Transcript 12th CROI. Boston, USA, February 22

Farmacocinética e
Interacciones
Dr. Esteve Ribera
Servei de Malalties Infeccioses
Hospital Universitari Vall d’Hebron. Barcelona
Correo electrónico: [email protected]
 Monitorización terapéutica
 Concentración mínima efectiva
 Interacciones entre ARV
 Interacciones ARV – otros fármacos
 Farmacogenómica – PK
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.
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 dose
Increase
Decrease
Fluctuation
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 dose
Increase
Decrease
Fluctuation
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 dose
Increase
Decrease
Fluctuation
Determinants of the Need for Therapeutic Drug
Monitoring: Rates and Predictors from CCTG 578
Haubrich R, et al. CROI 2005, poster 640
Determinants of the Need for Therapeutic Drug
Monitoring: Rates and Predictors from CCTG 578
Haubrich R, et al. CROI 2005, poster 640
 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)
No resultados de eficacia y toxicidad en ambos grupos!!!
 Monitorización terapéutica
 Concentración mínima efectiva
 Interacciones entre ARV
 Interacciones ARV – otros fármacos
 Farmacogenómica – PK
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]
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
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
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
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
Atazanavir Ctrough Is Associated with Efficacy and Safety:
Definition of Therapeutic Range
Gonzalez de Requena D, et al. CROI 2005, poster 645
Pharmacokinetic and Pharmacodynamic Determinants of
Virological Response to Enfuvirtide-based Regimens
Bonora S, et al. CROI 2005, poster 643
N=38
 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.
 Monitorización terapéutica
 Concentración mínima efectiva
 Interacciones entre ARV
 Interacciones ARV – otros fármacos
 Farmacogenómica – PK
Didanosina – Atazanavir
Pharmacokinetics of Didanosine Enteric Coated Capsules
Co-administered with Atazanavir or Atazanavir/Ritonavir
Kaul S, et al. CROI 2005, poster 648
ATV
400 mg QD
fed
ddl-EC
400 mg SD
fasted
ATV
400 mg QD
fed
ATV/RTV
300/100 mg QD
fed
ddl-EC
400 mg SD
fed
ATV/RTV
300/100 mg QD
fed
ddl-EC
400 mg SD
fed
Day 1
Day 2–7
Day 8
Days 9-18
Day 19
24 h PK
ddl
24 h PK on
Day 7
ATV
24 h PK
ddl, ATV
24 h PK on
Day 18
ATV, RTV
24 h PK
ddl, ATV, RTV
n=35
SD = single dose; QD = once daily; fed = light meal (303 kcal from 68% carbohydrates, 20% (8.1g) fat, and 12% protein)
Pharmacokinetics of Didanosine Enteric Coated Capsules
Co-administered with Atazanavir or Atazanavir/Ritonavir
Kaul S, et al. CROI 2005, poster 648
Pharmacokinetics of Didanosine Enteric Coated Capsules
Co-administered with Atazanavir or Atazanavir/Ritonavir
ddI plasma conc (ng/mL)
Kaul S, et al. CROI 2005, poster 648
3000
1000
ddI-EC (day 1)
ddI-EC + ATV (day 8)
ddI-EC + ATV/RTV (day 19)
100
10
1
0.1
0
4
8
12 16
Time (h)
20
24
Pharmacokinetics of Didanosine Enteric Coated Capsules
Co-administered with Atazanavir or Atazanavir/Ritonavir
Kaul S, et al. CROI 2005, poster 648
Geometric Mean Ratios (90% CI)
PK
400 ddI+400 ATV
fed
Parameter vs 400 ddI fasted
400 ddI+400 ATV
fed
vs 400 ATV fed
400 ddI+300/100 ATV/r
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
fed
Amprenavir –
Lopinavir/r Efavirenz
Steady-state Pharmacokinetics of Amprenavir, Lopinavir,
and Efavirenz Combination in HIVinfected Patients
Pham P, et al. CROI 2005, oral abstract 79
Amprenavir 750 mg (5c) bid
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
Steady-state Pharmacokinetics of Amprenavir, Lopinavir,
and Efavirenz Combination in HIVinfected Patients
Pham P, et al. CROI 2005, oral abstract 79
Lopinavir 533/133 mg (4c) bid
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
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
8.4 (5.18, 19.51)
5.72 (2.70, 9.54)
0.108
Tmax (h)
Half-life (h)
Steady-state Pharmacokinetics of Amprenavir, Lopinavir,
and Efavirenz Combination in HIVinfected Patients
Pham P, et al. CROI 2005, oral abstract 79
Conclusions
 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.
Atazanavir - RTV/SQV
PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose
Atazanavir in HIVneg Volunteers: ASPIRE I
Becker S, et al. CROI 2005, poster 655
 ASPIRE I is a prospective, open-label, three-way sequential crossover
clinical trial in seronegative volunteers (n=16)
24-hour PK
SQV/r
1600/100mg
QD
1
10 11 12
24-hour PK
Washout
SQV/ATV
1600/400mg
QD
21 22
31 32 33
24-hour PK
Washout
42 43
Day
 Saquinavir was administered as Invirase 200mg capsules
SQV/ATV
2000/400mg
QD
52 53
PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose
Atazanavir in HIVneg Volunteers: ASPIRE I
Becker S, et al. CROI 2005, poster 655
SQV plasma concentration (ng/mL)
Figure 1a: Mean (SD) plasma SQV
concentration-time profiles for
10000
Saquinavir
1000
100
10
0
4
SQV/r 1600/100
8
12
Time (hr)
SQV/ATV 2000/400
16
20
24
SQV/ATV 1600/400
PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose
Atazanavir in HIVneg Volunteers: ASPIRE I
Becker S, et al. CROI 2005, poster 655
ATV plasma concentration (ng/mL)
Figure 1b: Mean (SD) plasma concentration-time profiles for
ATV
Atazanavir
10000
1000
100
10
0
4
8
12
Time (hr)
SQV/ATV 2000/400
16
20
SQV/ATV 1600/400
24
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
• 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.
Inhibidores CCR5 - IP/NN
The PK Interaction between the CCR5 Antagonist 873140
and Lopinavir/Ritonavir in Healthy Subjects
Adkison K, et al. CROI 2005, poster 664
The PK Interaction between the CCR5 Antagonist 873140
and Lopinavir/Ritonavir in Healthy Subjects
Adkison K, et al. CROI 2005, poster 664
The PK Interaction between the CCR5 Antagonist 873140
and Lopinavir/Ritonavir in Healthy Subjects
Adkison K, et al. CROI 2005, poster 664
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 +Subjects
Muirhead G, et al. CROI 2005, poster 663
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 +Subjects
Muirhead G, et al. CROI 2005, poster 663
Conclusions
• 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.
 Monitorización terapéutica
 Concentración mínima efectiva
 Interacciones entre ARV
 Interacciones ARV – otros fármacos
 Farmacogenómica – PK
Rifampicina - Atazanavir
Omeprazol - Atazanavir
Effect of Rifampin on Steady-state Pharmacokinetics of
Atazanavir and Ritonavir in Healthy Subjects
Burger D, et al. CROI 2005, poster 657
Effect of Rifampin on Steady-state Pharmacokinetics of
Atazanavir and Ritonavir in Healthy Subjects
Burger D, et al. CROI 2005, poster 657
Effect of Rifampin on Steady-state Pharmacokinetics of
Atazanavir and Ritonavir in Healthy Subjects
Burger 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.
Efavirenz levels and clinical outcomes in patients with TB
and HIV treated concomitantly with ART and rifampin
Jack, et al. CROI 2005, poster 891
• 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 RFP
Durante 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 indetectable
CD4: +148
19/20 (95%) curación TB
• Conclusión: La dosis de 600 mg es suficiente (800 si peso >60?)
PK Effect of Omeprazole on Atazanavir with Ritonavir in
Healthy Subjects
Agarwala S., et al. CROI 2005, poster 658
PK Effect of Omeprazole on Atazanavir with Ritonavir in
Healthy Subjects
Agarwala S., et al. CROI 2005, poster 658
Conclusions
 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 (5666% decreases) did not mitigate this reduction.
 A smaller reduction in the steady-state PK of RTV (~25 30%) was also observed.
Tacrolimus - ARV
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
Management of Drug-Drug Interactions between
Tacrolimus and Highly Active Antiretroviral Therapy
Teicher E., et al. CROI 2005, poster 662
35
Oral clearance (L/h)
30
25
nucleoside analog
20
efavirenz
15
nelfinavir
10
lopinavir/ritonavir
5
0
without antiretroviral agent
with antiretroviral agent
Management of Drug-Drug Interactions between
Tacrolimus and Highly Active Antiretroviral Therapy
Teicher E., et al. CROI 2005, poster 662
250
Half-life (h)
200
150
nucleoside analog
efavirenz
100
nelfinavir
lopinavir/ritonavir
50
0
without antiretroviral agent
with antiretroviral agent
Management of Drug-Drug Interactions between
Tacrolimus and Highly Active Antiretroviral Therapy
Teicher E., et al. CROI 2005, poster 662
Period A
Period B
Antiretroviral agent
Dose
every
Dose
every
at period B
0,5 mg
48h
0,5mg
24h
Nelfinavir + lamivudine + tenofovir
1 mg
12h
0,5 mg
24h
Nelfinavir + abacavir + tenofovir
2mg
12h
1,5 mg
144h
Lopinavir/ritonavir + didanosine + lamivudine
6mg
12h
0,5 mg
240 h
Lopinavir/ritonavir + lamivudine + tenofovir
4 mg
12h
1 mg
192h
Lopinavir/ritonavir + abacavir + tenofovir
2,5 mg
12h
3 mg
12 h
Efavirenz + zidovudine + lamivudine
2 mg
12h
1,5 mg
12h
Efavirenz + lamivudine + abacavir
0,5
12h
2 mg
12h
Lamivudine + stavudine + tenofovir
Efavirenz Decreases Buprenorphine Exposure, but Is Not Associated
with Opiate Withdrawal in Opioid Dependent Individuals
McCance-Katz EF., et al. CROI 2005, poster 653
• Approx 50% decrerase in Buprenorphine exposure
• No clinical opioid withdrawal
Buprenorphine may be more appropriate than methadone with Efavirenz ART
 Monitorización terapéutica
 Concentración mínima efectiva
 Interacciones entre ARV
 Interacciones ARV – otros fármacos
 Farmacogenómica – PK
MRP4, MRP2, and BCRP Gene Polymorphisms in HIV
Infected Patients: Relationships with ZDV- and 3TCtriphosphate Concentrations and IDV Clearance
Anderson P.L., et al. CROI 2005, poster 649
Pharmacogenetics 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
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
G516T Polymorphism at the CYP2B6 Isoenzyme
Significantly Influences Efavirenz Plasma Levels and
the Risk of Neurological Symptoms
Novoa SR, et al. CROI 2005, poster 652