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

2. Monitorización terapéutica
Concentración mínima efectiva
Interacciones entre ARV
Interacciones ARV – otros fármacos
Farmacogenómica – PK

3. Mentree F, et al. CROI 2005, poster 639
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.

4. Mentree F, et al. CROI 2005, poster 639
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

5. Mentree F, et al. CROI 2005, poster 639
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

6. Mentree F, et al. CROI 2005, poster 639
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

7. 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

8. 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!!!

9. Monitorización terapéutica
Concentración mínima efectiva
Interacciones entre ARV
Interacciones ARV – otros fármacos
Farmacogenómica – PK

10. 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]

11. 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

12. 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]
Nevirapine
Efavirenz

13. 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]
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

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

15. Gonzalez de Requena D, et al. CROI 2005, poster 645
Atazanavir Ctrough Is Associated with Efficacy and Safety: Definition of Therapeutic Range
Gonzalez de Requena D, et al. CROI 2005, poster 645

16. Bonora S, et al. CROI 2005, poster 643
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.

17. Monitorización terapéutica
Concentración mínima efectiva
Interacciones entre ARV
Interacciones ARV – otros fármacos
Farmacogenómica – PK

18. Didanosina – Atazanavir

19. 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
ATV 400 mg QD fed
ATV/RTV 300/100 mg QD fed
ATV/RTV 300/100 mg QD fed
ddl-EC 400 mg SD fasted
ddl-EC 400 mg SD fed
ddl-EC 400 mg SD fed
Day 1
Day 2–7
Day 8
Days 9-18
Day 19
24 h PK on Day 7 ATV
24 h PK on Day 18 ATV, RTV
24 h PK ddl
24 h PK ddl, ATV
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)

20. Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or Atazanavir/Ritonavir
Kaul S, et al. CROI 2005, poster 648

21. ddI plasma conc (ng/mL)
Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or Atazanavir/Ritonavir
Kaul S, et al. CROI 2005, poster 648
3000
1000
100 10 1
0.1 4 8 12 16 20 24
Time (h)
ddI plasma conc (ng/mL)
ddI-EC (day 1)
ddI-EC + ATV (day 8)
ddI-EC + ATV/RTV (day 19)

22. Geometric Mean Ratios (90% CI)
Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or Atazanavir/Ritonavir
Kaul 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 ( ) -
0.617 ( )
AUC, ddI
0.662 ( )
0.658 ( )
Cmax, ATV
1.026 ( )
1.038 ( )
AUC, ATV
0.993 ( )
0.995 ( )
No PK interaction between ddI-EC and atazanavir

23. Amprenavir – Lopinavir/r - Efavirenz

24. Pham P, et al. CROI 2005, oral abstract 79
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)
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

25. Pham P, et al. CROI 2005, oral abstract 79
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)
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, )
94244 (55061, 96414)
0.398
Half-life (h)
8.4 (5.18, 19.51)
5.72 (2.70, 9.54)
0.108

26. Pham P, et al. CROI 2005, oral abstract 79
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.

27. Atazanavir - RTV/SQV

28. Becker S, et al. CROI 2005, poster 655
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)
Saquinavir was administered as Invirase 200mg capsules

29. Becker S, et al. CROI 2005, poster 655
PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose Atazanavir in HIVneg Volunteers: ASPIRE I
Becker S, et al. CROI 2005, poster 655
Figure 1a: Mean (SD) plasma concentration-time profiles for
SQV/r 1600/100
SQV/ATV 2000/400
SQV/ATV 1600/400
Saquinavir

30. Becker S, et al. CROI 2005, poster 655
PK QD Saquinavir with Low-Dose Ritonavir or Full-Dose Atazanavir in HIVneg Volunteers: ASPIRE I
Becker S, et al. CROI 2005, poster 655
Figure 1b: Mean (SD) plasma concentration-time profiles for
Atazanavir
SQV/ATV 2000/400
SQV/ATV 1600/400

31. Becker S, et al. CROI 2005, poster 655
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.

32. Inhibidores CCR5 - IP/NN

33. Adkison K, et al. CROI 2005, poster 664
The PK Interaction between the CCR5 Antagonist and Lopinavir/Ritonavir in Healthy Subjects
Adkison K, et al. CROI 2005, poster 664

34. Adkison K, et al. CROI 2005, poster 664
The PK Interaction between the CCR5 Antagonist and Lopinavir/Ritonavir in Healthy Subjects
Adkison K, et al. CROI 2005, poster 664

35. Adkison K, et al. CROI 2005, poster 664
The PK Interaction between the CCR5 Antagonist and Lopinavir/Ritonavir in Healthy Subjects
Adkison K, et al. CROI 2005, poster 664

36. Muirhead G, et al. CROI 2005, poster 663
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 A

38. Muirhead G, et al. CROI 2005, poster 663
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.

39. Monitorización terapéutica
Concentración mínima efectiva
Interacciones entre ARV
Interacciones ARV – otros fármacos
Farmacogenómica – PK

40. Rifampicina - Atazanavir Omeprazol - Atazanavir

41. 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

42. 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

43. 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.

44. 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?)

45. 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

48. 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.] ( % 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 (~ %) was also observed.

49. Tacrolimus - ARV

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

51. Teicher E., et al. CROI 2005, poster 662
Management of Drug-Drug Interactions between Tacrolimus and Highly Active Antiretroviral Therapy
Teicher E., et al. CROI 2005, poster 662

52. Teicher E., et al. CROI 2005, poster 662
Management of Drug-Drug Interactions between Tacrolimus and Highly Active Antiretroviral Therapy
Teicher E., et al. CROI 2005, poster 662

53. Teicher E., et al. CROI 2005, poster 662
Management of Drug-Drug Interactions between Tacrolimus and Highly Active Antiretroviral Therapy
Teicher E., et al. CROI 2005, poster 662

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

55. Monitorización terapéutica
Concentración mínima efectiva
Interacciones entre ARV
Interacciones ARV – otros fármacos
Farmacogenómica – PK

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