Farmacocinética e Interacciones

Dr. Esteve RiberaServei de Malalties Infeccioses

Hospital Universitari Vall d’Hebron. Barcelona

Barcelona, 26 de febrero de 2010

Total: 44 comunicaciones

Interacciones ARV – ARV Interacciones ARV – otros fármacos Farmacocinética Farmacogenómica Tejidos y reservorios Embarazo Pediatría

CROI 2009: Farmacología

Entre ARV:

• ETR-RAL-DRV/r (606)

• ATV y ATV/r – GSK1349572 (616)

Interacciones

N=10

ATV ATV/r

AUC 91 62 %

Cmax 50 34 %

Ctr 180 121 %

• Well tolerated in healthy adult subjects.

• No dose adjustment is necessary

Interacciones

ARV – otros fármacos:

• LPV/r – buprenorf/naloxona (620)

• FPV – posaconazol (621)

• EFV – levonorgestrel (934)

• NVP – lumefantrina (603)

• NVP – RFP (602)

Pla

sma

Co

nce

ntr

atio

n (

ng

/mL

)

• HIV-seronegative subjects

• LPV/r did not have effect on [BUP] or [naloxone]

• LPV/r did reduce [norBUP] (BUP metabolite).

• Dosage modification of BUP/NLX is not likely to be required when it is co-administered with LPV/r.

• Posaconazole (400 mg BID)

• FPV/ritonavir (700/100 mg BID)

• Posaconaz + FPV (700 mg BID)

• FPV no potenciado reduce las conc. de posaconazol.

• Posaconazol no puede sustituir a ritonavir como potenciador.

0 2 4 6 8 10 12 140

2000

4000

6000

8000

10000

12000LNG 0.75 mg

LNG 0.75 mg +EFV 600 mg QHS

Time (hrs)

LN

G C

on

cen

trati

on

(p

cg

/mL

)

AUC 58%; Cmax 45%;Cmin 69%

• Higher LNG doses may be required to prevent pregnancy.

• These results reinforce the importance of dual methods of contraception, including a barrier device, in women taking EFV.

Naïve (n=18) Nevirapine (n=18) P

Cmax (ug/mL) 8.76 (5.52-14.90) 10.9 (6.70-22.50) 0.0598

AUC(ug.h/mL) 436.92 (334.4-893.1) 679.84 (395.2-1684.9) 0.0011

1,00

02,

000

3,00

04,

000

5,00

06,

000

200/400 400/400

02,

000

4,00

06,

000

8,00

0

200/400 400/400

02,

000

4,00

06,

000

8,00

0

200/400 400/400

3000 ng/mL(MEC)

DAY 7 (Esc, n=7) DAY 14 (Esc, n=6) DAY 21 (Esc, n=5)

Comparison of NVP C12 in Escalation and Full dose NVP arms

• With rifampicin NVP PK with dose escalation is less favorable than that of full dose.

• Using NVP 400mg daily, NVP concentrations were also below the MEC in both arms.

• Evaluation of the PK and safety of higher NVP doses (e.g 600 mg daily) after the first 14 days should be considered.

Farmacocinética ARV:

• EFV en pelo (604)

• TDF/FTC/EFV solución (605)

• RAL intracelular (614)

Only hair EFV levels remain strongly correlated with viral load undetectability

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0 10 20 30 40 50

Time (hr)

TDF

Con

cent

ratio

n (m

g/L) Liquid

Tablet

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

0 10 20 30 40 50

Time (hr)

EF

V C

on

cen

trati

on

(m

g/L

)

Liquid

Tablet

0.0

0.5

1.0

1.5

2.0

2.5

0 10 20 30 40 50

Time (hr)F

TC

Co

nce

ntr

atio

n (

mg

/L)

Liquid

Tablet

• 90% CI for FTC Cmax and AUC fell within the range of 0.8-1.25 (bioequivalence was met)

• EFV Cmax below the range of bioequivalence, AUC slightly above the range and

• TDF Cmax and AUC fell above the range (40% and 20% higher).

• Both formulations are not bioequivalent for two drugs; the clinical implications are unknown.

• RAL Ctot are well correlated with Ccell (r=0.86), supporting the use of Therapeutic Drug Monitoring based on Ctot as a surrogate of Ccell.

• Despite this good general correlation, each patient exhibited a distinct intracellular accumulation for RAL, with Ccell/Ctot ratios ranging from 0.013 to 0.196 (a15-folddifference).

Concentración de ARV en tejidos y reservorios:

• RAL genital (608, 609)

• DRV genital (610, 611)

• MVC LCR y genital (oral 85, 612)

• Good penetration of RAL in the genital tract of HIV-1 infected women with a ratio CVF/BP= 2.3and a concentration 16 fold higher than the IC95 on wild type HIV-1

• Likely contributing to virological control in the compartment

• These data also suggest a potential use of raltegravir in combination with others ARVs with known penetration in the genital tract of HIV infected women when targetting an impact on prevention of transmission and resistance.

N=14

• [DRV] Seminal plasma 8.6% (5.7-22.2%) the Blood Plasma concentrations.

• DRV Seminal Plasma (344 ng/ml) 6 fold above EC50 of WT HIV-1 strains (55 ng/ml).

• Only 3 DRV SP concentrations were < 55 ng/mL.

• No relationship between DRV concentrations and HIV-RNA was evidenced.

10

100

1000

10000

0 5 10 15 20 25 30

TIME POST DOSE (h)

DR

V c

on

ce

ntr

ati

on

s (

ng

/ml)

RES PC EC50 550 ng/ml

WT PC EC50 55g/ml

SP:BP DRV AUC 0-24h ratio = 0.17 (0.07-

0.19)

n=18

Semen (SP) vs Blood (BP) Darunavir Concentrations in 18 HIV Men & SP AUC0-24h vs BP AUC0-24h

Time post Drug Ingestion

1-3h 4-6h 22-24h

Median BP

[DRV] IQR

ng/ml

5579

(4639-7505)

3734

(2935-4586)

2445

(1365-3167)

Median SP

[DRV] IQR

588

(509-778)

490

(479-640)

217

(172-261)

Median

SP:BP ratio

IQR

0.11

(0.09-0.15)

n=8

0.13

(0.07-0.18)

n=13

0.11

(0.09-0.15)

n=14

Median multiple above

PC EC 50 for WT

virus 55ng/ml

11 fold

(6-45)

9 fold

(3-21)

4 fold

(2-16)

Blood

Semen

124,7 150

0,723

2,6

0,022

Median

Ratio to plasma

• MVC achieves levels in CSF within the range of IC50 or higher.

• In semen, MVC exceeds several times the IC50.

• Most patients undetectable plasma/reservoirs VL (some viral replication in semen)

MVC 273% a

TVF 510% h

IDV 100% z

ABC 150% z

3TC 667% g

ZDV 228% y

d4T 2% vSQV 3% p

NFV 7% r LPV 5 % j

APV 20% cc

RTV 3% q

ENF ND sEFV 3.3% s

Equivalent Blood andGenital Tract Exposures

Higher Genital Tract Exposures

Lower Genital Tract Exposures

NVP 80% bb

APV 50% bb

d4T 5% cEFV 0.4% c SQV bb

RTV 26% c

ZDV 235% c

TVF 75% c

TVF* 110% c

3TC 411% c FTC 395% cIDV/r 380% aa

ddI 992% b

DLV 20% bbATV 18% c

ABC 58% b

LPV 30% b

ddI 21% c

GT/BP AUC ratios

GT/BP ratios paired samples

LPV 2-3% t

Semen/BP AUC ratios

Semen/BP ratios paired samples

RTV 7% jLPV 6% q

EFV 9% w

ABC 8% c LPV 8% c

3TC 319% b

FTC 150% b

EFV 1% b

DLV 16% x

LPV 3% b

ZDV 330% g

d4T 350% v

ABC 560% d

LPV ND u

ATV 10% k

RTV ND p

NVP 61% v

IDV 140% pIDV 145% bbIDV/r 132% aa

SQV ND d RTV 3% b

LPV 5% bb

RAL 93% f

RAL 142% m

ZDV 590% b

TVF 515% b

RTV 81% b

LPV 12% b

NVP 130% bb

DLV 5% bb

IDV 70% bb*

RTV 19 b

ddI 114% b*

ZDVtp 33% g

3TCtp 100% g

MVC 190% a*

TVF 330% i

DRV 150% nETR 130% n

100%

200%

300%

400%

500%

600%

0%

80%

60%

40%

20%

Men Women

EFV ND i

TVFdp >1000%h

3TC 460% o

ZDV 190% o

TVF 90% o

RTV 54% oNFV 54% o

From Dumond, Cohen and Kashuba 2007; adapted by Taylor and Davies 2010 *CROI 2010; P611; Taylor, Jayasuryia , Dufty et al

MVC 200% *

MVC 2800 % * Rectal Tissue

Vaginal Tissue

*DRV 12%*DRV 17%

MVC 71%

MVC 62%

RAL 230 %

RAL 160%

RAL 642%

*DRV 9%

MVC 72%

84LB

84LB

84LB

P608

P609

P609

P612

P610P611

P611

PK – embarazo y neonatos:

• LPV (906)

• ATV (907)

• FPV (908)

• NVP (910, 911)

• The reduction of LPV drug exposure compared to non-pregnant women was less pronounced in Thai women than in US women (~ 25% versus 50%).

• In this PK study all women achieved an HIV RNA viral load <400 copies/mL before delivery.

• Standard LPV/r dosing in during the 3rd trimester provides adequate drug exposure.

Postpartum

3rd trimester

• Dose adjustment for ATV/r in pregnancy is not required.

• ATV/r, in combination with AZT/3TC, was well tolerated in pregnant women.

APV 3rd Tri Postpart Ratio (90CI)

AUC0-12 32.4 50.7 0.69 (0.51-0.94)

Cmax 5.93 5.68 0.95(0.64-1.40)

Cmin 1.70 2.43 0.86 (0.55-1.34)

• Boosted FPV is well tolerated and was associated with good viral suppression (all VL<400).

• APV AUC is reduced during the 3rd trimester vs. post-partum and historical controls.

• APV concentrations during the 3rd trimester are greater than seen with unboosted FPV and trough concentrations achieved during the 3rd trimester are adequate for patients without PI resistance mutations.

PK - pediatría:• RAL (oral 161,872, 873)

• LPV/r (877)

• Overall, the C12hr was similar for all three formulations.

• Both pediatric formulations had moderately higher AUC and Cmax values vs POL formulation.

• A high-fat meal slowed the rate of absorption from the EC formulation, with no statistically meaningful change in extent of absorption.

•These data support further clinical investigation of the OG and EC pediatric formulations

• Open label study of RAL in treatment experienced HIV+ youth– Cohort I: 12-18 yrs adult formulation– Cohort IIA: 6-11 yrs adult formulation– Cohort IIB: 6-11 yrs chewable (OCT) formulation– Cohort III: 2-5 yrs chewable (OCT) formulation

0

1,000

2,000

3,000

4,000

5,000

0 2 4 6 8 10 12

Time Post Dose (h)

RA

L C

on

c (

ng

/mL

)

P1066 Chewable Tablet

P1066 Adult Formulation

Adults (400 mg bid, n=45)

**Adult Data - Luber et al. 49th ICAAC, September 12-15, 2009, San Francisco, CA

RAL chewable tablets safe and well tolerated. Wk 12 efficacy data were favorable

LPV Whole Crushed Ratio (90CI)

AUC0-12 141 92 0.60 (0.48 –0.72)

Cmax 10.4 9.2 0.81 (0.65 –0.98)

Cmin 6.3 4.8 0.67 (0.48 –0.86)

• Administration of a single dose of two crushed 200/50 mg LPV/RTV tablets to pediatric patients decreased oral absorption of LPV and RTV by approximately 40%.

• The reduced and variable exposure and lack of steady-state pharmacokinetic data with crushed tablet dosing reinforces the need to discourage this dosing practice.

• n=12, aleatorizado

• Niños con VIH en tto con LPV/r

• Dosis única de 2 compr. de LPV/r enteros o triturados.

PK: Resumen y Conclusiones

ETR-RAL-DRV/r: No interacción clín. significativa

ATV, ATV/r: [GSK12349572] (similar RAL, no toxicidad)

ARV- otros fármacos:

• LPV/r: [buprenorfina/naloxona] (no ajuste dosis)

• EFV: [anticonceptivos orales] (levonorgestrol)

• NVP: rifampicina ¿iniciar con dosis plena?, ¿mayor dosis?

Buena correlación entre [EFV] en pelo y eficacia

RAL: correlación [plasma] – [intracelular]

Atripla compr vs jarabe casero: No bioequivalencia (casi !!)

Tracto genital masculino y femenino:

• RAL y MVC: excelentes concentraciones

• DRV: concentraciones aceptables

Embarazo:

• [LPV/r] y [FPV/r] pero eficaz (no ajustar dosis)

• [ATV/r], eficaz y bien tolerado (no ajustar dosis)

Pediatría:

• RAL: compr. adultos, gránulos y masticable (OK)

• LPV/r: desaconsejable triturar los comprimidos!

PK: Resumen y Conclusiones