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Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: Farmacocinética.

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Presentation on theme: "Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall dHebron. Barcelona Correo electrónico: Farmacocinética."— Presentation transcript:

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

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

3 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 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 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 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 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 Determinants of the Need for Therapeutic Drug Monitoring: Rates and Predictors from CCTG 578 Haubrich R, et al. CROI 2005, poster 640

8 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!!!

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

10 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 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 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] NevirapineEfavirenz

13 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] C min cut-off for predicting virologic failure Risk of failure increased when C min for NVP <3.1/2.3 or EFV <1.1 C min / AUC 24h are poor predictors of V. failure (low sensitivity) Neg. predictor value is better

14 Atazanavir C trough Is Associated with Efficacy and Safety: Definition of Therapeutic Range Gonzalez de Requena D, et al. CROI 2005, poster 645 Virological responseBilirrubin > 2 mg/dL (total and uncongugated

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

16 Pharmacokinetic and Pharmacodynamic Determinants of Virological Response to Enfuvirtide-based Regimens Bonora S, et al. CROI 2005, poster 643 An enfuvirtide C trough 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

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 n=35 SD = single dose; QD = once daily; fed = light meal (303 kcal from 68% carbohydrates, 20% (8.1g) fat, and 12% protein) ATV 400 mg QD fed ATV/RTV 300/100 mg QD fed ddl-EC 400 mg SD fasted ddl-EC 400 mg SD fed Day 1Day 2–7Day 8Days 9-18Day 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

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

21 Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or Atazanavir/Ritonavir Kaul S, et al. CROI 2005, poster Time (h) ddI plasma conc (ng/mL) ddI-EC (day 1) ddI-EC + ATV (day 8) ddI-EC + ATV/RTV (day 19)

22 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 C max, ddI0.640 ( ) ( ) AUC, ddI0.662 ( ) ( ) C max, ATV ( )1.038 ( ) AUC, ATV ( )0.995 ( ) No PK interaction between ddI-EC and atazanavir

23 Amprenavir – Lopinavir/r - Efavirenz

24 Steady-state Pharmacokinetics of Amprenavir, Lopinavir, and Efavirenz Combination in HIVinfected Patients Pham 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 C max (ng/mL) 3768 (3215, 8063)2468 (1781, 4721)0.128 T max (h) 2.1 (1.23, 2.87)2.4 (2.08, 3.03)0.19 C min (ng/mL) 860 (606, 1712)1053 (704, 1240)0.735 AUC (ng·h/mL) (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

25 Steady-state Pharmacokinetics of Amprenavir, Lopinavir, and Efavirenz Combination in HIVinfected Patients Pham 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 C max (ng/mL)11403 (10241, 13007)10336 (8997, 10965)0.272 T max (h)5.16 (5.07, 6.11)6.38 (3.03, 6.42)0.611 C min (ng/mL)4824 (3968, 6806)5027 (1637, 6130)0.447 AUC (ng·h/mL) (73281, )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

26 Steady-state Pharmacokinetics of Amprenavir, Lopinavir, and Efavirenz Combination in HIVinfected Patients Pham 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 C min 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

27 Atazanavir - RTV/SQV

28 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

29 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 1600/100SQV/ATV 2000/400SQV/ATV 1600/400 Saquinavir

30 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/ATV 2000/400SQV/ATV 1600/400 Figure 1b: Mean (SD) plasma concentration-time profiles for Atazanavir

31 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

32 Inhibidores CCR5 - IP/NN

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

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

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

36 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 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

37

38 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 C max but no effect on AUC 12. 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 +Subjects Muirhead G, et al. CROI 2005, poster 663 Conclusions

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

40 Omeprazol - Atazanavir Rifampicina - Atazanavir

41 Effect of Rifampin on Steady-state Pharmacokinetics of Atazanavir and Ritonavir in Healthy Subjects Burger D, et al. CROI 2005, poster 657

42 Effect of Rifampin on Steady-state Pharmacokinetics of Atazanavir and Ritonavir in Healthy Subjects Burger D, et al. CROI 2005, poster 657

43 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 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: /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 rifampin Jack, et al. CROI 2005, poster 891

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

46

47

48 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. PK Effect of Omeprazole on Atazanavir with Ritonavir in Healthy Subjects Agarwala S., et al. CROI 2005, poster 658 Conclusions

49 Tacrolimus - ARV

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

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

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

54 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

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 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 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


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