementcompetitively displacement Class I drugs:Class I drugs: Dose less than available binding Dose less than available binding

sites. sites. Most drug molecules are bound to the Most drug molecules are bound to the proteins and free drug concentration is low.proteins and free drug concentration is low.

Class II drugs:Class II drugs: Dose greater than available Dose greater than available binding sites. binding sites. Most proteins contain a bound Most proteins contain a bound drug and free drug concentration is significant.drug and free drug concentration is significant.

Class I + Class II drugs:Class I + Class II drugs: Displacement of Displacement of Class I drug occures when a Class II drug is Class I drug occures when a Class II drug is administered simultaneously.administered simultaneously.

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(2) Physic-chemical properties of the drug(2) Physic-chemical properties of the drug

(3) Blood flow and re-distribution(3) Blood flow and re-distribution

(4) Affinity to organs or tissues(4) Affinity to organs or tissues

(5) Barriers(5) Barriers

Blood-brain barrier (BBB)Blood-brain barrier (BBB)

Placental barrierPlacental barrier

Blood-eye barrier Blood-eye barrier

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Blood-brain barrier (BBB)Blood-brain barrier (BBB)

Able to pass throughAble to pass through Unable to pass throughUnable to pass through

Small moleculesSmall molecules Large moleculesLarge molecules

Lipid-solubleLipid-soluble Water-solubleWater-soluble

Transporter-mediation Transporter-mediation

Structure of liver Structure of liver capillary and brain capillary and brain

capillarycapillary

Amount of drug passing through blood-Amount of drug passing through blood-brain barrierbrain barrier

Percentage of drug in Percentage of drug in c.s.f.c.s.f.

Increases whenIncreases when

InflammationInflammation

Larger doses usedLarger doses used

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

BBB BBB permeability permeability increases in increases in

inflammationinflammation

Placental barrier:Placental barrier:

More permeableMore permeable

3.3 Biotransformation (drug metabolism)3.3 Biotransformation (drug metabolism)

(1) Biotransformation sites(1) Biotransformation sites

Liver:Liver: most of the drugsmost of the drugs Other organs/tissues:Other organs/tissues: intestine, kidney, intestine, kidney,

lung, plasma, etc.lung, plasma, etc.

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(2) Phases of biotransformation(2) Phases of biotransformation

Phase I: Phase I: Oxidation reduction hydrolysisOxidation reduction hydrolysis most drugs are inactivatedmost drugs are inactivated few (few (prodrugsprodrugs) are activated) are activated

Phase II: Phase II: ConjugationConjugation inactivatedinactivated

Metabolites: Metabolites: more water-soluble more water-soluble easier to excreteeasier to excrete

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Drugs or other substancesDrugs or other substances Phase IPhase I

inactivatedinactivated （（ few: activatefew: activatedd ））

Phase IIPhase II

inactivatedinactivated

ExcretionExcretion

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(3) Enzymes in biotransformation(3) Enzymes in biotransformation

Enzymes in Phase I: Enzymes in Phase I: cytochrome-P450cytochrome-P450 many other enzymesmany other enzymes

Enzymes in Phase II: Enzymes in Phase II: acetylase acetylase glucuronosyltransferaseglucuronosyltransferase etc.etc.

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Superfamily of Superfamily of cytochrome-P450cytochrome-P450

CYP3A4CYP3A4（（ cytochrome / cytochrome /

family / subfamily / family / subfamily / membermember ））

(4) Hepatic enzymes of drug metabolism(4) Hepatic enzymes of drug metabolism

hepatic microsomal mixed function oxidase hepatic microsomal mixed function oxidase system system （肝药酶）（肝药酶）

Extraction > 0.7: Extraction > 0.7: hepatic blood flow hepatic blood flow dependentdependent

－ － nitroglucerin, propranolol, …nitroglucerin, propranolol, …Extraction < 0.3: Extraction < 0.3: hepatic enzyme dependenthepatic enzyme dependent － － diazepam, phenobarbital, …diazepam, phenobarbital, …

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Induction of hepatic enzymes by drugsInduction of hepatic enzymes by drugs example: example: phenobarbitalphenobarbital －－ steroids, warfarinsteroids, warfarin

Inhibition of hepatic enzymes by drugsInhibition of hepatic enzymes by drugs example: example: cimetidinecimetidine －－ diazepamdiazepam

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

肝药酶诱导剂对双香豆素血浓度及凝血作用的影响肝药酶诱导剂对双香豆素血浓度及凝血作用的影响

3.4 Excretion3.4 Excretion

(1) Excretion routes(1) Excretion routes KidneyKidney BileBile LungLung GI tractGI tract MilkMilk Secretion glandsSecretion glands

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

(2) Renal excretion(2) Renal excretion

Glomerular filtrattionGlomerular filtrattion renal blood flowrenal blood flow

Active tubule secretionActive tubule secretion specific carriers / competitionspecific carriers / competition

Passive tubule reabsorptionPassive tubule reabsorption urine pH, urine flowurine pH, urine flow

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Renal excretionRenal excretion

Glumerular fitrationGlumerular fitration

Active secretionActive secretion

Passive reabsorptionPassive reabsorption

(3) Bile excretion(3) Bile excretion

Carrier-mediated activeCarrier-mediated active

transporttransport

Hepato-enteral circulationHepato-enteral circulation

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

3.5 Elimination and Accumulation3.5 Elimination and Accumulation

Elimination:Elimination: BiotransformationBiotransformation ExccretionExccretion Distribution (stored in fat, hair, etc)Distribution (stored in fat, hair, etc)

Accumulation:Accumulation: Dosing rate > elimination rate Dosing rate > elimination rate

Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes

Part BPart B Kinetic ProcessesKinetic Processes

1 Drug concentration-time curve1 Drug concentration-time curve

2 Kinetic rate processes2 Kinetic rate processes

3 Pharmacokinetic models3 Pharmacokinetic models

4 Pharmacokinetic parameters and 4 Pharmacokinetic parameters and implicationsimplications

5 Multiple dosing5 Multiple dosing

Part BPart B Kinetic ProcessesKinetic Processes

1.1. Drug concentration-time curve Drug concentration-time curve (C-T curve)(C-T curve)

Maximal (peak) concentration:Maximal (peak) concentration: CCmaxmax C Cpp

Time to maximal concentration (Peak time ) :Time to maximal concentration (Peak time ) : TTmaxmax T Tpp

Area under the curve:Area under the curve: AUCAUC Multiple dosing (steady state): Multiple dosing (steady state):

CCssss max max C Css minss min C Cssss

t

C

i.m.i.m.

s.c.s.c.

OralOral

i.v.i.v.

←

←

←

←

CCmaxmax

CCpp

↑ ↑ ↑TTmax, max, TTpp

TTmaxmax 、、 CCmaxmax and AUC and AUC

↑Tmax

←Cmax

AUC↙

C-T curve after multiple dosing C-T curve after multiple dosing （（ same dose and intervalsame dose and interval ））

Temporal characteristics of drug effect and Temporal characteristics of drug effect and relattionship to therapeutic windowrelattionship to therapeutic window

2. 2. Kinetic rate processesKinetic rate processes

dC / dt dC / dt ＝ ＝ KCKCnn

Part BPart B Kinetic ProcessesKinetic Processes

2.1 Zero order kinetics2.1 Zero order kinetics

n n ＝ ＝ 00 dC / dt dC / dt ＝ －＝ － KK CCt t ＝ ＝ CC00 －－ K tK t CC00 －－ Ct Ct ＝ ＝ K tK t when Cwhen Ctt ＝＝ 1/2 C1/2 C00,,

then then t = tt = t1/21/2, 0.5 C, 0.5 C00 ＝＝ K tK t1/2 1/2

tt1/21/2 ＝＝ 0.5 C0.5 C0 0 / K/ K

Part BPart B Kinetic ProcessesKinetic Processes

Zero order kineticsZero order kinetics

A.A. same amounts of drug are same amounts of drug are eliminated per unit timeeliminated per unit time

B. B. t t1/21/2 is not a constant is not a constant

C. C. C-T curve is linear C-T curve is linear

D. D. no Css theoretically no Css theoretically

Part BPart B Kinetic ProcessesKinetic Processes

Kinetic properties of C-T curves after Kinetic properties of C-T curves after single bolus injection of drugsingle bolus injection of drug

2.2 First order kinetics2.2 First order kinetics n n ＝ ＝ 11 dC / dt dC / dt ＝ －＝ － KCKC CCt t ＝ ＝ CC00ee －－ KtKt lnClnCt t ＝ ＝ lnClnC00 －－ Kt Kt KtKt ＝＝ lnClnC00 －－ lnClnCtt ＝＝ ln(Cln(C00 / C / Ctt)) when Cwhen Ctt ＝＝ 1/2C1/2C00 ，， tt ＝＝ tt1/21/2 ，， tt1/21/2 ＝＝ ln2/Kln2/K ＝＝ 0.693/K0.693/K

Part BPart B Kinetic ProcessesKinetic Processes

First order kineticsFirst order kinetics

A.A. eliminated at same rate per unit time eliminated at same rate per unit time

B.B. t t1/21/2 is a constant is a constant

C.C. logC-T curve is linear logC-T curve is linear

D.D. steady state (Css) after 4-5 t steady state (Css) after 4-5 t1/21/2

Part BPart B Kinetic ProcessesKinetic Processes

Kinetic properties of C-T curves after Kinetic properties of C-T curves after single bolus injection of drugsingle bolus injection of drug

2.3 Non-linear kinetics2.3 Non-linear kinetics

Higher concentration (or dose):Higher concentration (or dose): zero order kineticszero order kineticsLowerconcentration (or dose):Lowerconcentration (or dose): first order kineticsfirst order kinetics

Because of limits in elimination capacity Because of limits in elimination capacity Examples:Examples: aspirin, phenytoin, ethanolaspirin, phenytoin, ethanol

Part BPart B Kinetic ProcessesKinetic Processes

Michaelis-Menten kineticsMichaelis-Menten kinetics

dC / dt = VdC / dt = Vmax max C / (KC / (Kmm + C) + C) if if Km >> C Km >> C dC / dt = VdC / dt = Vmax max C / KC / Kmm

VVmaxmax / K / Kmm = K = Ke e － － First orderFirst order

ifif C >> Km C >> Km dC / dt = VdC / dt = Vmax max C / CC / C dC / dt = -VdC / dt = -Vmaxmax － － Zero orderZero order

Part BPart B Kinetic ProcessesKinetic Processes

Kinetic properties of C-T curves after Kinetic properties of C-T curves after single bolus injection of drugsingle bolus injection of drug

3 3 Pharmacokinetic modelsPharmacokinetic models

2.1 One-compartment model2.1 One-compartment model

If the drug rapidly distributed in the body If the drug rapidly distributed in the body after administration, then eliminated at after administration, then eliminated at same rate.same rate.

Part BPart B Kinetic ProcessesKinetic Processes

One-compartment modelOne-compartment model

BodyBody logC

t

iv

Part BPart B Kinetic ProcessesKinetic Processes

D E

2.2 Two-compartment model2.2 Two-compartment model

D → → E D → → E

↑↓ ↑↓

PeripheralPeripheral

CentralCentral

First, enter the centralFirst, enter the central

compartmentcompartment

Then, distributed to Then, distributed to peripheral compartment, peripheral compartment, and eliminnatedand eliminnated

CentralCentral

PeripheralPeripheral

Part BPart B Kinetic ProcessesKinetic Processes

D → → E

↑↓logC

t

iv

α β

βα

Distribution over, Distribution over, and eliminationand elimination

C-T curveC-T curve

CentralCentral

PeripheralPeripheral

DistributionDistribution EliminationElimination

Part BPart B Kinetic ProcessesKinetic Processes

2.3 Other models2.3 Other models

Physiological pharmacokinetic modelPhysiological pharmacokinetic model

Combined pharmacokinetic-Combined pharmacokinetic- pharmacodynamic modelpharmacodynamic model

Statistical momentStatistical moment

Part BPart B Kinetic ProcessesKinetic Processes

4. 4. Pharmacokinetic parameters and Pharmacokinetic parameters and their implicationstheir implications

4.1 Bioavailability 4.1 Bioavailability ( F )( F )

Bioavailability is the fraction of Bioavailability is the fraction of administered drug (oral) that reaches the administered drug (oral) that reaches the systemic circulationsystemic circulation

Part BPart B Kinetic ProcessesKinetic Processes

Absolute bioavailabilityAbsolute bioavailability

F = AUCF = AUC(po, sc, im)(po, sc, im) / AUC / AUC (iv)(iv)

Relative bioavailabilityRelative bioavailability

F = AUCF = AUC(tested)(tested) / AUC / AUC(standard)(standard)

Implication:Implication: Evaluation for absorption Evaluation for absorption and drug quality controland drug quality control

Part BPart B Kinetic ProcessesKinetic Processes

4.2 Apparent volume of distribution (4.2 Apparent volume of distribution (VdVd))

The volume of distribution (Vd) relates the The volume of distribution (Vd) relates the amount of drug in the body to the concentration amount of drug in the body to the concentration of drug (C) in the blood or plasma.of drug (C) in the blood or plasma. iv iv Vd = D / C Vd = D / C popo Vd = FD / C Vd = FD / C

Part BPart B Kinetic ProcessesKinetic Processes

Implications of VImplications of Vdd

Ratio of drug amount and plasma drug Ratio of drug amount and plasma drug concentrationconcentration

Properties of drug distributionProperties of drug distribution

Used for pharmacokinetic calculationUsed for pharmacokinetic calculation

Part BPart B Kinetic ProcessesKinetic Processes

4.3 Half-life (4.3 Half-life (tt1/21/2))

The half-life (tThe half-life (t1/21/2) is the time takes for the ) is the time takes for the plasma concentration or the amount of drug in plasma concentration or the amount of drug in the body reduced by 50%.the body reduced by 50%.

tt1/21/2 = 0.693 / Ke = 0.693 / Ke ＝ ＝ Vd / ClVd / Cl

Part BPart B Kinetic ProcessesKinetic Processes

Implications of Implications of tt1/21/2

Elimination rateElimination rate

Estimating the times of fully elimination and Estimating the times of fully elimination and reaching steady statereaching steady state

Classifying short- and long-acting drugsClassifying short- and long-acting drugs

Adjusting dosage regimens for patients with Adjusting dosage regimens for patients with hepatic or renal failureshepatic or renal failures

Part BPart B Kinetic ProcessesKinetic Processes

Elimination of single dose and accumulation after multiple dosing (at same dose and interval) of a first order kinetic drug

Elimination after single dosingElimination after single dosing

t1/2 0 100%

1 50%

2 25%

3 12.5%

4 6.25%

5 3.13%

6 1.57%

…………

Accumulation after multiple Accumulation after multiple dosing at same dose and dosing at same dose and intervalinterval （（ tt1/21/2))

t1/2 0 0 ～ 100%

1 50 ～ 150%

2 75 ～ 175%

3 87.5 ～ 187.5%

4 93.8 ～ 193.8%

5 96.9 ～ 196.9%

6 98.4 ～ 198.4%

…………

4.4 Clearance (Cl)4.4 Clearance (Cl)

A A constant fractionconstant fraction of drug in the body is eliminated of drug in the body is eliminated per unit of time (per unit of time (first-order kineticsfirst-order kinetics).).

Cl = Ke Cl = Ke Vd Vd A A constant amountconstant amount of drug in the body is eliminated of drug in the body is eliminated per unit of time (per unit of time (zero-order kineticszero-order kinetics).).

4.5 Elimination rate constant (Ke)4.5 Elimination rate constant (Ke)

KeKe = 0.693 / = 0.693 / tt1/21/2 ＝ ＝ Cl / VdCl / Vd

Part BPart B Kinetic ProcessesKinetic Processes

tt (min)(min)

lnClnCtt

lnClnCtt = lnC = lnC00 － － KKeett

slope = - Kslope = - Kee

tt1/21/2 = 0.693 / K = 0.693 / Kee

VVdd = D / C = D / C00

Cl = VCl = Vdd × K × Kee

lnClnC00

slope = - Kslope = - Kee

First order kineticsFirst order kinetics

One compartment modelOne compartment model

Intravenous administrationIntravenous administration

5.5. Multiple dosing Multiple dosing

Steady state: 4Steady state: 4 ～～ 5 5 tt1/21/2

Varying according to dose and Varying according to dose and intervalsintervals

Part BPart B Kinetic ProcessesKinetic Processes

Same dose and different intervalsSame dose and different intervals

Different doses and same intervalDifferent doses and same interval

Same total doses and different intervalsSame total doses and different intervals

Same dose and same interval, but first Same dose and same interval, but first dose × 2dose × 2

C-T curves of drug after multiple dosing at same C-T curves of drug after multiple dosing at same interval and same doseinterval and same dose

Loading dose (DLoading dose (DLL)) DDLL = target C = target Cssss VVd ssd ss / F / F

Maintenance doseMaintenance dose raterate (DDm m )) DDmm ＝＝ target Ctarget Cssss CL / FCL / F

Part BPart B Kinetic ProcessesKinetic Processes