Farmacocinética e Interacciones

Barcelona, 11 de marzo de 2011

Dr. Esteve RiberaServei de Malalties Infeccioses

Hospital Universitari Vall d’Hebron. Barcelona

� Interacciones IPs VHC

� Interacciones ARV – ARV

� Interacciones ARV – otros fármacos

� Farmacocinética

� Farmacogenómica

� Tejidos y reservorios

� Embarazo

� Pediatría

CROI 2011: Farmacología42 comunicaciones

Nuevos IPs frente a VHC:

• Telaprevir (TVR) (629,119)

• Boceprevir (BOC) (118)

Interacciones y PK

� In vitro studies suggested that Telaprevir (TVR) is both a substrate and an inhibitor of CYP3A .

� In vivo studies in rats demonstrated an increased plasma ex posure of TVR when co-administered with ritonavir ( RTV).

A: TVR 250/12h+RTV 100/12hB: TVR 750/12h+RTV 100/12hC: TVR 750/8h

� Study C122: LPV/r 400/100 mg bid and ATV/r 300/100 mg qd� Study C124: DRV/r 600/100 mg bid and fAPV/r 700/100 m g bid

All drugs were taken with foodPer study, two different RTV-boosted PIs were evalua ted in separate panels of 20 volunteers each

Session 1TVR 750 mg q8h for 10 days

PK profileSession 2

RTV-boosted PI for 20 days

PK profilePK profile

TVR 750 mg q8h for 10 days

Mean Telaprevir profiles. Effect of ARV on Telaprev ir (steady-state)

TVR alone

TVR + ARV

n=14n=17 n=16 n=20

n=12 n=14 n=11 n=18

Time (hours)

0

1000

2000

3000

TV

R c

once

ntra

tion

(ng/

mL)

LPV 400/100 bid ATV 300/100 qd DRV 600/100 bidFPV 700 /100 bid

0 2 4 6 8 0 2 4 6 8

0 2 4 6 8 0 2 4 6 8

• AUC ���� 54% ���� 20% ���� 35% ���� 32%• Cmax ���� 53% ���� 21% ���� 36% ���� 33%• Cmin ���� 52% ���� 15% ���� 32% ���� 30%

Study C122 : LPV/r or ATV/r +TVRStudy C124 : DRV/r or FPV/r +TVR

TVR is a substrate and inhibitor of CYP3A

LPV/r

AUC ���� (����6%)Cmax ���� (����4%)Cmin ���� (����14%)

n=19

n=12

Time (hours)

0

4000

8000

12000

LPV

con

cent

ratio

n (n

g/m

L)

0 2 4 6 8 10 12

PI alonePI + TVR

ATV/r

n=11

n=7

AT

V c

once

ntra

tion

(ng/

mL)

0 6 12 18 24Time (hours)

4000

3000

2000

1000

0

PI alonePI + TVR

AUC ���� (����17%)Cmax ���� 15%Cmin ���� 85%

0 2 4 6 8 10 12

DRV/r

n=16

n=11

Time (hours)

DR

V c

once

ntra

tion

(ng/

mL)

6000

4000

2000

0

PI alonePI + TVR

AUC ���� 40%Cmax���� 40%Cmin ���� 42%

0 2 4 6 8 10 12

FPV/r

n=20

n=18AP

V c

once

ntra

tion

(ng/

mL)

Time (hours)

4000

3000

2000

1000

0

PI alonePI + TVR

AUC ���� 47%Cmax���� 35%Cmin ���� 56%

Wash out

E+T + TVR 1500 mg q12h (7d)E+T + TVR 1125 mg q8h (7d)

E+T + TVR 1500 mg q12h (7d) E+T + TVR 1125 mg q8h (7d)

EFV+TDF 600/300 mg qd (7d)

TVR 750 mg q8h (7d)

No wash outSequence A Sequence B

PK profile PK profile

HIV/HCV negative, healthy volunteers, n=20

TVR 750 mg q8h (n=20, reference)

TVR 1500 mg q12h + E/T (n=16)

TVR 1125 mg q8h + E/T (n=15)

Time (hours)

TV

R c

once

ntra

tion

(ng/

mL)

Effect of EFV/TDF on Telaprevir (steady-state)

AUC Cmax Cmin� TVR 750 q8h reference� TVR 1125 q8h ���� 18% ���� 14% ���� 25% � TVR 1500 q12h ���� 20% ���� (����3%) ���� 48%

Study C134 : EFV and TDF + TVR

EFV 600 mg qd (n=18, reference)

EFV + TVR 1125 mg q8h (n=15)

EFV + TVR 1500 mg q12h (n=16)

Time (hours)

EF

V c

once

ntra

tion

(µg/

mL)

Time (hours)

Ten

ofov

ir co

ncen

trat

ion

(ng/

mL)

TDF + TVR 1125 mg q8h (n=16)

TDF + TVR 1500 mg q12h (n=15)

AUC Cmax Cmin� EFV600 reference� 1125 q8h ���� 18% ���� 24% ���� 10% � 1500 q12h ���� 15% ���� 20%) ���� 11%

Effect of Telaprevir on Efavirenz

AUC Cmax Cmin� TDF300 reference� 1125 q8h ���� 10% ���� 22% ���� 17%� 1500 q12h ���� 10% ���� 24% ���� (����6%)

Effect of Telaprevir on Tenofovir

• RTV-boosted HIV PIs + TVR 750 mg q8h– Mutual drug interactions were observed

• Reduced exposure to TVR, variable effects on HIV PIs

– Protein displacement may play a role in reduction of total concentrations (in-vitro evaluation ongoing)

– Appropriate doses have not been established

• EFV and Tenofovir + TVR 1125 mg q8h– Small changes in TVR, EFV and tenofovir exposure – Higher TVR dose (1125 mg q8h) partly offset interaction with EFV

• Based on these results, a pilot study of TVR in HIV/HCV co-infection was initiated with ATV/r 300/100 mg qd + TVR 750 mg q8h or EFV 600 mg qd + TVR 1125 mg q8h (plus Peg-IFN and ribavirin)– Interim results will be presented by Sulkowski et al. during the late breaker

session tomorrow

• Substrate of 1C2 and 1C3 isoforms of aldo-keto reductase (AKR)• Substrate and inhibitor of CYP3A4/5 and P-gp • Rapid and extensive metabolism to a primary ketone-reduced

metabolite (feces: 79%+8% as parent),

Boceprevir: Preclinical Metabolism

Evaluate inhibitors of AKR and CYP3A4 pathways to ↓↓↓↓ BOC clearance ���� ↓↓↓↓ dosing frequency from TID

� Diflunisal (NSAID) inhibits AKR� Ritonavir inhibits CYP3A4 � Concurrently administer clarithromycin (inhibits P-gp and

CYP3A4) and diflunisal (AKR)

Coadministration of BOC and:� HIV medications (ritonavir, tenofovir, efavirenz)� Pegylated IFN-α

Day 17

BOC 400 mg TID

BOC 400 mg TID* + RTV 100 mg QD

BOC 400 mg BID* + RTV 100 mg BIDDay 1

Day 6

*BOC stopped at day 15 in both arms

N = 16 healthy subjects

BOC + RTV (100 mg QD) vs BOCAUC(T) ratio: 81% (90% CI: 73–91)Cmax ratio: 73% (90% CI: 57–93)

BOC + RTV (100 mg BID) vs BOC AUC(T) ratio:82% (90% CI: 75–88)Cmax ratio: 66% (90% CI: 56–78)

AUC(T), area under the plasma concentration versus time c urve from time 0 dosing interval; BID, two time a d ay; BOC, boceprevir; CI, confidence interval; RTV, ritonavir; TID, three times a day.

800

600

400

200

020 4 6 8 10

Time (h)

BOC (400 mg TID)

BOC (400 mg TID) + RTV (100 mg QD)

BOC (400 mg BID) + RTV (100 mg BID)

Boc

epre

vir

(ng/

mL)

1000

1200

12

Ritonavir no potencia a Boceprevir

Ritonavir

10

2500

2000

1500

1000

500

020 4 6 8

Time (h)

BOC (400 mg BID) + DIF (500 mg BID) on day 6

BOC (400 mg SINGLE DOSE) + DIF (500 mg TID) + CLA (500 mg BID) on day 10

Boc

epre

vir

(ng/

mL)

12

AUC(T), area under the plasma concentration versus time c urve from time 0 dosing interval; BID, two times a day; BOC, boceprevir; CI, confidence interval; CLA, clarithromycin; DIF, diflunisal; TID, three times a day.

0 2 4 6 8 10 12Days

BOC 400 mg BID

DIF 500 mg BID DIF 500 mg TID + CLA 500 mg BIDN = 7 healthy subjects

Clarithromycin and Diflunisal

Metabolic inhibitors (even in combination) did not alter BOC PK profile substantially

BOC + DIF vs BOCAUC(T) 96% (90%CI 79–117)Cmax 86% (56–132)Cmin 131% (104–165)

BOC + DIF + CLA vs BOC + DIFAUC(T) 121% (90% CI: 106–138)Cmax 136% (104–178)

A: BOC (800 mg) TID B: TFV (300 mg) QDC: BOC + TFV

A or B or C

for 7 days

A or B or C

for 7 days

A or B or C

for 7 days≥≥≥≥7 days ≥≥≥≥7 days

N = 18 healthy subjects (n = 2 discontinued due to vomiting and viral infection)

6

BOC vs BOC + TFVAUC(0-8h) ratio 108% (90% CI: 102–114)

Cmax ratio 105% (90%CI: 98–112)

TFV vs TFV + BOCAUC(0-8h) ratio 105% (90% CI: 101–109)

Cmax ratio 132% (90% CI: 119–145)

900

600

300

020 4

Time (h)

Boceprevir aloneBoceprevir + Tenofovir

Boc

epre

vir

(ng/

mL) 1200

8

1500400

350

300

250

200

150

100

50

04 8 12 16 20 240

Tenofovir aloneTenofovir + Boceprevir

Mea

n C

once

ntra

tion

of

Ten

ofov

ir (n

g/m

L)

Time (h)

Tenofovir

No interacción significativa entre Boceprevir y Tenofo vir

A: PEG 1.5 µg/kg/wk for 2 weeks B: BOC 400 mg TID for 1 weekC: PEG + BOC for 2 weeks

A or B or C

A or B or C

A or B or C≥≥≥≥2 weeks

N = 12 Chronic HCV G1 nonresponders to previous PEG ±±±± RBV (n = 2 d/c due to neutropenia/leucopenia)

≥≥≥≥2 weeks

Pegylated Interferon (IFN- αααα 2b)

BOC vs BOC + PEGAUC(tf) ratio 100% (90% CI: 89–113)

Cmax ratio 88% (90%CI: 66–118)

PEG vs PEG + BOCAUC(0-168 h) ratio 98.5% (90% CI: 83–117)

Cmax: N/A

600

500

400

300

200

100

00 2 4 6 8

Time (h)

1000

800

600

500

200

00 24 48 72 96 120 144 168

Combination

Monotherapy

Day 1, 400 mg CombinationDay 8, 400 mg CombinationDay 1, 400 mg Monotherapy

Mea

n C

once

ntra

tion

of

Boc

epre

vir

(ng/

mL)

Mea

n C

once

ntra

tion

ofP

EG

-intr

on (

pg/m

L)

Time (h)

No interacción significativa entre Boceprevir e IFN pe gilado (Pegintron®)

EFAVIRENZ Treatment LS Mean a Ratio % (90% CI)

Effect of EFV (600 mg QD) on BOC (800 mg TID)

Cmax (ng/mL) BOCBOC + EFV

20381871

92 (78–108)

AUC(0-8h) (ng·h/mL) BOCBOC + EFV

69135630

81 (75–89)

Cmin (ng/mL) BOCBOC + EFV

94.452.5

56 (42–74)

Effect of BOC (800 mg TID) on EFV (600 mg QD)

Cmax (ng/mL) EFVEFV + BOC

45735077

111 (102–120)

AUC(0-24h) (ng·h/mL) EFVEFV + BOC

7866794655

120 (115–126)

Days 1–5: BOC 800 mg TIDDay 6: BOC 800 mg single dose

Days 1–10: •EFV 600 mg QD

Days 11–15: BOC 800 mg TIDDay 16: BOC 800 mg single doseDays 11–16: EFV 600 mg QD

Washout≥7 days

N = 12 healthy volunteers

• Metabolic inhibitors (even in combination) did not alter BOC PK profile substantially to change BOC’s dose or schedule

• Diflunisal (AKR inhibitor) did not alter BOC exposure

• Ritonavir (CYP 3A4 inhibitor) did not substantively affect exposure to BOC

• Clarithromycin (CYP3A4, P-gp inhibitor) did not affect exposure to BOC

• No dosage adjustment is needed for the coadministrati on of BOC with tenofovir or peginterferon

• Clinical implications of a ↓↓↓↓ mean BOC trough concentration when coadministered with efavirenz will be clearer as data from coinfected populations are obtained

Entre ARV:

• RAL qd – ATV qd (634)

• RAL qd, bid – DRV/r qd (638)

• MVC qd – DRV/r qd (636)

• NNRTI – RAL, GSK2248761 (631)

• TMC278 tras EFV (630)

Interacciones

Raltegravir Atazanavir

No diferencias significativas en ningún parámetro PK

RAL 400 mg BID vs. 800 mg QD (+ ATV 600 mg QD + 3TC 300 mg QD or FTC 200mg QD)

• RAL 800 mg QD in presence of ATV 600 mg and 3TC or FTC results in comparable AUC0-24 to RAL 400 mg BID.

• The regimen was well tolerated and VL remained unde tectable.

PK parameter AUC0-t (h.mg/L) Cmax (mg/L) Cmin (mg/L)

RAL 400 mg BID , GM (95%CI) 7.5 (5.4-10.5) 1.9 (1.4-2.6) 0.08 (0.05-0.16)

RAL 800 mg QD , GM (95%CI) 13.7 (9.6-19.6) 2.6 (1.8-3.7) 0.03 (0.01-0.05)

QD versus BID , GMR (90%CI) 1.82 (1.26-2.63) 1.36 (0.93-2.00) 0.27 (0.15-0.49)

RAL 400 mg BID, 21 days

Period 1 (n=24) Period 2 (n=24)

RAL 400 mg BID +DRV/r 800/100 mg QD, 14 d

G 1: continue RAL 400 mg BID

G 2: switch to RAL 800 mg QD

random

DRV/r 800/100 mg QD, 14 dStop RAL

intracellular

plasma intracellular

plasma

Period 3 (n=24)

Darunavir Raltegravir

There was no evidence of an interaction between ral tegravir and QD darunavir/ritonavir.

The intracellular raltegravir reported here differs from previously reported data (rapid washout)

N=10 N=36 N=16

• 300mg MVC qd with DRV/r 800/100 qd achieved compara ble MVC Cpeak and

higher Ctrough compared to 300 mg BD dosed with NRTIs (no boosted PIs)

• MVC 150mg qd with DRV/r 800/100 qd achieved compara ble Ctrough compared to 300 mg bid dosed with NRTIs (no boosted PIs)

• The planned phase 3 study (A4001095) is using a do se of 150 mg of MVC OD with DRV/r 800/100

� Co-administration of RAL 400 mg q12h with GSK2248761 200 mg q24h resulted in no significant drug interaction

Mean GSK2248761 PK Alone and with RAL Mean RAL PK Alone and with GSK2248761

↑ 15% AUC

↑ 16% Cmax

↓↓↓↓ 18% AUC

↓↓↓↓ 18% Cmax

A B C

RPV AUC24h, ng·h/mL (mean ± SD) Mean Ratio Switch : Reference

(90%CI)

Ex Vivo Activity

Mean RPV EC50 > 50%

n (%)RPV reference

(n=20)EFV -> RPV

(n=16)

Day 1 1095 ± 327 602 ± 204 0.54 (0.46, 0.64) Day 2, 4, 7 17 (100%)

Day 14 2528 ± 596 1940 ± 528 0.82 (0.75, 0.89) Day 14 15 (88%)

Day 21 - 2089 ± 526 0.84 (0.74, 0.94) Day 21 14 (82%)

Day 28 - 2298 ± 548 0.91 (0.82, 1.01) Day 28 15 (88%)

Interacciones

ARV – otros fármacos:

• RAL – pH gástrico (635)

• RAL – inmunosupresores (644)

• LPV/r – rifabutina (650)

• Anticonceptivos orales (637)

• ARV – epilepsia (646)

���� liposolubilidad

AUC-MPA PRERAL = 28,8 ugxh/mLAUC-MPA POSRAL = 38,7 ugxh/mL

0123456

0 2 4 6 8 10 12 14

time (h)

[MP

A] (

ug/m

L)

AUC-RAL POSRAL = 17,8 ugxh/mL

01234567

0 5 10 15time (h)

[RA

L] (u

g/m

L)� Raltegravir combined with two NRTIs was effective and safe and made it possible to normalize the dose of calcineurin inhibitors (CsA and FK) in the absence of PK interactions in HIV-infected SOT recipients. � RAL does not significantly interfere with the metabolism of MPA, and the PK of RAL is not altered in the presence of MPA.

mycophenolic acid

• 16/31 (51.6%) SOT recipients were taking RAL and 2 NRTIs

• Virological results: All patients had VL <50 copies /mL for a median of 19 months.

NVP (Triomune®) 200/12hNVP (Triomune®) 200/12h

N=9 (3xgrupo) EE 30μμμμg + LNG 300μμμμg/d (LoFemenal®)

Nevirapina no ↓↓↓↓ [EE/LNG] ni ↓↓↓↓ su efecto (inhibición de la ovulación)

1: NVP 200 mg/12h (Triomune®)N=9 (3xgrupo) All: EE 30 μμμμg + LNG 300μμμμg/d (LoFemenal®)

HIV neg

No TAR

TAR

HIV neg

No TAR

TAR

Nevirapina no ↓↓↓↓ [EE/LNG] ni ↓↓↓↓ su efecto (inhibición de la ovulación)

EI-AED Other AEDAdjusted OR

(95% CI) or Diff ±±±± SE

Virologic failure 19/30 (63.3%) 34/122 (27.9%) 4.19 (1.54 – 11.44)

Average log10 VL during period

3.3 ± 1.3 (n=34) 2.5 ± 1.3 (n=142) 0.7 ± 0.3 (P=0.007)

VL <400 c/mL at 6 m 8/28 (28.6%) 84/121 (69.4%) 0.25 (0.07 – 0.86)

VL <400 c/mL at 12 m 9/23 (39.1%) 71/96 (74.0%) 0.22 (0.06 – 0.75)

• EI-AED: enzyme-inducing antiepileptics (phenytoin, carbamazepine, or phenobarbital)• Other AED: not enzyme-inducing antiepileptics (lamotrigine, levetiracetam, pregabalin or gabapentin)

� Concurrent EI-AED and HAART use has greater risk of virologic failure� Sole availability of EI-AEDs in resource limited areas may have significant clinical ramifications� EI-AEDs should be avoided with HAART if possible. Valproic acid may be a potential alternative� If EI-AEDs must be used:

� Consider using alternative HAART regimens� Triple NRTIs or raltegravir-based regimens, if available� Monitor clinical and virologic response more frequently

Farmacocinética ARV, PK-PD:

• NVP: PK y toxicidad (647)

• ATV PK (648,639)

• DRV/r y ATV/r tras suspensión (632)

• TDF/FTC intracelular (641)

• RAL qd Thais (649)

• ZDV ic y mtDNA (640)

• Cvalle necesaria (633)

� ↑↑↑↑ [NVP] se asoció a rash grado 3 pero no a toxicidad hepática en mujeres africanas.

� CD4>250 c/mm3 se asoció a rash/toxicidad hepática grado 3, toxicidad hepática grado 2 y a interrupción de TAR por toxicidad cutánea o hepática

� 359 women

� naïve

� TDF/FTC+NVP

10

20

30

40

50

60

70

80

90

100

AT

V A

UC

(m

g*h/

L

Males Females

34.329.6

34.3

P<0.001

� ddI-EC + FTC + ATV 400 mg QD

� n= 359 (178 women, 181 men)

� Population PK modeling analysis (NONMEM®)

� Sex and geographical location were associated with ATV clearance.

� ATV clearance was significantly reduced in females and lower by 20%

C24 (ng/mL): 93.5 vs 182.1 (p<0.001)

MRP 1-2 (ABCC1-2)

P-gp (ABCB1)

SLCO3A1

PXR

• ATV plasma Ctrough 543 ng/ml (430 - 724)

• Intracellular concentration 1461 ng/ml (872 - 2344)

• Cellular accumulation ratio (CAR) was 2.45 (1.91 – 5.88)

These data suggest that the SLCO3A1 uptake transporter is a key determinant

of intracellular ATV concentrations.

AUC0-24 AUC0-72 C24 C72 half-life 0-24 half-life 0-72 C30 (>550/150ng/mL)

DRV 53910 70686 1008 12 10.70 6.48 851 (16/17)

ATV 34851 43394 693 6 13.72 6.74 392 (17/17)

In conclusion , our study has explored the pharmacokinetic forgiveness of two boosted PI and showed a relatively constant decline of both darunavir and atazanavir over 72 hours following

drug intake cessation, resulting in a delayed onset of sub‐therapeutic concentrations

Darunavir Atazanavir

Use of low dose RAL could be a safe and cost-saving option for maintenance therapy that would allow mor e people in resource-limited settings to access-third line treatment

HIV negative participants received 300 mg ZDV/150 m g 3TC twice daily for twelve days.

GMR (95%CI): 0.75 (0.72-0.78), p<0.001

GMR (95%CI): 1.02 (0.97-1.07), p=0.46

� Twelve days of ZDV/3TC was associated with slight mtDNA decreases in adipose tissue of HIV negative volunteers.

� The concentration-effect relationship between adipose tissue and TP in PBMC, but not parent drug in plasma, may reflect similarities in the multifaceted phosphorylation pathway in both tissue types and the dependency of adverse events on this pathway.

Farmacogenómica ARV:

• ETR (479)

� Co-medication and genetic factors explain 10% of the variance in ETV clearance.

� The opposing contributions of co-medication and genetic variants may result in mutual compensation, a consideration when attempting personalization of ETV dosage adjustment.

Concentración de ARV en tejidos y reservorios:

• DRV, ETR LCR (643)

• MVC LCR (642)

Total plasma Unbound plasma

Total CSF Unbound CSF

Hours Post Dose

CSF 1% exceed wild-type HIV IC 50 by >18 fold CSF 4% exceed wild-type HIV IC 50 by >13 fold

� In this HIV-infected neuroasymptomatic population studied on a standardized antiretroviral regimen, mean MVC CSF:plasma ratio of 1.01% was observed. � Interestingly, increases in cerebral metabolite markers of neuronal integrity (NAA/Cr ratios) were also observed and were associated with MVC trough plasma concentration

PK – embarazo y neonatos:

• EFV (754)

• 3TC, FTC, TDF (755,756)

• LPV/r meltrex (645)

� EFV was well tolerated during pregnancy.

� Placental transport of EFV is good, with a median ratio of EFV cord blood to maternal delivery concentration of 49% (virologically suppressive conc. cross placenta)

� Lower EFV C 24, but given the small magnitude of change the impact is likely not clinically significant.

� Standard EFV dosing provided adequate drug exposure during 3 rd trimester of pregnancy.

� Maternal, fetal and amniotic fluid lamivudine pharmacokinetics was accurately described by the proposed model.

� Lamivudine apparent clearance was increased by 22% in pregnant women compared to non pregnant or parturient women.

� Exposures in pregnant women being close to the non pregnant adult reported values, no dose adjustment should be needed .

� Maternal-to-fetal transfer was assessed using an exposure ratio that was about 86%. Accumulation into the amniotic fluid compartment expressed as a constant AUC ratio was 3.

Maternal FetalAmniotic

fluid

� The proposal maternal readministration of two tablets of TDF/FTC to the mother after 12 hours if she had not delivered yet was confirmed.

� In neonates, the 13 mg/kg TDF dose produced similar plasma TFV and intracellular active TFV-DP concentrations as in adults whereas the 2 mg/kg FTC dose produced a high exposure to the active FTC-TP despite plasma FTC concentrations equivalent to adults.

TDF-DPTDF

FTC-TP

Adult (mother)

Neonate

Fetus (cord)

Median FTC-TP exposure were respectively 5.9 and 6.8 higher in the fetus and the neonate than in the adult

Total AUC 12h Unbound AUC 12h Total C 12h Unbound C 12h

400/100 bidPK1 (20-24w)

61.3 (57.7 to 73.0) 1.6 (1.3 to 1.9) 5.2 (3.9 to 5.7) 0.15 (0.08 to 0.16)

400/100 bidPK2 (30w)

64.1 (51.3 to 69.7) 1.6 (1.3 to 1.9) 4.0 (3.4 to 5.4) 0.10 (0.08 to 0.15)

500/125 bidPK3 (32w)

69.1 (55.2 to 78.2) 1.8 (1.3 to 2.1) 4.9 (4.4 to 6.0) 0.12 (0.10 to 0.15)

400/100 bidPK43 (8w PP)

98.0 (67.1 to 115.1) 2.6 (1.6 to 3.6) 7.2 (6.1 to 9.3) 0.16 (0.14 to 0.27)

� Total and unbound LPV exposures increased linearly with the dose increase. � In this study, a 25% dose increase did not achieve PP exposure.� However, in the third trimester, total C12h concentrations were above target concentration (>1mg/mL) and all unbound C12h exposures were >70x the unbound IC50 HIVWT before the PK3 dose increase. � These data suggest that LPV/r dose adjustment may not be necessary for all women during pregnancy.

PK - pediatría:

• ATV/r (712)

• DRV/r (714)

• LPV/r (709)

• NVP (716,717)

• ZDV, 3TC (718,719)

Scatter-plot of the lopinavir AUC 0-

12h with bodyweight

� This study demonstrated adequate pharmacokinetic parameters of low dose LPV/r tablet formulation in Thai children. A larger randomized clinical study to assess efficacy should be explored.

� The successful usage of low dose LPV/r could have a significant public health impact in reducing side effects and costs related to treating complications and procuring drugs.

PK: Resumen y Conclusiones

Telaprevir y Boceprevir – ARV:• Interacciones bilaterales no predecibles

• RTV no potencia a telaprevir ni a boceprevir

• LPV/r , DRV/r (600/100bid), FPV/r y ATV/r: ↓↓↓↓[TVR]

• TVR: ↓↓↓↓[FPV/r, DRV/r (600/100bid) ],~ [LPV/r], ↑↑↑↑ [Cmin ATV/r]

• EFV: ↓↓↓↓[TVR]. Aumentar dosis TVP a 1125 mg/8h

• Eficacia clínica de TVR + EFV y TVR + ATV/r

• BOC: IP/r ?, ↓↓↓↓[EFV] ajuste dosis ?, TDF e IFN OK

• Estudios clínicos BOC con IP/r o RAL en marcha.

� [RAL 800 qd] ~ [RAL 400 bid] (+ATV 600 + 3TC/FTC)

� No interacciones entre DRV/r qd y RAL (plasma, cel)

� [MVC 300 bid (TDF/FTC) ] ~ [MVC 150 qd (DRV/r 800/100]

� [TMC278] ↓↓↓↓ inicial tras EFV, ↑↑↑↑ progresivo (~ sem 4)

� No interacción RAL-inmunsupres. (inc. micofenolato)

� Ojo con antiepilepticos inductores de CYP450 (phenytoin, carbamazepine, or phenobarbital)

PK: Resumen y Conclusiones

PK: Resumen y Conclusiones

� Relación entre [NVP] elevadas y rash grado 3-4

� ↓↓↓↓ 20% Clearance ATV en mujeres ( ↑↑↑↑ [ATV])

� Variabilidad [ETR]: 10% genes y comedicación

� Concentr. eficaces de DRV, ETR y MVC en LCR

� ‘Efecto perdón’ relativ. prolongado con DRV y ATV

� Embarazada:

• EFV: Concentraciones similares a postparto.

• LPV/r meltrex: ~ clásico ( ↓↓↓↓ conc. pero no ajustar dosis)