PharmacokineticsinDrugDevelopment

EdwardP.Acosta,PharmDProfessor&DirectorDivisionofClinicalPharmacologyDirector,CCCPK/PDCore

Findingnewdrugs:Acrapshoot

ClinicalDevelopment

Phase I Phase II Phase III Phase IV

SAD

MAD

Formulations

Food Effect

ADME

Relative BA

Safety DDIBiopharm Special Pop

DDI #1

DDI #2

ECGSpecial Pop

Special Pop

DDI #3

Special Pop

BE

From Frank LaCreta, Bristol-Meyers Squibb

Dose Finding

ClinicalDrugDevelopment

Pharmacokineticcausesofdrugfailure

1. Poorbioavailabilityduetolowaqueoussolubilityand/orhighfirstpassmetabolism

2. Inadequatedurationofactionduetohighclearanceandshorthalf-life

3. Unanticipateddruginteractions– OftenrevealedinPhaseIIBandIII– ResultsinvariablePKproperties– Undesirableeffectsondrugefficacyandsafety

ClinicalDrugDevelopment

Reasonsforattritionbetween1990and2000

Kola I. Clin Pharmacol Ther 2008 83(2): 227-230

PKvs.PD

•Pharmacokinetics:thetimecourseofadruginhumans–Whatthebodydoestothedrug

•Pharmacodynamics:relationshipsbetweenthedoseorconcentrationofdruginthebodyandmeasuredeffects–Whatthedrugdoestothebody

Whyarepharmacokineticsimportant?• Ultimateaimofdrugtherapyistoachieveefficacywithouttoxicity

minimum effective concentration

minimum toxic concentration

Plas

ma

drug

con

cent

ratio

n

Time

Therapeutic Window/Index

Toxic

Ineffective

Absorption

•Movementofdrugmoleculesacrossbiologicalbarriersfromthesiteofadministrationtothebloodstream

Routeofadministration• Oral• Parenteral:IV,SQ,IM• Other:Inhalation,rectal,topical,transdermal

Bioavailability(F)• Thefractionofdrugthatreachesthesystemiccirculation• Doesnotdictaterateofdrugabsorption

AbsorptionFirstPassMetabolism• BloodsupplyoftheupperGItractpassesthroughtheliverbeforereachingthesystemiccirculation

• Drugmaybemetabolizedbythegutwallandliver

F = fabs · (1-fg) · (1-fh)

pHandDrugAbsorption

• Foracidicdrugs– AsthepH¯,amountionizeddrug¯– BetterabsorbedatlowpH–Mostofdruginstomachisun-ionized,favoringabsorption

• Forbasicdrugs– AsthepH ¯,amountionizeddrug­– BetterabsorbedathigherpH–Mostofthedruginthestomachisionized

Distribution• Reversibletransferofdrugfromonelocationtoanotherwithinthebody

Bloodflowthroughtissues• Equilibrationrapidlyachievedwithheart,lungs,kidneysand

brain

Permeabilityofdruginthetissues• Watersoluble(bloodandinterstitialspace)vs.fatsoluble(fatty

tissue)• DrugswhichpasstheBBBintoCNSaretypicallysmallandhighly

lipophilic

ProteinBinding

• Drugstransportedasfree(unbound)drugandpartlyreversiblyboundtobloodcomponents

• Onlyfreedrugisactive• 2factorsdeterminedegreeofproteinbinding

1. Affinityofdrugforplasmaprotein• Albumin-acidic• α1-acidglycoprotein-basic

2. #ofbindingsitesavailable• Drugscompetewithotherdrugs,hormonesorendogenoussubstancesforsites

VolumeofDistribution(V)

Volumethatwouldberequiredinthebodytocontaintheadministereddoseifthatdosewasevenlydistributedattheconcentrationmeasuredinplasma

VolumeofDistribution• LowVd(3-5L)distributeinplasma–DrugswithverylargeMWorboundstronglytoplasmaproteins

•MediumVd(12-14)distributeinextracellularspace–DrugswithlowMWbuthydrophilic-cannotcrosslipidmembranestoenterphaseinsidethecell

• HighVd(>42L)distributeintissues– LowMWandhydrophobic– DrugsstoredinfatmayhaveVd>TBF

Elimination

•Theirreversiblelossofdrugfromthesiteofmeasurement

•Metabolism:conversionofonechemicalspeciestoanother

•Excretion:irreversiblelossofchemicallyunchangeddrug

Metabolism•Enzymesinvolvedindrugmetabolismarepresentinmanytissues–Canproduceanactiveorinactivemetabolite(s)–Overallgoaltoproducemorepolarcompound

•Drugmetabolismratesvaryamongpatients–geneticfactors–coexistingdisorders(chronicliverdisorders)–druginteractions(especiallythoseinvolvinginductionorinhibitionofmetabolism)

PhaseI• Involveformationofanewormodifiedfunctionalgroupthroughoxidation,reduction,hydrolysis

•MostimportantenzymesysteminthisphaseisCytochromeP-450– Microsomalsuperfamilyofisoenzymesthatcatalyzethe

oxidationofmanydrugs– Severalfamilies:3A4,2C9,2C19,1B6,etc.– Enzymescanbeinducedorinhibitedbymanydrugsand

substances

CytochromeP450

• MostdrugsmetabolizedbyCYP4503A4isoenzymes(substrate)

• Somedrugsinduce(speedup)CYP450– ¯ inplasmaconcentrationof

otherdrugswhicharesubstrates

• Somedrugsinhibit(slowdown)CYP450– ­ inplasmaconcentrationof

otherdrugswhicharesubstrates

3A2D6

2C

1A2 2E1

PhaseIIReactions

•ManyPhaseImetabolitesaretoolipophilictoberetainedinthekidneytubules

•Conjugationreactionswithanendogenoussubstrateoranaminoacidresultsinmorewatersolublecompounds– Glucuronicacid(glucuronidation)– Sulfuricacid(sulfation)– Aceticacid(acetylation)

Excretion

• Eliminationofunchanged(notchangedbytheliver)ormetabolite(changedbytheliver)fromthebody

• Drugsmaybeeliminatedkidneys,lungs,saliva,sweat,breastmilk

• EnterohepaticCirculation– Drugexcretedinthebile,storedinandreleasedfromthegallbladder,transitintothesmallintestineandthenreabsorbedintothecirculation

RenalExcretion• Glomerularfiltration

– Smallmolecules/drugsfilteredthroughtheglomerulus

– Drugsboundtoplasmaproteinsaretoolarge

• Tubularreabsorption– Lipidsolubledrugsarereabsorbedfromthelumenofthenephronbackintothesystemiccirculation(ex:diuretics)

• Tubularsecretion– Carrier-mediatedactivetransportsystemthatrequiresenergy

– Showscompetitioneffects:probenecid(weakacid)competesforsamesystemaspenicillinthus¯rateofpenicillinexcretion

DRUG

RenalClearance

• Canbecalculatedtoinvestigatethemechanismofdrugexcretion

CLrenal ~120 ml/min Filtration onlyCLrenal <120 ml/min Filtration and reabsorptionCLrenal > 120 ml/min Filtration and secretion

TotalClearanceandHalf-lifeClearance (CL)• Measureoftheabilityofthebodytoeliminatedrug• Notanindicatorofhowmuchdrugisremovedbutthevolumeofplasmaclearedofdruginagivenperiodoftime– Expressedasavolumeperunittime(mL/minorL/hr)

Half-life(t½)• Timeforplasmadrugconcentrationtobereducedby50%• 5half-lives:afterstartingadrugdosingregimenbeforefulleffectswillbeseen(steady-state)andforadrugtobeeliminatedfromthebody

TotalClearance

• CLtotal =CLrenal +CLliver +CLother•Metabolicclearance(CLliver)isdependentondrugmetabolizingenzymes,whilerenalandbiliaryclearancearelargelydependentondrugtransporters

• Enzymesandtransportersaresubjectto– Inhibition(mostprevalent)or– Inductionbyotherdrugs– Geneticpolymorphism(differentsubpopulationswillbesensitivetoDDItodifferentdegrees)

ApplicationtoDrugDevelopment

Pre-ClinicalandClinicalStudies•ConductSADandMADstudiesusinganadequatedosingrange–Aminimumof3dosesovera≥10-foldrangeofdoses

•Useanadequatesamplesize•Collectsamplesoveranappropriatetimeframe•Examineconcentration-responserelationshipsinsteadofdosinguntiltoxicity

Howarethepharmacokineticsofadrugdetermined?

SampleCollection

•Invasive–Blood,plasma,serum–Spinalfluid,biopsy–Intensivevs.sparsesampling

•Noninvasive–Urine,feces,breath,saliva,breastmilk,semen,vaginalsecretions

•Mostanalyticalmethodsdesignedforplasmaanalysis

AnalyticalMethodsHighPerformanceLiquidChromatography(HPLC)Advantages• Multipleanalytesinoneassay• Worksonpolarity• UPLC:betterresolutionandshorterruntimes

Disadvantages• Backgroundnoiseduetomatrix• Coelutiondifficulttodetect• Cannotdeterminethespecificcompound

MassSpectrometryAdvantages• Sensitive,SelectiveandSpecific

• Abilitytoidentifyanalytes• UsefulforsmallvolumesDisadvantages• VeryExpensive• Difficulttorunandmaintain

RepresentativePharmacokineticProfile

PeakConcentration(Cmax)

AbsorptionPhase

EliminationPhase(t1/2)

TroughConcentration(Cmin at24hours)

AreaUnderCurve(AUC24)

AssessmentofArea-Under-the-Curve(AUC)Pl

asm

a D

rug

Con

cent

ratio

n (m

g/L)

Time (h)0 1 2 3 4 5 6 7 8

•

•

•

•••• •

Area 1

Area 2

Area 3

Area 4

AUC = (Cn +Cm)*Δt(n,m)2

( )0110

1 t t 2

C C AUC -+

=

( )1221

2 t t 2

C C AUC -+

=

( )2332

3 t t 2

C C AUC -+

=

UsefulEquations

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çèæ=

po

iv

iv

po

DoseDose

AUCAUCF

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çèæ´÷

øö

çèæ==

A

B

B

A

DoseDose

AUCAUCF Relative

B

A

FF

e

last

tlast KCpAUC =

¥-e1/2

K0.693T =

VDose

Cp =0

CLxVdt 693.0

2/1 =

AUCDoseCL =

AUC = (Cn +Cm)*Δt(n,m)2

ModelingPhilosophies

• Describedata•Quantifyprocesses• Exploremechanisms•Makepredictions

Can get AUC, CL, Vd, t1/2, etc. from NCA• Can get these from modeling as well, and

• assess covariate effects (age, weight, CLcr, etc.)• describe absorption characteristics• explore metabolite formation rate constants• simulate concentrations to predict effects• directly link PK model with response

One-CompartmentModel

R KeVd

Two-CompartmentModel

RKcp

Kpc

Ke

Vc Vp

Time (h)

Con

cent

ratio

n -l

og

Elimination Phase

0.01

0.1

1

0 1 2 3 4 5

Model Goodness of Fit

Visual Predictive Check (VPC)

Median95% CICIs for simulated data

DolutegravirAntiviralActivity

Dosing period Follow-up period

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1(BL)

2 3 4 7 8 9 10 11 14 21(FU)

Day

Mea

n Ch

ange

from

Bas

elin

e in

HIV

-1 R

NA

(log 1

0co

pies

/mL)

2 mg10 mg50 mgPBO

Song I, et al. IAS 2009, Cape Town, poster #WEPEB250

Exposure-ResponseRelationship fromPhaseIIA

Song I, et al. IAS 2009, Cape Town, poster #WEPEB250

DolutegravirPlasma Concentrations on Day 10

0.01

0.10

1.00

10.00

0 5 10 15 20Time (hour)

Dolu

tegr

avir

Conc

entra

tion

(μg/

mL)

50mg QD10mg QD2mg QD

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Placebo2mg QD10mg QD50mg QDModel Fit, Emax= -2.6, EC50= 0.036μg/mL

Day

11 lo

g 10

VL C

hang

e fro

m B

asel

ine

Maximum Effect (Emax) Model of DolutegravirExposure vs. Response

Ctrough (μg/mL)

RelevanceofEarly-PhasePK/PD

• Understandingthepharmacokineticsandestablishingpharmacodynamicrelationshipswiththesecompoundsisclinicallyvitalto:– ensureproperdoseselectionduringearlyphasedevelopment;goornogodecisions

– evaluatetheclinicalsignificanceofdruginteractions

– explorealternativedosingschedules– introducenewformulationswithdifferentpharmacokineticcharacteristics

– bringadrugintothepediatricpopulation

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Placebo2mg QD10mg QD50mg QDModel Fit, Emax= -2.6, EC50= 0.036µg/mL

Day 11 log10VL Change from Baseline

Maximum Effect (Emax) Model of DolutegravirExposure vs. Response

Ctrough (µg/mL)

CONCLUSIONS

•UnderstandingthebasicprinciplesofPKcanassistinthedrugdiscoveryanddevelopmentprocess

•PropercollectionofPKdatainanimalstudiescanprovideusefulinsightonADMEinhumans

•Establishingconcentration-responserelationshipsiscriticalforproperdoseselection–Animalmodelsorhumans

QUESTIONS?