Presentation on theme: "Farmacocinética e Interacciones Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron. Barcelona Barcelona, 26 de febrero."— Presentation transcript:
Farmacocinética e Interacciones Dr. Esteve Ribera Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron. Barcelona Barcelona, 26 de febrero de 2010
Total: 44 comunicaciones
Interacciones ARV – ARV Interacciones ARV – otros fármacos Farmacocinética Farmacogenómica Tejidos y reservorios Embarazo Pediatría CROI 2009: Farmacología
Entre ARV: ETR-RAL-DRV/r (606) ATV y ATV/r – GSK (616) Interacciones
ATV ATV/r AUC 91 62 % C max 50 34 % C tr 180 121 % Well tolerated in healthy adult subjects. No dose adjustment is necessary
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.
Naïve (n=18)Nevirapine (n=18)P C max (ug/mL) 8.76 ( )10.9 ( ) AUC(ug.h/mL) ( ) ( )0.0011
3000 ng/mL (MEC) DAY 7 (Esc, n=7) DAY 14 ( Esc, n=6) DAY 21 ( Esc, n=5) Comparison of NVP C 12 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.
Farmacocinética ARV: EFV en pelo (604) TDF/FTC/EFV solución (605) RAL intracelular (614)
Only hair EFV levels remain strongly correlated with viral load undetectability
DrugFormulation C max (mg/L)AUC 0-∞ (mg*h/L) GM (%CV) Ratio of GM Liquid vs. Tablet (90% CI) GM (%CV) Ratio of GM Liquid vs. Tablet (90% CI) EFV Liquid1.3 (28.8) 0.86 ( ) 56.7 (80.0) 0.97 ( ) Tablet1.5 (39.0)58.7 (57.5) FTC Liquid2.1 (21.0) 1.15 ( ) 10.8 (15.9) 0.99 ( ) Tablet1.8 (32.3)10.9 (24.7) TDF Liquid0.3 (27.7) 1.38 ( ) 2.2 (36.3) 1.21 ( ) Tablet0.2 (47.8)1.8 (29.2) 90% CI for FTC C max and AUC fell within the range of (bioequivalence was met) EFV C max below the range of bioequivalence, AUC slightly above the range and TDF C max and AUC fell above the range (40% and 20% higher). Both formulations are not bioequivalent for two drugs; the clinical implications are unknown.
RAL C tot are well correlated with C cell (r=0.86), supporting the use of Therapeutic Drug Monitoring based on C tot as a surrogate of C cell. Despite this good general correlation, each patient exhibited a distinct intracellular accumulation for RAL, with C cell /C tot ratios ranging from to (a15-folddifference).
Concentración 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% ( %) the Blood Plasma concentrations. DRV Seminal Plasma (344 ng/ml) 6 fold above EC 50 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 ( ) n=18 Semen (SP) vs Blood (BP) Darunavir Concentrations in 18 HIV Men & SP AUC 0-24h vs BP AUC 0-24h Time post Drug Ingestion 1-3h4-6h22-24h Median BP [DRV] IQR ng/ml 5579 ( ) 3734 ( ) 2445 ( ) Median SP [DRV] IQR 588 ( ) 490 ( ) 217 ( ) Median SP:BP ratio IQR 0.11 ( ) n= ( ) n= ( ) n=14 Median multiple above PC EC 50 for WT virus 55ng/ml 11 fold (6-45) 9 fold (3-21) 4 fold (2-16) Blood Semen
124, ,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 several times the IC50. Most patients undetectable plasma/reservoirs VL (some viral replication in semen)
MVC 273% a TVF 510% h IDV 100% z ABC 150% z 3TC 667% g ZDV 228% y d4T 2% v SQV 3% p NFV 7% r LPV 5 % j APV 20% cc RTV 3% q ENF ND s EFV 3.3% s Equivalent Blood and Genital Tract Exposures Higher Genital Tract Exposures Lower Genital Tract Exposures NVP 80% bb APV 50% bb d4T 5% c EFV 0.4% c SQV bb RTV 26% c ZDV 235% c TVF 75% c TVF* 110% c 3TC 411% c FTC 395% c IDV/r 380% aa ddI 992% b DLV 20% bb ATV 18% c ABC 58% b LPV 30% b ddI 21% c GT/BP AUC ratios GT/BP ratios paired samples LPV 2-3% t Semen/BP AUC ratios Semen/BP ratios paired samples RTV 7% jLPV 6% q EFV 9% w ABC 8% cLPV 8% c 3TC 319% b FTC 150% b EFV 1% b DLV 16% x LPV 3% b ZDV 330% g d4T 350% v ABC 560% d LPV ND u ATV 10% k RTV ND p NVP 61% v IDV 140% p IDV 145% bb IDV/r 132% aa SQV ND d RTV 3% b LPV 5% bb RAL 93% f RAL 142% m ZDV 590% b TVF 515% b RTV 81% b LPV 12% b NVP 130% bb DLV 5% bb IDV 70% bb* RTV 19 b ddI 114% b* ZDVtp 33% g 3TCtp 100% g MVC 190% a* TVF 330% i DRV 150% n ETR 130% n 100% 200% 300% 400% 500% 600% 0% 80% 60% 40% 20% MenWomen EFV ND i TVFdp >1000%h 3TC 460% o ZDV 190% o TVF 90% o RTV 54% oNFV 54% o From Dumond, Cohen and Kashuba 2007; adapted by Taylor and Davies 2010 *CROI 2010; P611; Taylor, Jayasuryia, Dufty et al MVC 200% * MVC 2800 % * Rectal Tissue Vaginal Tissue *DRV 12% *DRV 17% MVC 71% MVC 62% RAL 230 % RAL 160% RAL 642% *DRV 9% MVC 72% 84LB P608 P609 P612 P610 P611
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.
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.
APV3 rd Tri Postpart Ratio (90CI) AUC ( ) C max ( ) C min ( ) 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.
Overall, the C12hr was similar for all three formulations. Both pediatric formulations had moderately higher AUC and C max 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+ youth –Cohort I: 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
**Adult Data - Luber et al. 49th ICAAC, September 12-15, 2009, San Francisco, CA RAL chewable tablets safe and well tolerated. Wk 12 efficacy data were favorable
LPV Whole Crushed Ratio (90CI) AUC (0.48 –0.72) C max (0.65 –0.98) C min (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 Niños con VIH en tto con LPV/r Dosis única de 2 compr. de LPV/r enteros o triturados.
PK: Resumen y Conclusiones ETR-RAL-DRV/r: No interacción clín. significativa ATV, ATV/r: [GSK ] (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 !!)
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! PK: Resumen y Conclusiones