8HIV-seronegative subjects Plasma Concentration (ng/mL)HIV-seronegative subjectsLPV/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.
9Posaconazole (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.
10AUC 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.
12DAY 7 (Esc, n=7) DAY 14 (Esc, n=6) DAY 21 (Esc, n=5) Comparison of NVP C12 in Escalation and Full dose NVP arms3000 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 600 mg daily) after the first 14 days should be considered.
13Farmacocinética ARV: EFV en pelo (604) TDF/FTC/EFV solución (605) RAL intracelular (614)
15TDF Cmax and AUC fell above the range (40% and 20% higher). DrugFormulationCmax (mg/L)AUC0-∞ (mg*h/L)GM(%CV)Ratio of GMLiquid vs. Tablet(90% CI)EFVLiquid1.3 (28.8)0.86 ( )56.7 (80.0)0.97 ( )Tablet1.5 (39.0)58.7 (57.5)FTC2.1 (21.0)1.15 ( )10.8 (15.9)0.99 ( )1.8 (32.3)10.9 (24.7)TDF0.3 (27.7)1.38 ( )2.2 (36.3)1.21 ( )0.2 (47.8)1.8 (29.2)90% CI for FTC Cmax and AUC fell within the range of (bioequivalence was met)EFV Cmax below the range of bioequivalence, AUC slightly above the range andTDF Cmax and AUC fell above the range (40% and 20% higher).Both formulations are not bioequivalent for two drugs; the clinical implications are unknown.
16RAL Ctot are well correlated with Ccell (r=0 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 to (a15-folddifference).
17Concentración de ARV en tejidos y reservorios: RAL genital (608, 609)DRV genital (610, 611)MVC LCR y genital (oral 85, 612)
20Likely contributing to virological control in the compartment 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-1Likely contributing to virological control in the compartmentThese 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.
22[DRV] Seminal plasma 8. 6% (5. 7-22 [DRV] Seminal plasma 8.6% ( %) 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.
23Time post Drug Ingestion Semen (SP) vs Blood (BP) Darunavir Concentrations in 18 HIV Men & SP AUC0-24h vs BP AUC0-24hTime post Drug Ingestion1-3h4-6h22-24hMedian BP[DRV] IQRng/ml5579( )3734( )2445( )Median SP[DRV] IQR588( )490( )217( )MedianSP:BP ratioIQR0.11( )n=80.13( )n=13n=14Median multiple abovePC EC 50 for WT virus 55ng/ml11 fold(6-45)9 fold(3-21)4 fold(2-16)BloodSemenn=18SP:BP DRV AUC 0-24h ratio = ( )
25124,71500,7232,60,022MedianRatio to plasmaMVC 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)
28The 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.
29Postpartum3rd trimesterDose adjustment for ATV/r in pregnancy is not required.ATV/r, in combination with AZT/3TC, was well tolerated in pregnant women.
30APV 3rd Tri Postpart Ratio (90CI) AUC ( )Cmax ( )Cmin ( )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.
32Overall, 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
3480.7 (182 nM)56.8 (128 nM)109 (246 nM)Cmin(ng/mL)51.2 (68%)21.2 (38%)49.6 (152%)CL/F (L/hr, %CV)7.4 (16.7mMh)10.0 (22.57.0 (15.8h)AUC12(mgh/L)Adults(400 mg bid, fasting)**N=45Cohort IIB6 mg/kg bid, fasting)N=10Cohort IIA(400 mg bid, fasting)N=11ParameterRAL 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
35Niños con VIH en tto con LPV/r n=12, aleatorizadoNiños con VIH en tto con LPV/rDosis única de 2 compr. de LPV/r enteros o triturados.LPV Whole Crushed Ratio (90CI)AUC (0.48 –0.72)Cmax (0.65 –0.98)Cmin (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.
36PK: Resumen y Conclusiones ETR-RAL-DRV/r: No interacción clín. significativaATV, 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 eficaciaRAL: correlación [plasma] – [intracelular]Atripla compr vs jarabe casero: No bioequivalencia (casi !!)
37PK: Resumen y Conclusiones Tracto genital masculino y femenino:RAL y MVC: excelentes concentracionesDRV: concentraciones aceptablesEmbarazo: [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!