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Farmacocinética e Interacciones

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  1. Barcelona, 26 de febrero de 2010 Farmacocinética e Interacciones Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron. Barcelona

  2. Total: 44 comunicaciones

  3. CROI 2009: Farmacología • Interacciones ARV – ARV • Interacciones ARV – otros fármacos • Farmacocinética • Farmacogenómica • Tejidos y reservorios • Embarazo • Pediatría

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

  5. N=10


  6. ATV ATV/r AUC  91  62 % Cmax 50  34 % Ctr180 121 % • Well tolerated in healthy adult subjects. • No dose adjustment is necessary

  7. Interacciones • ARV – otros fármacos: • LPV/r – buprenorf/naloxona (620) • FPV – posaconazol (621) • EFV – levonorgestrel (934) • NVP – lumefantrina (603) • NVP – RFP (602)

  8. 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.

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

  10. 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.

  11. Comparison of NVP C12 in Escalation and Full dose NVP arms 3000 ng/mL (MEC) DAY 7 (Esc, n=7) DAY 14 (Esc, n=6) DAY 21 (Esc, n=5) • 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 600mg daily) after the first 14 days should be considered.

  12. Farmacocinética ARV: • EFV en pelo (604) • TDF/FTC/EFV solución (605) • RAL intracelular (614)

  13. Only hair EFV levels remain strongly correlated with viral load undetectability

  14. 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.

  15. RALCtotarewellcorrelatedwithCcell(r=0.86),supportingtheuseofTherapeuticDrugMonitoringbasedonCtotasasurrogateofCcell.RALCtotarewellcorrelatedwithCcell(r=0.86),supportingtheuseofTherapeuticDrugMonitoringbasedonCtotasasurrogateofCcell. • Despitethisgoodgeneralcorrelation,eachpatientexhibitedadistinctintracellularaccumulationforRAL,withCcell/Ctotratiosrangingfrom0.013to0.196(a15-folddifference).

  16. Concentración de ARV en tejidos y reservorios: • RAL genital (608, 609) • DRV genital (610, 611) • MVC LCR y genital (oral 85, 612)

  17. N=14 • 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 dataalsosuggest 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.

  18. [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-1strains (55 ng/ml). • Only 3 DRV SP concentrations were < 55 ng/mL. • No relationship between DRV concentrationsand HIV-RNA was evidenced.

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

  20. 124,7 150 0,723 2,6 0,022 Median Ratio to plasma • MVC achieves levels in CSF within the range of IC50 or higher. • In semen, MVC exceeds severaltimes the IC50. • Most patients undetectable plasma/reservoirs VL (some viralreplication in semen)

  21. Men Women ddI 992% b TVFdp>1000%h Rectal Tissue MVC 2800 % * 3TC 667% g RAL 642% 84LB 600% ZDV 590% b P609 ABC 560% d Semen/BP ratios paired samples Semen/BP AUC ratios GT/BP AUC ratios GT/BP ratios paired samples TVF 515% b TVF 510% h 500% Higher Genital Tract Exposures 3TC 460% o 3TC 411% c 400% FTC 395% c IDV/r 380% aa d4T 350% v TVF 330% i ZDV 330% g 300% 3TC 319% b P608 MVC 273% a Vaginal Tissue MVC 200% * RAL 230 % ZDV 235% c P609 ZDV 228% y 200% ZDV 190% o MVC 190% a* FTC 150% b RAL 160% Equivalent Blood and Genital Tract Exposures ABC 150% z RAL 142% m DRV 150% n IDV 145% bb IDV/r 132% aa ETR 130% n IDV 140% p NVP 130% bb ddI 114% b* TVF* 110% c 100% IDV 100% z 3TCtp 100% g TVF 90% o RAL 93% f 84LB 80% RTV 81% b NVP 80% bb MVC 72% TVF 75% c 84LB IDV 70% bb* MVC 71% MVC 62% P612 NVP 61% v 60% ABC 58% b Lower Genital Tract Exposures NFV 54% o RTV 54% o APV 50% bb 40% ZDVtp 33% g LPV 30% b RTV 26% c APV 20% cc 20% ddI 21% c P610 DLV 16% x P611 DLV 20% bb *DRV 17% ATV 18% c RTV 19 b *DRV 12% ATV 10% k EFV 9% w *DRV 9% P611 LPV 6% q NFV 7% r RTV 7% j LPV 12% b LPV 5 % j ABC 8% c LPV 8% c DLV 5% bb LPV 5% bb d4T 2% v SQV 3% p RTV 3% q LPV 2-3% t LPV 3% b EFV 3.3% s d4T 5% c RTV 3% b 0% EFV 1% b EFV 0.4% c EFV ND i ENF ND s RTV ND p SQV ND d LPV ND u SQV bb *CROI 2010; P611; Taylor, Jayasuryia , Dufty et al From Dumond, Cohen and Kashuba 2007; adapted by Taylor and Davies 2010

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

  23. 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 <400 copies/mL before delivery. • Standard LPV/r dosing in during the 3rd trimester provides adequate drug exposure.

  24. Postpartum 3rd trimester • Dose adjustment for ATV/r in pregnancy is not required. • ATV/r, in combination with AZT/3TC, was well tolerated in pregnant women.

  25. APV 3rd Tri Postpart Ratio (90CI) AUC0-12 32.4 50.7 0.69 (0.51-0.94) Cmax 5.93 5.68 0.95(0.64-1.40) Cmin 1.70 2.43 0.86 (0.55-1.34) • Boosted FPV is well tolerated and was associated with good viral suppression (all VL<400). • APV AUC is reduced during the 3rd trimester vs. post-partum and historical controls. • APV concentrations during the 3rd trimester are greater than seen with unboosted FPV and trough concentrations achieved during the 3rd trimester are adequate for patients without PI resistance mutations.

  26. PK - pediatría: • RAL (oral 161,872, 873) • LPV/r (877)

  27. 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

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

  29. Cohort IIA Cohort IIA Cohort IIB Cohort IIB Adults Adults Parameter Parameter (400 mg bid, fasting) (400 mg bid, fasting) 6 mg/kg bid, fasting) 6 mg/kg bid, fasting) (400 mg bid, fasting)** (400 mg bid, fasting)** N=11 N=11 N=10 N=10 N=45 N=45 · · m m · · m m · · m m · · AUC AUC (mg (mg h/L) h/L) 7.0 (15.8 7.0 (15.8 M M h h ) ) 10.0 (22.5 10.0 (22.5 M M h) h) 7.4 (16.7 7.4 (16.7 M M h) h) 12 12 C C (ng/mL) (ng/mL) 109 (246 nM) 109 (246 nM) 56.8 (128 nM) 56.8 (128 nM) 80.7 (182 nM) 80.7 (182 nM) min min CL/F (L/hr, %CV) CL/F (L/hr, %CV) 49.6 (152%) 49.6 (152%) 21.2 (38%) 21.2 (38%) 51.2 (68%) 51.2 (68%) RAL chewable tablets safe and well tolerated. Wk 12 efficacy data were favorable **Adult Data - Luber et al. 49th ICAAC, September 12-15, 2009, San Francisco, CA

  30. n=12, aleatorizado • Niños con VIH en tto con LPV/r • Dosis única de 2 compr. de LPV/r enteros o triturados. LPVWholeCrushed Ratio (90CI) AUC0-12 141 92 0.60 (0.48 –0.72) Cmax 10.4 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.

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

  32. PK: Resumen y Conclusiones • 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) • Pediatría: • RAL: compr. adultos, gránulos y masticable (OK) • LPV/r: desaconsejable triturar los comprimidos!