1. Farmacocinética e Interacciones
Barcelona, 26 de febrero de 2010
Farmacocinética e Interacciones
Dr. Esteve Ribera
Servei de Malalties Infeccioses
Hospital Universitari Vall d’Hebron. Barcelona

2. Total: 44 comunicaciones

3. CROI 2009: Farmacología Interacciones ARV – ARV
Interacciones ARV – otros fármacos
Farmacocinética
Farmacogenómica
Tejidos y reservorios
Embarazo
Pediatría

4. Entre ARV: Interacciones ETR-RAL-DRV/r (606)
ATV y ATV/r – GSK (616)

5. N=10

6. ATV ATV/r AUC  91  62 % Cmax  50  34 % Ctr 180 121 %
Well tolerated in healthy adult subjects.
No dose adjustment is necessary

7. Interacciones ARV – otros fármacos: LPV/r – buprenorf/naloxona (620)
FPV – posaconazol (621)
EFV – levonorgestrel (934)
NVP – lumefantrina (603)
NVP – RFP (602)

8. HIV-seronegative subjects
Plasma Concentration (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.

9. 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.

10. 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.

11. Cmax (ug/mL) Naïve (n=18) Nevirapine (n=18) P 8.76 (5.52-14.90)
10.9 ( )
0.0598
AUC(ug.h/mL)
( )
( )
0.0011

12. 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
3000 ng/mL
(MEC)
DAY 7 (Esc, n=7) DAY 14 (Esc, n=6) DAY 21 (Esc, n=5)
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.

13. Farmacocinética ARV: EFV en pelo (604) TDF/FTC/EFV solución (605)
RAL intracelular (614)

14. Only hair EFV levels remain strongly correlated with viral load undetectability

15. TDF Cmax and AUC fell above the range (40% and 20% higher).
Drug
Formulation
Cmax (mg/L)
AUC0-∞ (mg*h/L) GM
(%CV)
Ratio of GM
Liquid vs. Tablet
(90% CI)
EFV
Liquid
1.3 (28.8)
0.86 ( )
56.7 (80.0)
0.97 ( )
Tablet
1.5 (39.0)
58.7 (57.5)
FTC
2.1 (21.0)
1.15 ( )
10.8 (15.9)
0.99 ( )
1.8 (32.3)
10.9 (24.7)
TDF
0.3 (27.7)
1.38 ( )
2.2 (36.3)
1.21 ( )
0.2 (47.8)
1.8 (29.2)
90% CI for FTC Cmax and AUC fell within the range of (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.

16. RAL Ctot are well correlated with Ccell (r=0
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 to (a15-folddifference).

17. Concentración de ARV en tejidos y reservorios:
RAL genital (608, 609)
DRV genital (610, 611)
MVC LCR y genital (oral 85, 612)

20. Likely contributing to virological control in the compartment
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.

22. [DRV] Seminal plasma  8. 6% (5. 7-22
[DRV] Seminal plasma  8.6% ( %) 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.

23. Time post Drug Ingestion
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
( )
3734
( )
2445
( )
Median SP
[DRV] IQR
588
( )
490
( )
217
( )
Median
SP:BP ratio
IQR
0.11
( )
n=8
0.13
( )
n=13
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
n=18
SP:BP DRV AUC 0-24h ratio = ( )

25. 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)

26. *CROI 2010; P611; Taylor, Jayasuryia , Dufty et al
Men
TVFdp >1000%h
Women
ddI 992% b
Rectal Tissue
MVC % *
3TC 667% g
84LB
RAL 642%
P609
600%
ZDV 590% b
ABC 560% d
Semen/BP ratios
paired samples
Semen/BP AUC ratios
GT/BP AUC
ratios
GT/BP ratios
paired samples
TVF 510% h
TVF 515% b
500%
Higher
Genital
Tract
Exposures
400%
3TC 411% c
FTC 395% c
3TC 460% o
d4T 350% v
IDV/r 380% aa
TVF 330% i
ZDV 330% g
300%
P608
3TC 319% b
MVC 273% a
MVC 200% *
Vaginal Tissue
P609
ZDV 228% y
ZDV 235% c
RAL 230 %
200%
MVC 190% a*
ZDV 190% o
FTC 150% b
RAL 160%
Equivalent
Blood and
Genital
Tract
Exposures
RAL 142% m
ABC 150% z
DRV 150% n
ETR 130% n
IDV/r 132% aa
IDV 145% bb
IDV 140% p
NVP 130% bb
IDV 100% z
3TCtp 100% g
100%
TVF* 110% c
ddI 114% b*
RAL 93% f
TVF 90% o
84LB
80%
RTV 81% b
NVP 80% bb
MVC 72%
84LB
TVF 75% c
MVC 71%
IDV 70% bb*
P612
NVP 61% v
MVC 62%
60%
Lower
Genital
Tract
Exposures
ABC 58% b
NFV 54% o
RTV 54% o
APV 50% bb
40%
ZDVtp 33% g
LPV 30% b
RTV 26% c
P610
APV 20% cc
20%
ddI 21% c
P611
DLV 16% x
*DRV 17%
ATV 18% c
DLV 20% bb
RTV 19 b
*DRV 12%
*DRV 9%
ATV 10% k
EFV 9% w
P611
LPV 6% q
NFV 7% r
RTV 7% j
LPV 5 % j
LPV 12% b
ABC 8% c
LPV 8% c
SQV 3% p
RTV 3% q
LPV 2-3% t
d4T 2% v
LPV 3% b
LPV 5% bb
DLV 5% bb
EFV 3.3% s
d4T 5% c
RTV 3% b
ENF ND s
RTV ND p
SQV ND d
LPV ND u
EFV ND i 0%
EFV 0.4% c
SQV bb
EFV 1% b
*CROI 2010; P611; Taylor, Jayasuryia , Dufty et al
From Dumond, Cohen and Kashuba 2007; adapted by Taylor and Davies 2010 26

27. PK – embarazo y neonatos:
LPV (906)
ATV (907)
FPV (908)
NVP (910, 911)

28. 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.

29. 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.

30. APV 3rd Tri Postpart Ratio (90CI)
AUC ( )
Cmax ( )
Cmin ( )
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.

31. PK - pediatría:
RAL (oral 161,872, 873)
LPV/r (877)

32. 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

33. Open label study of RAL in treatment experienced HIV+ youth
Cohort I: 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

34. 80.7 (182 nM)
56.8 (128 nM)
109 (246 nM) C
min
(ng/mL)
51.2 (68%)
21.2 (38%)
49.6 (152%)
CL/F (L/hr, %CV)
7.4 (16.7 m M h)
10.0 (22.5
7.0 (15.8 h )
AUC 12
(mg
h/L)
Adults
(400 mg bid, fasting)**
N=45
Cohort IIB
6 mg/kg bid, fasting)
N=10
Cohort IIA
(400 mg bid, fasting)
N=11
Parameter
RAL chewable tablets safe and well tolerated. Wk 12 efficacy data were favorable
**Adult Data - Luber et al. 49th ICAAC, September 12-15, 2009, San Francisco, CA

35. Niños con VIH en tto con LPV/r
n=12, aleatorizado
Niños con VIH en tto con LPV/r
Dosis única de 2 compr. de LPV/r enteros o triturados.
LPV Whole Crushed Ratio (90CI)
AUC (0.48 –0.72)
Cmax (0.65 –0.98)
Cmin (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.

36. PK: Resumen y Conclusiones
ETR-RAL-DRV/r: No interacción clín. significativa
ATV, ATV/r:  [GSK ] (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 !!)

37. PK: Resumen y Conclusiones
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!