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Farmacología y Farmacogenética de los medicamentos antirretrovirales Farmacología y Farmacogenética de los medicamentos antirretrovirales A Telenti Institute of Microbiology Biology and Medical School www.chuv.ch/imul A Telenti Institute of Microbiology Biology and Medical School www.chuv.ch/imul

Farmacología y Farmacogenética de los medicamentos ... · El « Dogma Central » de la Farmacología clínica Pharmacokinetics PK Pharmacodynamics NH PD N N N HO O N N Doses, intervals,

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Farmacología y Farmacogenética de losmedicamentosantirretrovirales

Farmacología y Farmacogenética de losmedicamentosantirretrovirales

A Telenti

Institute of Microbiology

Biology and Medical School

www.chuv.ch/imul

A Telenti

Institute of Microbiology

Biology and Medical School

www.chuv.ch/imul

El « Dogma Central »de la Farmacología clínica

PharmacokineticsPK

PharmacodynamicsPDNH

NN

N

OH O

N

N

Doses,intervals,route

Concentration profile ataction site

Intendedor adverseeffects

Relación PK-PD

D D D DD D D D

PK : «what thebody does

with a drug»

� Relation between the administration schedule of an agent and the resulting development of a clinical effect profile

PD : «what a drugdoes to

the body»

time

co

nc

en

tra

tio

ne

ffe

ct

Descripción PK

AUC 0-∞∞∞∞

AUC 0-last

t max

C max

t

C

Terminal phase :decreasingexponential t½

Optimalrange

130 unselected patients under Efavirenz 600 mg q.d. :

C. Marzolini & al. AIDS 2001, 15:71±75

0

20

40

60

80

100

Average Efavirenz concentration (µg/l)

100 1000 10000

Viral control

CNS toxicity

Pro

ba

bili

ty(%

)

Perfil PD In vivo

PK: farmacocinética de losantirretrovirales

Gibbons, et al. AIDS. 2000;14(suppl 4):S89.

Hard gel

caps

Soft gel

caps

SQV

Soft gel

caps + RTV

Alone + RTV

IDV NFV

10

100

1000

10,000

Pla

sm

a c

on

ce

ntr

atio

n(n

g/m

L)

Unselected patients under various PIs :

PK Variabilidad

Intracellularlevels

HIV

CD4 lymphocytes

and HIV targetcells

Transporters

Total circulating levels

liver

Transporters

CYP

blood

GI Lumen enterocytes

Transporters

CYP3A

Antiretroviraldrugs

Determinantes de la concentración

intracelular de los antirretrovirales

-el proceso ADME-

αααα1-glycoprotein acid isoforms

Free-bound

Ritonavir CYP3A4/5, 2D6Indinavir 3A4/5Saquinavir 3A4/5Nelfinavir 3A4/5, 2D6, 2C9, 2C19Amprenavir 3A4/5Efavirenz 3A4, 2B6Nevirapina 3A4, 2B6

Metabolismo de los inhibidores de la proteasa y de los NNRTI

Fellay et al. Lancet 2002

Rotger et al. Pharmacogenetics 2005

Haas et al. AIDS 2005

Tsuchiya et al.Biochem Biophys Res Comm 2004

Intracellularlevels

HIV

CD4 lymphocytes

and HIV targetcells

Transporters

Total circulating levels

liver

Transporters

CYP

blood

GI Lumen enterocytes

Transporters

CYP3A

Antiretroviraldrugs

αααα1-glycoprotein acid isoforms

Free-bound

Determinantes de la concentración intracelular de los antirretrovirales

Concentraciones intracelulares vs. plasmáticas del NFV

Nelfinavir logIC = f (logEC)

2.5 3.0 3.5 4.0

2.5

3.5

4.5

p < 0.0001r = 0.85slope =0.93

log (EC)

log

(IC

)

Nelfinavir logIC = f (logEC)

2.5 3.0 3.5 4.0

2.5

3.5

4.5

p < 0.0001r = 0.85slope =0.93

log (EC)

log

(IC

)

Concentraciones intracelulares vs. plasmáticas del EFV

Efavirenz logIC = f (logEC)

2.0 2.5 3.0 3.5 4.0 4.5

2

3

4

p < 0.0001r = 0.6slope = 0.69

log (EC)

log

(IC

)

Efavirenz logIC = f (logEC)

2.0 2.5 3.0 3.5 4.0 4.5

2

3

4

p < 0.0001r = 0.6slope = 0.69

log (EC)

log

(IC

)

Nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors (NRTIs)

require intracellular phosphorylation for activity (Anderson, CID 38:743, 2004)

Farmacología de los NRTI

Conclusiones I

• La farmacología de los antirretrovirales es compleja

• Los niveles plasmáticos son muy variables

• Múltiples etapas caracterizan el proceso ADME

• La medida de niveles plasmáticos puede ayudar en la práctica

• La farmacología intracelular o intracompartimental es poco conocida

Determinantes farmacogenéticosde la farmacocinética

1. Observe si hay diferencias entre individuos(“fenotipo”).

Un estudio de genética

Interindividual variation in efavirenz plasma values

All4.0

4.5

5.0

5.5

6.0

log

10 E

FV

pla

sm

a A

UC

Rotger et al Pharmacogen Gen 2005

1. Observe si hay diferencias entre individuos(“fenotipo”).

2. Identifique patrones de fenotipo singulares

Un estudio de genética

Co

un

t

0

5

10

15

20

25

30

35

log10 EFV AUC (µg*h/ml)

0.5 1.0 1.5 2.0 2.5 3.0 3.5

Cu

mu

lative

Fre

qu

en

cy

1

10

30

50

70

90

99

99.9

99.99

Co

un

t

0

5

10

15

20

25

30

35

log10 EFV AUC (µg*h/ml)

0.5 1.0 1.5 2.0 2.5 3.0 3.5

Cu

mu

lative

Fre

qu

en

cy

1

10

30

50

70

90

99

99.9

99.99

Distribution of Efavirenz AUC valuesRotger et al. Clin Pharm Ther 2007

Extensive metabolizer

Slow metabolizer

Rapid metabolizer

1. Observe si hay diferencias entre individuos(“fenotipo”).

2. Identifique patrones de fenotipo singulares3. Qué se conoce?

Un estudio de genética

<5% total CYPs in human liver

Metabolism of efavirenz

Highly polymorphic (21 alleles described)

CYP2B6

Cluster of basic residues

Cluster of prolines

Membrane binding domaine

Conserved domain: Glu-X-X-Arg

Heme Binding site: Phe-X-X-Gly-X-Arg-X-Cys-X-Gly

SRS: Substrates-recognition sites

P167AR487C

D257NM46V

Q172H I328TQ21L

R22CR29S/P K139R

R140K T168I

S259RI391N

P428TM459V

Q485LG476D

T26S R336CD28G

G99E

K262R

491AA

SRS1

1 26

MBD

98 117

SRS2 SRS3 SRS5SRS4 SRS6HBS

199 210 235 240 290 304 360 369 429 438 470 47934

Allelic frequency Q172H

Blacks: 30-47%

Whites: 21-28%

Asians: 14-19%

1. Observe si hay diferencias entre individuos(“fenotipo”).

2. Identifique patrones de fenotipo singulares3. Qué se conoce?4. Ya sabemos todo?

Un estudio de genética

Extensive genotyping and resequencing of CYP2B6The grey interval: thresholds above and below which AUC values deviate from the normality distribution.

1. Observe si hay diferencias entre individuos(“fenotipo”).

2. Identifique patrones de fenotipo singulares3. Qué se conoce?4. Ya sabemos todo?5. Qué hacer después?

Un estudio de genética

CYP2B6*1

Exons 1 5 97 84 62 3

Amino acid change

CYP2B6*27

Exons 1 5 97 84 62 3

M198T

15708T>C

18273G>A

CYP2B6*28

Exons 1 5 97 84 62 3

T306S, R378stop

18783C>G 21160C>T

15837C>T 18273G>A18627G>A18912G>C

CYP2B6*1

Exons 1 5 97 84 62 3

Amino acid change

CYP2B6*27

Exons 1 5 97 84 62 3

M198T

15708T>C

18273G>A

CYP2B6*28

Exons 1 5 97 84 62 3

T306S, R378stop

18783C>G 21160C>T

15837C>T 18273G>A18627G>A18912G>C

Schematic view of novel alleles. Black arrows: non-synonymous SNPs. Light-

grey arrows: intronic SNPs. Dark-grey arrows: SNPs in promoter region.

% o

f W

T

activity

WT *6 M198T0

10

20

30

40

50

60

70

80

90

100

∗∗

M198T0

10

20

30

40

50

60

70

80

90

% o

f W

T

activity

WT *6 M198T0

10

20

30

40

50

60

70

80

90

100

∗∗

M198T0

10

20

30

40

50

60

70

80

90

Heterologous expression of CYP2B6*6 and of novel allele 2B6*27 in COS-1 cells.Bupropion hydroxylase activity of CYP2B6 variants normalized to CYP2B6 protein amount

Transportadores

Transportadores y antirretrovirales

TransporterTransporterTransporterTransporter ARTARTARTART

MRP1 (ABCC1MRP1 (ABCC1MRP1 (ABCC1MRP1 (ABCC1)))) PIsPIsPIsPIs

PIs PIs PIs PIs MRP2 (ABCC2MRP2 (ABCC2MRP2 (ABCC2MRP2 (ABCC2))))

MRP4 (ABCC4)MRP4 (ABCC4)MRP4 (ABCC4)MRP4 (ABCC4) AzidothymidineAzidothymidineAzidothymidineAzidothymidineLamivudineLamivudineLamivudineLamivudine, , , , StavudineStavudineStavudineStavudine

MRP5 (ABCC5)MRP5 (ABCC5)MRP5 (ABCC5)MRP5 (ABCC5) AzidothymidineAzidothymidineAzidothymidineAzidothymidineLamivudineLamivudineLamivudineLamivudine, , , , StavudineStavudineStavudineStavudine

Inhibitors: PIsInhibitors: PIsInhibitors: PIsInhibitors: PIsBCRP (ABCG2)BCRP (ABCG2)BCRP (ABCG2)BCRP (ABCG2)

PIsPIsPIsPIsMDR1 (ABCB1)MDR1 (ABCB1)MDR1 (ABCB1)MDR1 (ABCB1)

SNPsSNPsSNPsSNPs

7777

27 27 27 27

16161616

39393939

Colombo et al. Pharmacogen Genet 2005

ABCB1_N21D ABCB1_C3435T ABCB1_Intron 26

Intracellular Nelfinavir AUC (ng*h/ml) for MDR1

(ABCB1) genotypes with a significant association with

phenotype

Colombo et al. Pharmacogen Genet 2005

Conclusiones II

• La farmacogenética ha identificado asociaciones

entre:

- CYP2B6 y PK de Efavirenz y Nevirapina

- CYP3A5 y PK de Saquinavir e indinavir

- CYP2C19 y PK de Nelfinavir

- MDR1 y transporte de varias IP

- MRP4 y fosforilación de varios NRTIs

- ORM y niveles plasmáticos libres de varias IP

Determinantes farmacogenéticosde la toxicidad

• efavirenz + lamivudine/FTC+ (zidovudine or tenofovir or abacavir)

• lopinavir/ritonavir (Kaletra®) + lamivudine/FTC + (zidovudine or tenofoviror abacavir)

• atazanavir + lamivudine/FTC+ (zidovudine or tenofovir or abacavir)

Equivalentes ……pero no iguales

Podemos escoger entreopciones similares con tests

genéticos?

EfavirenzLopinavir/r

AtazanavirAbacavir

EfavirenzLopinavir/r

AtazanavirAbacavir

Neuropsychological toxicityHyperlipidemia

HyperbilirubinemiaHypersensitivity reactions

Neuropsychological toxicityHyperlipidemia

HyperbilirubinemiaHypersensitivity reactions

Co

un

t

0

5

10

15

20

25

30

35

log10 EFV AUC (µg*h/ml)

0.5 1.0 1.5 2.0 2.5 3.0 3.5

Cu

mu

lative

Fre

qu

en

cy

1

10

30

50

70

90

99

99.9

99.99

Co

un

t

0

5

10

15

20

25

30

35

log10 EFV AUC (µg*h/ml)

0.5 1.0 1.5 2.0 2.5 3.0 3.5

Cu

mu

lative

Fre

qu

en

cy

1

10

30

50

70

90

99

99.9

99.99

Extensive metabolizer

Slow metabolizer

Rapid metabolizer

Distribución de las concentraciones de efavirenz

Rotger et al. Clin Pharm Ther 2007

Infarto de miocardio y Infarto de miocardio y Infarto de miocardio y Infarto de miocardio y

exposiciexposiciexposiciexposicióóóón a antirretroviralesn a antirretroviralesn a antirretroviralesn a antirretrovirales

0

1

2

3

4

5

6

7

8

None <1 1-2 2-3 3-4 >4

Incidence per 1000 PY/ 95% CI

No. events

No. PYFU

3 9 14 22 31 47

5,714 4,140 4,801 5,847 7,220 8,477

CART Exposure/Yrs Total

126

36.199

Test for trendP<0.00001

Friis-Moeller, NEJM 2003

IIIII

Genotype

Score

I

1

2 ART Group

3

0

10

20

30

40

50

60

70

%

I II

Genotype Score III

1

2 ART Group

3

0

10

20

30

40

50

60

70

80

%

Efecto del genotipo ABCA1/APOA5/APOC3/APOE/CETP y tipo de ART sobre los niveles de lípidos

High triglyceride levels Low HDL levels.

Arnedo et al Pharmacogenetics and Genomics 2007

Síndrome de Gilbert e ictericia en individuos que reciben indinavir o atazanavir

•The polymorphism in the promoter of UGT1A1, leads to a 50% reduction in bilirubin-conjugating activity

promoter TATA element of the gene encoding UGT1A1

Rotger et al, JID 2006

4208 prescriptions4208 prescriptions4208 prescriptions4208 prescriptions(1512 patients, 1 (1512 patients, 1 (1512 patients, 1 (1512 patients, 1 yearyearyearyear, , , , ’’’’02020202----’’’’03)03)03)03)

82 prescriptions (2%) 82 prescriptions (2%) 82 prescriptions (2%) 82 prescriptions (2%) discontinueddiscontinueddiscontinueddiscontinued because of because of because of because of

«««« hypersensitivityhypersensitivityhypersensitivityhypersensitivity »»»»(45 patients, 3%)(45 patients, 3%)(45 patients, 3%)(45 patients, 3%)

M. Rickenbach

Discontinuación del tratamiento por reacción de hipersensibilidad (‘02-‘03)

Región HLA de hipersensibilidad al abacavirMallal et al. Lancet 2002

�MHC-restricted presentation of drug or drug metabolites with direct binding of these non-peptide antigens to MHC molecules and/or haptenation to endogenous proteins prior to T cell presentation

Mal

lal

CN

A30

027

CN

A30

032

(RC

D)

CN

A30

032

(SC

D)

CN

A30

032

(RC

D)

CN

A30

032

(SC

D)

CN

A30

032

(RC

D)

CN

A30

032

(SC

D)

0

25

50

75

100

%

White Hispanics Black

SensitivityPositive predictive value

SpecificityNegative predictive value

HLA-B*5701 en diversas poblaciones y definición de caso. Hughes et al. Pharmacogenomics 2004

Reacciones severas de hipersensibilidad

Stevens JohnsonToxic epidermal necrolysis

•Similar to abacavir hypersensitivity it occurs between 1 and 6 weeks after treatment initiation.

Reacciones de hipersensibilidad a la NevirapinaMHC class I or class II ??

•In contrast, more frequent at high CD4 T cell count suggestive of HLA Class II involvement.

•CD4+ T cell infiltration has been observed in animals treated with nevirapine.

‘NVP HSR’ (14)

HLA-DRB1*0101: OR = 4.9 (P = 0.009)

Reacciones de hipersensibilidad a la Nevirapina(n=26)

Isolated rash (12)

Rash

Fever

Hepatitis12

2

2

1

45

0

Mallal et al. AIDS 2005

JAPAN 11-18%

UK

22%

AUSTRALIA

~18%

US

Caucasian

~18%US Asian

~7%

US

African-

American

~3-4%

THAILAND

1%

MEDITERRANEAN

15-18%

US

Hispanic

~6%

Frecuencia HLA-DRB1*0101

Mallal et al. AIDS 2005

Pediatric Lipodystrophy

Lipodistrofia

CCR5-CCR2

SDF1

TSG101RANTES

IL-10

CX3CR1

MIP1αααα

+HLA/KIR

ABCA1/APOA5/C3/E/CETPCYP2B6

MDR1UGT1A1CYP3A5CFTR/SPINK1

TNF

• 20% of disease evolution, 10% of the explained fraction• Abacavir hypersensitivity, Nevirapine ? • Hyperlipidemic response to several boosted antiproteases• Gilbert syndrome with atazanavir• Pharmacokinetics of efavirenz (nelfinavir, saquinavir?)• Some fraction of virological / immunological response to ART• Predisposition to pancreatitis• (Predisposition to lipodystrophy)

• 20% of disease evolution, 10% of the explained fraction• Abacavir hypersensitivity, Nevirapine ? • Hyperlipidemic response to several boosted antiproteases• Gilbert syndrome with atazanavir• Pharmacokinetics of efavirenz (nelfinavir, saquinavir?)• Some fraction of virological / immunological response to ART• Predisposition to pancreatitis• (Predisposition to lipodystrophy)

Lo que conocemos cabe un chip de 50 pocillos

Farmacogenética

Toxicogenética

Farmacogenómica

Intracellularlevels

HIV

CD4 lymphocytes

and HIV targetcells

Transporters

Total circulating levels

liver

Transporters

CYP

blood

GI Lumen enterocytes

Transporters

CYP3A

Antiretroviraldrugs

αααα1-glycoprotein acid isoforms

Free-bound

Determinantes de la concentración

intracelular de los antirretrovirales

-el proceso ADME-

n=174

n=1783

n=471

Genes y variantes necesarias para explorar la farmacogenética de los antirretrovirales

126 Gene candidates2428 SNPs20 SNPs/gene

R. Lubomirov

Colombia – Suiza, 3-1