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Farmacocinética e Interacciones. Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron. Barcelona Correo electrónico: eribera@vhebron.net. Monitorización terapéutica Concentración mínima efectiva Interacciones entre ARV Interacciones ARV – otros fármacos

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


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

    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 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. • ITTefficacy: 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. 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

    5. 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

    6. 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

    7. 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. 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] Nevirapine Efavirenz

    13. Cmincut-off for predicting virologicfailure 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] • Risk of failure increased when Cminfor NVP<3.1/2.3 or EFV<1.1 • Cmin / AUC24hare poorpredictors of V. failure (low sensitivity) • Neg. predictor value is better

    14. 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. Atazanavir Ctrough 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 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 ATV400 mg QDfed ATV400 mg QDfed ATV/RTV300/100 mg QDfed ATV/RTV300/100 mg QDfed ddl-EC400 mg SDfasted ddl-EC400 mg SDfed ddl-EC400 mg SDfed Day 1 Day 2–7 Day 8 Days 9-18 Day 19 24 h PK onDay 7ATV 24 h PK onDay 18ATV, RTV 24 h PKddl 24 h PKddl, ATV 24 h PKddl, 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. 3000 ddI-EC (day 1) 1000 ddI-EC + ATV (day 8) ddI-EC + ATV/RTV (day 19) 100 ddI plasma conc (ng/mL) 10 1 0.1 0 4 8 12 16 20 24 Time (h) Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or Atazanavir/Ritonavir Kaul S, et al. CROI 2005, poster 648

    22. Pharmacokinetics of Didanosine Enteric Coated Capsules Co-administered with Atazanavir or Atazanavir/Ritonavir Kaul S, et al. CROI 2005, poster 648 No PK interaction between ddI-EC and atazanavir

    23. Amprenavir – Lopinavir/r -Efavirenz

    24. 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 Amprenavir 750 mg (5c) bid

    25. 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 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

    26. 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. 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. Figure 1a: Mean (SD) plasma concentration-time profiles for Saquinavir SQV/r 1600/100 SQV/ATV 2000/400 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

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

    31. 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. The PK Interaction between the CCR5 Antagonist 873140 and Lopinavir/Ritonavir in Healthy Subjects Adkison K, et al. CROI 2005, poster 664

    34. The PK Interaction between the CCR5 Antagonist 873140 and Lopinavir/Ritonavir in Healthy Subjects Adkison K, et al. CROI 2005, poster 664

    35. The PK Interaction between the CCR5 Antagonist 873140 and Lopinavir/Ritonavir in Healthy Subjects Adkison K, et al. CROI 2005, poster 664

    36. 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

    37. 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.

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

    39. Rifampicina - Atazanavir Omeprazol - Atazanavir

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

    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 Due to considerably lower ATV exposures relative toboth the ATV 400 mg and ATV/RTV 300/100 mgclinical dosing regimens, none of the three ATV/RTVonce daily dosing regimens studied in combinationwith RIF are recommended for clinical use.

    43. 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?)

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

    45. 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 (56-66% decreases) did not mitigate this reduction. • A smaller reduction in the steady-state PK of RTV (~25 - 30%) was also observed.

    46. Tacrolimus - ARV

    47. 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