farmacocinética e interacciones

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Barcelona, 2 6 de febrero de 20 10. Farmacocinética e Interacciones. Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron. Barcelona. Total: 44 comunicaciones. CROI 2009: Farmacología. Interacciones ARV – ARV Interacciones ARV – otros fármacos - PowerPoint PPT Presentation


  • Farmacocintica e InteraccionesDr. Esteve RiberaServei de Malalties InfecciosesHospital Universitari Vall dHebron. BarcelonaBarcelona, 26 de febrero de 2010

  • Total: 44 comunicaciones

  • Interacciones ARV ARV Interacciones ARV otros frmacos Farmacocintica Farmacogenmica Tejidos y reservorios Embarazo Pediatra CROI 2009: Farmacologa

  • Entre ARV: ETR-RAL-DRV/r (606) ATV y ATV/r GSK1349572 (616)Interacciones

  • N=10

  • Well tolerated in healthy adult subjects. No dose adjustment is necessary

  • InteraccionesARV otros frmacos: LPV/r buprenorf/naloxona (620) FPV posaconazol (621) EFV levonorgestrel (934) NVP lumefantrina (603) NVP RFP (602)

  • Plasma Concentration (ng/mL) HIV-seronegative subjects LPV/r did not have effect on [BUP] or [naloxone] LPV/r did reduce [norBUP] (BUP metabolite). Dosage modification of BUP/NLX is not likely to be required when it is co-administered with LPV/r.

  • Posaconazole (400 mg BID) FPV/ritonavir (700/100 mg BID) Posaconaz + FPV (700 mg BID) FPV no potenciado reduce las conc. de posaconazol. Posaconazol no puede sustituir a ritonavir como potenciador.

  • AUC 58%; Cmax 45%;Cmin 69% Higher LNG doses may be required to prevent pregnancy. These results reinforce the importance of dual methods of contraception, including a barrier device, in women taking EFV.

  • Nave (n=18)Nevirapine (n=18)PCmax (ug/mL)8.76 (5.52-14.90)10.9 (6.70-22.50)0.0598AUC(ug.h/mL)436.92 (334.4-893.1)679.84 (395.2-1684.9)0.0011

  • 3000 ng/mL(MEC) DAY 7 (Esc, n=7) DAY 14 (Esc, n=6) DAY 21 (Esc, n=5)Comparison of NVP C12 in Escalation and Full dose NVP arms With rifampicin NVP PK with dose escalation is less favorable than that of full dose. Using NVP 400mg daily, NVP concentrations were also below the MEC in both arms. Evaluation of the PK and safety of higher NVP doses (e.g 600 mg daily) after the first 14 days should be considered.

  • Farmacocintica ARV: EFV en pelo (604) TDF/FTC/EFV solucin (605) RAL intracelular (614)

  • Only hair EFV levels remain strongly correlated with viral load undetectability

  • 90% CI for FTC Cmax and AUC fell within the range of 0.8-1.25 (bioequivalence was met) EFV Cmax below the range of bioequivalence, AUC slightly above the range and TDF Cmax and AUC fell above the range (40% and 20% higher). Both formulations are not bioequivalent for two drugs; the clinical implications are unknown.

  • RAL Ctot are well correlated with Ccell (r=0.86), supporting the use of Therapeutic Drug Monitoring based on Ctot as a surrogate of Ccell. Despite this good general correlation, each patient exhibited a distinct intracellular accumulation for RAL, with Ccell/Ctot ratios ranging from 0.013 to 0.196 (a15-folddifference).

  • Concentracin de ARV en tejidos y reservorios:

    RAL genital (608, 609) DRV genital (610, 611) MVC LCR y genital (oral 85, 612)

  • Good penetration of RAL in the genital tract of HIV-1 infected women with a ratio CVF/BP= 2.3and a concentration 16 fold higher than the IC95 on wild type HIV-1 Likely contributing to virological control in the compartment These data also suggest a potential use of raltegravir in combination with others ARVs with known penetration in the genital tract of HIV infected women when targetting an impact on prevention of transmission and resistance.N=14

  • [DRV] Seminal plasma 8.6% (5.7-22.2%) the Blood Plasma concentrations. DRV Seminal Plasma (344 ng/ml) 6 fold above EC50 of WT HIV-1 strains (55 ng/ml). Only 3 DRV SP concentrations were < 55 ng/mL. No relationship between DRV concentrations and HIV-RNA was evidenced.

  • SP:BP DRV AUC 0-24h ratio = 0.17 (0.07-0.19)n=18 Semen (SP) vs Blood (BP) Darunavir Concentrations in 18 HIV Men & SP AUC0-24h vs BP AUC0-24h


    Time post Drug Ingestion1-3h4-6h22-24hMedian BP[DRV] IQRng/ml5579(4639-7505)3734(2935-4586)2445(1365-3167)Median SP [DRV] IQR588(509-778)490(479-640)217(172-261)Median SP:BP ratioIQR0.11(0.09-0.15)n=80.13(0.07-0.18)n=130.11(0.09-0.15)n=14Median multiple abovePC EC 50 for WT virus 55ng/ml 11 fold(6-45)9 fold(3-21)4 fold(2-16)

  • 124,71500,7232,60,022MedianRatio to plasma MVC achieves levels in CSF within the range of IC50 or higher. In semen, MVC exceeds several times the IC50. Most patients undetectable plasma/reservoirs VL (some viral replication in semen)

  • MVC 273% aTVF 510% hIDV 100% zABC 150% z3TC 667% gZDV 228% yd4T 2% vSQV 3% pNFV 7% rLPV 5 % jAPV 20% ccRTV 3% qENF ND sEFV 3.3% sEquivalent Blood andGenital Tract ExposuresHigher Genital Tract ExposuresLower Genital Tract Exposures

    NVP 80% bbAPV 50% bbd4T 5% cEFV 0.4% cSQV bb RTV 26% cZDV 235% cTVF 75% cTVF* 110% c 3TC 411% c FTC 395% cIDV/r 380% aaddI 992% bDLV 20% bbATV 18% cABC 58% bLPV 30% b ddI 21% cGT/BP AUC ratios GT/BP ratios paired samplesLPV 2-3% tSemen/BP AUC ratios Semen/BP ratios paired samples RTV 7% jLPV 6% qEFV 9% wABC 8% cLPV 8% c3TC 319% bFTC 150% bEFV 1% bDLV 16% xLPV 3% bZDV 330% gd4T 350% vABC 560% dLPV ND uATV 10% kRTV ND pNVP 61% vIDV 140% pIDV 145% bbIDV/r 132% aaSQV ND dRTV 3% bLPV 5% bbRAL 93% fRAL 142% mZDV 590% bTVF 515% bRTV 81% bLPV 12% b NVP 130% bbDLV 5% bbIDV 70% bb*RTV 19 bddI 114% b*ZDVtp 33% g3TCtp 100% gMVC 190% a*TVF 330% iDRV 150% nETR 130% n100%200%300%400%500%600%0%80%60%40%20%MenWomenEFV ND i TVFdp >1000%h 3TC 460% oZDV 190% oTVF 90% oRTV 54% oNFV 54% o From Dumond, Cohen and Kashuba 2007; adapted by Taylor and Davies 2010 *CROI 2010; P611; Taylor, Jayasuryia , Dufty et alMVC 200% *MVC 2800 % * Rectal TissueVaginal Tissue *DRV 12%*DRV 17% MVC 71%MVC 62%RAL 230 % RAL 160% RAL 642% *DRV 9% MVC 72% 84LB84LB84LBP608P609P609P612P610P611P611

  • PK embarazo y neonatos: LPV (906) ATV (907) FPV (908) NVP (910, 911)

  • The reduction of LPV drug exposure compared to non-pregnant women was less pronounced in Thai women than in US women (~ 25% versus 50%). In this PK study all women achieved an HIV RNA viral load
  • Postpartum3rd trimester Dose adjustment for ATV/r in pregnancy is not required. ATV/r, in combination with AZT/3TC, was well tolerated in pregnant women.

  • APV3rd Tri Postpart Ratio (90CI)AUC0-1232.450.7 0.69 (0.51-0.94)Cmax5.935.68 0.95(0.64-1.40)Cmin1.702.43 0.86 (0.55-1.34) Boosted FPV is well tolerated and was associated with good viral suppression (all VL
  • PK - pediatra: RAL (oral 161,872, 873) LPV/r (877)

  • Overall, the C12hr was similar for all three formulations. Both pediatric formulations had moderately higher AUC and Cmax values vs POL formulation. A high-fat meal slowed the rate of absorption from the EC formulation, with no statistically meaningful change in extent of absorption. These data support further clinical investigation of the OG and EC pediatric formulations

  • Open label study of RAL in treatment experienced HIV+ youthCohort I: 12-18 yrs adult formulationCohort IIA: 6-11 yrs adult formulationCohort IIB: 6-11 yrs chewable (OCT) formulationCohort III: 2-5 yrs chewable (OCT) formulation

  • **Adult Data - Luber et al. 49th ICAAC, September 12-15, 2009, San Francisco, CARAL chewable tablets safe and well tolerated. Wk 12 efficacy data were favorable

  • LPV Whole Crushed Ratio (90CI)AUC0-12 141 92 0.60 (0.48 0.72)Cmax10.4 9.2 0.81 (0.65 0.98)Cmin 6.3 4.8 0.67 (0.48 0.86) Administration of a single dose of two crushed 200/50 mg LPV/RTV tablets to pediatric patients decreased oral absorption of LPV and RTV by approximately 40%. The reduced and variable exposure and lack of steady-state pharmacokinetic data with crushed tablet dosing reinforces the need to discourage this dosing practice. n=12, aleatorizado Nios con VIH en tto con LPV/r Dosis nica de 2 compr. de LPV/r enteros o triturados.

  • PK: Resumen y Conclusiones ETR-RAL-DRV/r: No interaccin cln. significativa ATV, ATV/r: [GSK12349572] (similar RAL, no toxicidad) ARV- otros frmacos: LPV/r: [buprenorfina/naloxona] (no ajuste dosis) EFV: [anticonceptivos orales] (levonorgestrol) NVP: rifampicina iniciar con dosis plena?, mayor dosis? Buena correlacin entre [EFV] en pelo y eficacia RAL: correlacin [plasma] [intracelular] Atripla compr vs jarabe casero: No bioequivalencia (casi !!)

  • Tracto genital masculino y femenino: RAL y MVC: excelentes concentraciones DRV: concentraciones aceptables Embarazo: [LPV/r] y [FPV/r] pero eficaz (no ajustar dosis) [ATV/r], eficaz y bien tolerado (no ajustar dosis) Pediatra: RAL: compr. adultos, grnulos y masticable (OK) LPV/r: desaconsejable triturar los comprimidos!PK: Resumen y Conclusiones


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