pharmacokinetics in drug development...clinical drug development pharmacokinetic causes of drug...
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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
÷øö
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çèæ=
po
iv
iv
po
DoseDose
AUCAUCF
÷øö
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?