Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona...

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Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron. Barcelona Correo electrónico: Farmacocinética e Interacciones

Transcript of Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona...

Page 1: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Dr. Esteve RiberaServei de Malalties Infeccioses

Hospital Universitari Vall d’Hebron. Barcelona

Correo electrónico: [email protected]

Farmacocinética e Interacciones

Page 2: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Monitorización terapéutica

Concentración mínima efectiva

Interacciones entre ARV

Interacciones ARV – otros fármacos

Farmacogenómica – PK

Page 3: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Prospective Trial to Evaluate How Therapeutic Drug Monitoring of PI Increases Virologic Success and

Tolerance of HAART (COPHAR 2 - ANRS 111 Trial). Mentree F, et al. CROI 2005, poster 639

• 115 patients (42 IDV, 38 LPV, 35 NFV625).

• All PIs were dosed twice daily, and drug levels were measured at weeks 2, 8-16, 24, and 48 after initiating HAART. During the first 24 weeks, PI doses were adjusted if trough concentrations were outside of the manufacturers' recommended range.

• ITT efficacy: 70% IDV, 69% LPV, and 44% NFV at w48.

• A majority of the patients taking NFV had suboptimal levels early on in the study, with 62% being outside the therapeutic range at Week 8. Consequently, ritonavir was added to 10 of the participants' regimens. The additional ritonavir, was well-tolerated and efficiently increased the concentrations in 6 of the 10 participants.

Page 4: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Prospective Trial to Evaluate How Therapeutic Drug Monitoring of PI Increases Virologic Success and

Tolerance of HAART (COPHAR 2 - ANRS 111 Trial). Mentree F, et al. CROI 2005, poster 639

Inicial doseIncreaseDecreaseFluctuation

Page 5: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Prospective Trial to Evaluate How Therapeutic Drug Monitoring of PI Increases Virologic Success and

Tolerance of HAART (COPHAR 2 - ANRS 111 Trial). Mentree F, et al. CROI 2005, poster 639

Inicial doseIncreaseDecreaseFluctuation

Page 6: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Prospective Trial to Evaluate How Therapeutic Drug Monitoring of PI Increases Virologic Success and

Tolerance of HAART (COPHAR 2 - ANRS 111 Trial). Mentree F, et al. CROI 2005, poster 639

Inicial doseIncreaseDecreaseFluctuation

Page 7: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Determinants of the Need for Therapeutic Drug Monitoring: Rates and Predictors from CCTG 578

Haubrich R, et al. CROI 2005, poster 640

Page 8: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

67 (38%) of dosing strategies modified in the TDM arm

Higher dosages recommended in 98.4% of changes

Lopinavir- and efavirenz-containing regimens had higher incidence of dose adjustment (46% and 47%, respectively)

Weight, lopinavir use, and efavirenz use associated with dose adjustment in multivariate analysis

Weight, odds ratio (OR) 1.01 (P = .003)

Efavirenz use, OR 4.6 (P = .001)

Lopinavir use, OR 4.6 (P = .0008)

Determinants of the Need for Therapeutic Drug Monitoring: Rates and Predictors from CCTG 578

Haubrich R, et al. CROI 2005, poster 640

No resultados de eficacia y toxicidad en ambos grupos!!!

Page 9: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Monitorización terapéutica

Concentración mínima efectiva

Interacciones entre ARV

Interacciones ARV – otros fármacos

Farmacogenómica – PK

Page 10: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Minimum Plasma Concentrations of Nevirapine and Efavirenz in Relation to Virologic Failure in Naive

Patients. van Leth F, et al. CROI 2005, oral abstract 80 [2NN]

Page 11: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Minimum Plasma Concentrations of Nevirapine and Efavirenz in Relation to Virologic Failure in Naive

Patients. van Leth F, et al. CROI 2005, oral abstract 80 [2NN]

EFV

Page 12: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Minimum Plasma Concentrations of Nevirapine and Efavirenz in Relation to Virologic Failure in Naive

Patients. van Leth F, et al. CROI 2005, oral abstract 80 [2NN]

Nevirapine

Efavirenz

Page 13: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Minimum Plasma Concentrations of Nevirapine and Efavirenz in Relation to Virologic Failure in Naive

Patients. van Leth F, et al. CROI 2005, oral abstract 80 [2NN]

Cmin cut-off for predicting virologic failure

• Risk of failure increased when Cmin for NVP <3.1/2.3 or EFV <1.1

• Cmin / AUC24h are poor predictors of V. failure (low sensitivity)

• Neg. predictor value is better

Page 14: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Atazanavir Ctrough Is Associated with Efficacy and Safety: Definition of Therapeutic Range

Gonzalez de Requena D, et al. CROI 2005, poster 645

Virological response Bilirrubin > 2 mg/dL (total and uncongugated

Page 15: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Atazanavir Ctrough Is Associated with Efficacy and Safety: Definition of Therapeutic Range

Gonzalez de Requena D, et al. CROI 2005, poster 645

Page 16: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Pharmacokinetic and Pharmacodynamic Determinants of Virological Response to

Enfuvirtide-based RegimensBonora S, et al. CROI 2005, poster 643

An enfuvirtide Ctrough cut off > 2200 ng/ml of efficacy at w12 was found.

Therefore, our study, although it has limited sample size and follow up, pointed out that further evaluations of PK/PD of enfuvirtide are warranted.

N=38

Page 17: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Monitorización terapéutica

Concentración mínima efectiva

Interacciones entre ARV

Interacciones ARV – otros fármacos

Farmacogenómica – PK

Page 18: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Didanosina – Atazanavir

Page 19: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or

Atazanavir/RitonavirKaul S, et al. CROI 2005, poster 648

n=35

SD = single dose; QD = once daily; fed = light meal (303 kcal from 68% carbohydrates, 20% (8.1g) fat, and 12% protein)

ATV400 mg QD

fed

ATV400 mg QD

fed

ATV/RTV300/100 mg QD

fed

ATV/RTV300/100 mg QD

fed

ddl-EC400 mg SD

fasted

ddl-EC400 mg SD

fed

ddl-EC400 mg SD

fed

Day 1 Day 2–7 Day 8 Days 9-18 Day 19

24 h PKddl

24 h PK onDay 7ATV

24 h PKddl, ATV

24 h PK onDay 18

ATV, RTV

24 h PKddl, ATV, RTV

Page 20: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or

Atazanavir/RitonavirKaul S, et al. CROI 2005, poster 648

Page 21: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or

Atazanavir/RitonavirKaul S, et al. CROI 2005, poster 648

3000

0

1000

100

10

1

0.14 8 12 16 20 24

Time (h)

dd

I p

lasm

a c

on

c (

ng

/mL)

ddI-EC (day 1)ddI-EC + ATV (day 8)ddI-EC + ATV/RTV (day 19)

Page 22: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or

Atazanavir/RitonavirKaul S, et al. CROI 2005, poster 648

PK Parameter

Geometric Mean Ratios (90% CI) 400 ddI+400 ATV fed vs 400 ddI fasted

400 ddI+400 ATV fed vs 400 ATV fed

400 ddI+300/100 ATV/r fed vs 400 ddI fasted or 300/100 ATV/r fed

Cmax, ddI 0.640 (0.550-0.743) - 0.617 (0.516-0.737)

AUC, ddI 0.662 (0.596-0.735) - 0.658 (0.590-0.733)

Cmax, ATV - 1.026 (0.927-1.137) 1.038 (1.009-1.068)

AUC, ATV - 0.993 (0.914-1.078) 0.995 (0.962-1.031)

No PK interaction between ddI-EC and atazanavir

Page 23: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Amprenavir – Lopinavir/r -

Efavirenz

Page 24: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Steady-state Pharmacokinetics of Amprenavir, Lopinavir, and Efavirenz Combination in

HIVinfected PatientsPham P, et al. CROI 2005, oral abstract 79

APV PK Parameter

APV (+LPV/r)Median (IQR 25 to 75)

APV (+LPV/r+ EFV)Median (IQR 25 to 75)

p Value

Cmax(ng/mL) 3768 (3215, 8063) 2468 (1781, 4721) 0.128

Tmax (h) 2.1 (1.23, 2.87) 2.4 (2.08, 3.03) 0.19

Cmin(ng/mL) 860 (606, 1712) 1053 (704, 1240) 0.735

AUC(ng·h/mL) 23129 (16290, 37173) 21145 (11878, 28370) 0.176

Half-life (h) 6.68 (5.01, 11.51) 7.61 (5.45, 11.49) 0.933

Amprenavir 750 mg (5c) bid

Page 25: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Steady-state Pharmacokinetics of Amprenavir, Lopinavir, and Efavirenz Combination in

HIVinfected PatientsPham P, et al. CROI 2005, oral abstract 79

LPV PK Parameter

LPV (+APV)Median (IQR 25, 75)

LPV(+APV+EFV)Median (IQR 25, 75)

p Value

Cmax (ng/mL) 11403 (10241, 13007) 10336 (8997, 10965) 0.272

Tmax (h) 5.16 (5.07, 6.11) 6.38 (3.03, 6.42) 0.611

Cmin (ng/mL) 4824 (3968, 6806) 5027 (1637, 6130) 0.447

AUC(ng·h/mL) 95101 (73281, 121068) 94244 (55061, 96414) 0.398

Half-life (h) 8.4 (5.18, 19.51) 5.72 (2.70, 9.54) 0.108

Lopinavir 533/133 mg (4c) bid

Page 26: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Steady-state Pharmacokinetics of Amprenavir, Lopinavir, and Efavirenz Combination in

HIVinfected PatientsPham P, et al. CROI 2005, oral abstract 79

At the studied dose of LPV/r 533/133 bid + APV 750 bid, the PK profiles of LPV and APV were not significantly different in patients who also received EFV.

LPV pharmacokinetic parameters were similar to historical controls receiving LPV/r 400/100 bid.

APV Cmin was similar to that seen with LPV 400/100 bid + APV 600 or 750 mg bid or LPV/r 533/133 bid + FPV 1400 mg bid.

Conclusions

Page 27: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Atazanavir - RTV/SQV

Page 28: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

SQV/ATV2000/400mg

QDWashout

SQV/ATV1600/400mg

QDWashout

SQV/r1600/100mg

QD

1 10 11 12 21 22 31 32 33 42 43 52 53Day

24-hour PK 24-hour PK 24-hour PK

ASPIRE I is a prospective, open-label, three-way sequential crossover clinical trial in seronegative volunteers (n=16)

Saquinavir was administered as Invirase 200mg capsules

PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose Atazanavir in HIVneg Volunteers: ASPIRE I

Becker S, et al. CROI 2005, poster 655

Page 29: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose Atazanavir in HIVneg Volunteers: ASPIRE I

Becker S, et al. CROI 2005, poster 655

0 4 8 12 16 20 24Time (hr)

SQV10000

10

100

1000

SQ

V p

lasm

a co

ncen

trat

ion

(n

g/m

L)

0 4 8 12 16 20 24Time (hr)

SQV10000

10

100

1000

SQ

V p

lasm

a co

ncen

trat

ion

(n

g/m

L)

Figure 1a: Mean (SD) plasma concentration-time profiles for

SQV/r 1600/100 SQV/ATV 2000/400 SQV/ATV 1600/400

Saquinavir

Page 30: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose Atazanavir in HIVneg Volunteers: ASPIRE I

Becker S, et al. CROI 2005, poster 655

0 4 8 12 16 20 24Time (hr)

ATV10000

10

100

1000

AT

V p

lasm

a co

ncen

trat

ion

(ng

/mL)

SQV/ATV 2000/400 SQV/ATV 1600/400

Figure 1b: Mean (SD) plasma concentration-time profiles for

Atazanavir

Page 31: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

• RTV significantly increases SQV concentrations relative to the combination of SQV and ATV.

• SQV doses of 1600 and 2000mg do not alter ATV concentrations.

• Sex appears to influence exposure to all three PIs.

• SQV/ATV 2000/400mg QD reaches pharmacologically active exposure for both PIs and should be further evaluated in HIV-infected, PI-naïve subjects for PK, efficacy and tolerability.

PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose Atazanavir in HIVneg Volunteers: ASPIRE I

Becker S, et al. CROI 2005, poster 655

Conclusions

Page 32: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Inhibidores CCR5 - IP/NN

Page 33: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

The PK Interaction between the CCR5 Antagonist 873140 and Lopinavir/Ritonavir in Healthy Subjects

Adkison K, et al. CROI 2005, poster 664

Page 34: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

The PK Interaction between the CCR5 Antagonist 873140 and Lopinavir/Ritonavir in Healthy Subjects

Adkison K, et al. CROI 2005, poster 664

Page 35: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

The PK Interaction between the CCR5 Antagonist 873140 and Lopinavir/Ritonavir in Healthy Subjects

Adkison K, et al. CROI 2005, poster 664

Page 36: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

HIV + subjects who had been stable for at least 3 months on the following antiretroviral regimens were recruited into one of 4 cohorts:

cohort 1: Efavirenz + Combivir (n=8)

cohort 2: Efavirenz + ddI 250 mg + Tenofovir (n=8)

cohort 3: Nevirapine + 3TC + Tenofovir (n=8)

cohort 4: Kaletra + d4T 40 mg bid + 3TC (n=5)

historical PK data generated in study A4001007

A Novel Probe Drug Interaction Study to Investigate the Effect of Selected ARV on the PK of a Single Oral Dose of Maraviroc (UK-427,857) in HIV

+SubjectsMuirhead G, et al. CROI 2005, poster 663

Page 37: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.
Page 38: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

• Efavirenz-containing regimens resulted in approximately 50% reduction in systemic exposure to MVC while the regimen containing Kaletra resulted in an approximate doubling of exposure.

• The nevirapine-containing regimen resulted in a small increase in Cmax but no effect on AUC12.

• The results of this study confirmed the results previously seen in healthy volunteer studies and support the proposed dose adjustment recommendations for MVC.

• A single oral dose of 300 mg MVC was tolerated in HIV+ subjects when co-administered with each of four different ART regimens.

A Novel Probe Drug Interaction Study to Investigate the Effect of Selected ARV on the PK of a Single Oral Dose of Maraviroc (UK-427,857) in HIV

+SubjectsMuirhead G, et al. CROI 2005, poster 663

Conclusions

Page 39: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Monitorización terapéutica

Concentración mínima efectiva

Interacciones entre ARV

Interacciones ARV – otros fármacos

Farmacogenómica – PK

Page 40: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Omeprazol - Atazanavir

Rifampicina - Atazanavir

Page 41: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Effect of Rifampin on Steady-state Pharmacokinetics of Atazanavir and Ritonavir in

Healthy SubjectsBurger D, et al. CROI 2005, poster 657

Page 42: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Effect of Rifampin on Steady-state Pharmacokinetics of Atazanavir and Ritonavir in

Healthy SubjectsBurger D, et al. CROI 2005, poster 657

Page 43: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Effect of Rifampin on Steady-state Pharmacokinetics of Atazanavir and Ritonavir in

Healthy SubjectsBurger D, et al. CROI 2005, poster 657

Due to considerably lower ATV exposures relative to both the ATV 400 mg and ATV/RTV 300/100 mg clinical dosing regimens, none of the three ATV/RTV once daily dosing regimens studied

in combination with RIF are recommended for clinical use.

Page 44: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

• 20 pacientes con TB que inician ddI + 3TC + EFV• Conc EFV: 1,2,4,i 6 meses de tto con RFP

Entre 1 y 21 meses de finalizar RFPDurante el tto TB: 1,51 ng/ml (mediana)Al retirar la RFP: 1,37 ng/ml (mediana)

• Importante variabilidat interindividual• Estos resultados contrastan con otros en que AUC de EFV se reduce un 20-25% con RFP• Resultados clínicos

16/20 (80%): CV indetectableCD4: +14819/20 (95%) curación TB

• Conclusión: La dosis de 600 mg es suficiente (800 si peso >60?)

Efavirenz levels and clinical outcomes in patients with TB and HIV treated concomitantly with ART

and rifampinJack, et al. CROI 2005, poster 891

Page 45: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

PK Effect of Omeprazole on Atazanavir with Ritonavir in Healthy SubjectsAgarwala S., et al. CROI 2005, poster 658

Page 46: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.
Page 47: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.
Page 48: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

The co-administration of OMP 40 mg QD with ATV/RTV 300/100 mg QD resulted in substantial decreases (72-78%) in the steady-state PK of ATV compared to ATV/RTV 300/100 mg alone.

The creation of an acidic environment [cola 8oz.] (66 - 73% decreases) or the increase of the ATV dose to 400 mg (56-66% decreases) did not mitigate this reduction.

A smaller reduction in the steady-state PK of RTV (~25 - 30%) was also observed.

PK Effect of Omeprazole on Atazanavir with Ritonavir in Healthy SubjectsAgarwala S., et al. CROI 2005, poster 658

Conclusions

Page 49: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Tacrolimus - ARV

Page 50: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Management of Drug-Drug Interactions between Tacrolimus and Highly Active Antiretroviral Therapy

Teicher E., et al. CROI 2005, poster 662

• Ten HIV -infected patients transplanted for end-stage chronic hepatitis C

• HAART was stopped the day of liver transplantation and reintroduced ten days after

• All patients received tacrolimus, prednisolone as immunosuppressive agents and fluconazole 50 mg/day, trimetoprim / sulfametoxaxole and ganciclovir as primary prophylaxis

• Targets for tacrolimus blood concentrations were 8 to 20 ng/mL from day 0 up to week 6 and 5 to 15 ng/mL after week 6.

• Tacrolimus pharmacokinetic parameters were calculated by non-compartmental method (WinNonLin® V3.3 Pharsight), in 8 of these patients on 2 occasions :

period A : when liver function normalized (about 10 days post transplantation)

period B : 10 days after HAART reintroduction at standard doses

• Doses of tacrolimus were adjusted according to tacrolimus blood concentrations

Page 51: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

0

5

10

15

20

25

30

35

without antiretroviral agent with antiretroviral agent

Ora

l cle

aran

ce (

L/h

)

nucleoside analog

efavirenz

nelfinavir

lopinavir/ritonavir

Management of Drug-Drug Interactions between Tacrolimus and Highly Active Antiretroviral Therapy

Teicher E., et al. CROI 2005, poster 662

Page 52: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

0

50

100

150

200

250

without antiretroviral agent with antiretroviral agent

Hal

f-lif

e (h

)

nucleoside analog

efavirenz

nelfinavir

lopinavir/ritonavir

Management of Drug-Drug Interactions between Tacrolimus and Highly Active Antiretroviral Therapy

Teicher E., et al. CROI 2005, poster 662

Page 53: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Management of Drug-Drug Interactions between Tacrolimus and Highly Active Antiretroviral Therapy

Teicher E., et al. CROI 2005, poster 662

Antiretroviral agent

at period B

Nelfinavir + lamivudine + tenofovir

Nelfinavir + abacavir + tenofovir

Lopinavir/ritonavir + didanosine + lamivudine

Lopinavir/ritonavir + lamivudine + tenofovir

Lopinavir/ritonavir + abacavir + tenofovir

Efavirenz + zidovudine + lamivudine

Efavirenz + lamivudine + abacavir

Lamivudine + stavudine + tenofovir

Dose every Dose every

0,5 mg 48h 0,5mg 24h

1 mg 12h 0,5 mg 24h

2mg 12h 1,5 mg 144h

6mg 12h 0,5 mg 240 h

4 mg 12h 1 mg 192h

2,5 mg 12h 3 mg 12 h

2 mg 12h 1,5 mg 12h

0,5 12h 2 mg 12h

Period A Period B

Page 54: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Efavirenz Decreases Buprenorphine Exposure, but Is Not Associated with Opiate Withdrawal in Opioid Dependent

Individuals

McCance-Katz EF., et al. CROI 2005, poster 653

Buprenorphine may be more appropriate than methadone with Efavirenz ART

• Approx 50% decrerase in Buprenorphine exposure

• No clinical opioid withdrawal

Page 55: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

Monitorización terapéutica

Concentración mínima efectiva

Interacciones entre ARV

Interacciones ARV – otros fármacos

Farmacogenómica – PK

Page 56: Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: eribera@vhebron.net Farmacocinética.

MRP4, MRP2, and BCRP Gene Polymorphisms in HIV Infected Patients: Relationships with ZDV- and 3TC-triphosphate Concentrations and IDV

ClearanceAnderson P.L., et al. CROI 2005, poster 649Pharmacogenetics of Long-term Response to

Efavirenz- and Nelfinavir-containing Regimens: NWCS213, an Analysis of ACTG 384.

Haas DW, et al. CROI 2005, oral abstract 81

G516T Polymorphism at the CYP2B6 Isoenzyme Significantly Influences Efavirenz Plasma Levels

and the Risk of Neurological SymptomsNovoa SR, et al. CROI 2005, poster 652

Pharmacogenetics of efavirenz and selective pressure after treatment discontinuation:

NWCS214, an analysis of ACTG stuides A5095/A50975

Hass DW, et al. CROI 2005, poster 651