Pharmacological determinants oflong-term treatment success

Professor David BackLiverpool, UK

Pharmacological Issues withAntiretroviral Therapy

• Intrinsic potency

• Bioavailability

• Effect of food and otherdrugs on absorption

• Protein binding

• Plasma half-life

• Intracellular half-life

• Intracellular activation

• Sanctuary sites

• Drug interactions

w unfavourable

w pharmacoenhancement

• Tolerability and toxicity

• Dosage regimens inspecial patient groups

Three Key Parameters

• Potency of drug against the virus

• Protein binding– must have adequate concentrationin vivo of free drug

• In vivo pharmacokinetics(Cmax, Cmin, AUC, half-life)

Activation of Nucleoside Analogues

Adenosine

ddAddA-TP-TP

ddI - MP

ddA-MP

ddA-DP

ddI5’5’ Nucleotidase Nucleotidase

AdenylateAdenylate Synthetase Synthetase& Adenylate& Adenylate Lyase Lyase

Adenylate Kinase &Adenylate Kinase &PRPPPRPP Synthetase Synthetase

Adenylate Kinase &Adenylate Kinase &PRPPPRPP Synthetase Synthetase

Guanosine

ABC- MP

CBV-MP

CBV-DP

CBV-TPCBV-TP

ABCAdenosineAdenosine

PhosphotransferasePhosphotransferase

CytosolicCytosolic Enzyme Enzyme

KinaseKinase

KinaseKinase

Thymidine

ZDV-MP

ZDV

ZDV-DP

ZDV-TPZDV-TP

d4T

d4T-MP

d4T-DP

d4T-TPd4T-TP

ThymidylateThymidylate Kinase Kinase

NDP KinaseNDP Kinase

Thymidine KinaseThymidine Kinase

Cytidine

ddC 3TC

ddC-MP

ddC-DP

ddC-TPddC-TP

3TC-MP

3TC-DP

3TC-TP3TC-TP

NDP KinaseNDP Kinase

CMP/CMP/Dcmp Dcmp KinaseKinase

Deoxycytidine Deoxycytidine KinaseKinase

Metabolic Pathways of Cellular Nucleosides

IMP

GMP

GDP

dGDP

dGTP

ADP

dADP

dATP

AMP

dCMP

dCDP

dCTP dTTP

Thymidine

dUMP dTMP

dTDP

CytidineRBVRBV

CDPHUHU

HUHU

DPDDPD

11

22 22

33

1. IMP dehydrogenase 2. Ribonucleotide reductase 3. Carrier-mediated transport

De NovoPathway

Salvage Pathway(<20%)

MAMA

MRP4: A previously unidentified factor inresistance to nucleoside-based antiviral drugs

“Because MRP is expressed in normal tissues and

because HIV can infect a variety of cell types, high

levels of MRP4 expression at some anatomical sites

may allow growth and evolution of drug-resistant HIV

by decreasing the amount of intracellular drug to

levels below that necessary to inhibit HIV replication.”

Schuetz et al.Nature Medicine, September 1999

Organ Distribution of Transport Proteins

Brain MDR1 OAT3 MRP1 OATP1 MRP5 OATP2

Kidney MDR1 OATP1 MRP1 OATP2 NTCP1 OCT1 OAT1 OCT2 OAT3

Liver LST1 OAT2 MDR1 OAT3 MRP2 OATP1 MRP3 OCT1 NTCP1 SPGP

LymphocytesMDR1MRP4

Pharmacokinetic profile of a single PI administeredtwice daily and efavirenz given once daily

0 6 12 18 24

Time (h)

Pla

sma

Co

nce

ntr

atio

n

PI

EFV

IC95

Area of Potential Replication

NV 15107 StudySelection of Doses

AUC0–24h (µg.h.L-1)

Pea

k re

du

ctio

n in

HIV

-1 R

NA

(lo

g10

co

pie

s/m

l)

– 4

– 3

– 2

– 1

0

1

0 20,000 40,000 60,000 80,000

Fortovase 400 mg tid

Fortovase 800 mg tid

Fortovase 1200 mg tid

Relationship between peak reduction in plasma HIV RNAand SQV AUC0-24h for hard and soft gel formulations

AUC0–24h (µg.h.L-1)

Pea

k re

du

ctio

n in

HIV

-1 R

NA

(lo

g10

co

pie

s/m

l)

– 4

– 3

– 2

– 1

0

1

0 20,000 40,000 60,000 80,000

Hard gel Soft gel

EC50 = 3226 µg.h.L-1

Emax = -1.79 log10 copies/ml

Gieschke et al., 1999

Target Concentration

• Exposure target of approximately 20,000 µg.h.L-1

with maximal virological response.

• Target exposure may differ depending on

concomitant therapy and patient population.

• Exposure-response modelling gave the optimal

dose of SQV sgc of 1200 mg tid.

VIRADAPT

Design

• Retrospective analysis

• 81 subjects; all received PI in salvage regimen

• At least 3 samples available for analysis

Results• Negative correlation between drug concentration and VL

• Patients subdivided:

Optimal Concentration Suboptimal ConcentrationCtrough >IC50 on Ctrough <IC50 on

2 or more occasions 2 or more occasions

-1.23 log at 48 weeks -0.24 log at 48 weeks

Arguments for TDM of PIs

• Low plasma concentrations correlate with clinical failure

• Marked inter-individual variability in plasma drug concentrations

• Complex drug interactions

• High plasma concentrations may correlate with toxicity

• PI disposition affected by liver dysfunction

• Assessment of poor adherence in selected patients

• Cost of therapy

Potential Problems with TDM

• Relatively small data sets giving concentration-responserelationships

• Target PI concentrations largely defined from in vitrostudies with exposure to single PI? Antiretrovirals in combination

• Changing patterns of adherence

• What measure is best ?w AUCw Troughw Trough and peak

Indinavir tds vs bd dosing

0.01

0.1

1

10

100

0 2 4 6 8 10 12

Time (h)

Pla

sma

Ind

inav

ir (

µg

/ml)

0.1 µg/ml(100 ng/ml)

Effect of ritonavir (100 mg)on indinavir pharmacokinetics

0.1

1

10

100

0 2 4 6 8 10 12Time (h)

Pla

sm

a I

nd

ina

vir

(µ

g/m

l)

IND (n=6)

IND + 100 mg RIT

ABT-378

0.001

0.01

0.1

1

10

0 4 8 12 16 20 24

Time (h)

Pla

sma

AB

T-3

78 (

µg

/ml)

Alone

+ 50 mg RIT

EC50

(WT, 50% HS)

Sham et al., 1998

Efavirenz(SUSTIVA , STOCRIN )

NH

O

O

F3 C CCl

C

Efavirenz – Summary of Pharmacokinetics

• Good oral absorption; can be given without regard to food

• Half-life 40–55 h; allows once daily dosing

• Highly protein bound (99.5%), but penetrates CSF

• Metabolised by CYP3A4 (also CYP2B6)

• Induces CYP3A4 (also autoinduction)

• Inhibits CYP3A4

• Renal excretion as glucuronide conjugate

Efavirenz Mean Plasma Concentration

0

2

4

6

8

10

12

14

16

0 6 12 18 24

Time (h)

EF

V P

lasm

a C

on

cen

trat

ion

(µ

M)

AUC0-t= 248 µmol.L-1.h

Cmax = 15.7 µmol.L-1

t1/2 ~ 50 h

Efavirenz “Free” Plasma Concentration

0

10

20

30

40

50

60

70

80

0 6 12 18 24

Time (h)

EF

V P

lasm

a C

on

cen

trat

ion

(n

M) Protein Binding = 99.5%

IC95 of WT & clinical isolates = 0.5–10 nM

IC95 ofWT

IC95 ofK103N

Time

Pla

sma

Co

nce

ntr

atio

n

Pharmacokinetic-Surrogate Relationship

MIC

Cmax

AUC

T > MIC

AUIC = AUC/MIC

Population Pharmacokinetics of Efavirenz

0

2

4

6

8

10

12

14

0 1 2

Pre

dic

ted

24

h

EF

V p

las

ma

co

nc

en

tra

tio

n (

µM

)

Non-Failure Failure0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25

Pro

bab

ility

of

Su

cces

s

Predicted 24 hEFV plasma concentration (µM)

Efavirenz – Induction & Inhibition

CYP3A4

SQVSQV

SQVSQV

EFVEFV

EFVEFV

CYP3A4INDUCED

EFVEFV

EFVEFV

NLFNLF

NLFNLF

CYP3A4INDUCED

+ EFVIncrease in

SQV metabolism(AUC ↓ 60%)

+ EFVDecrease in

NLF metabolism(AUC ↑ 20%)

CONTROL