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Raltegravir Elvitegravir Dolutegravir Bictegravir

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Raltegravir Elvitegravir Dolutegravir Bictegravir Pharmacology of integrase inhibitors Laura Waters CNWL, Mortimer Market Centre London, UK Content • INSTI pharmacology – Metabolism – Impact on transporters – Forgiveness • Drug-drug interactions – Antiretroviral – Non-antiretroviral – Communication Apology DRUG PHARMACOLOGY BASICS Absorption from gut: includes passive diffusion & diffusion or pumping via transporters Distribution: in plasma & other compartments; depends on molecule size, protein binding & other characteristics Metabolism: mainly liver & usually to less active/inactive affected by enzyme induction/inhibition, genetics, age, gender, liver disease Excretion: mainly renal (glomerular filtration, active tubular secretion) affected by age, transporter competition/inhibition PK parameters Simon Collins, iBase PK parameters dose IC50 = concentration required to inhibit 50% replication IC95 = concentration required to inhibit 95% replication Simon Collins, iBase PK parameters Simon Collins, iBase PHARMACOLOGY OF INSTI Clinical Pharmacology Profile of InSTI RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR Clinical dose 400 mg BID OR 150 mg QD 50 mg QD 50 mg QD with 1200 mg QD boosted with cobi (INI-naïve), BID FTC/TAF + FTC/TDF or TAF (INI-resistant) Metabolism and UGT1A1 CYP3A (major), UGT1A1 (major), UGT1A1 and Excretion renal elimination UGT1A1/3 CYP3A (minor), CYP3A (equal) ~ 9% (minor), renal renal elimination renal elimination elimination ~7% <1%. <1%. Renal Weak inhibition COBI inhibits Inhibition of Limited inhibition transporters OCT2 MATE-1 OCT2 & MATE-1 of OCT2 & MATE- 1 Half Life t1/2 ~9 hours ~12.9 hours ~14 hours ~18 hours (boosted) DDI Potential Least Highest Slightly greater Moderate than RAL 1. Tivicay SmPC updated October 2015. 2. Min S, et al. Antimicrob Agents Chemother 2010;54:254–8. 3. Min S, et al. AIDS 2011;25:1737–45. 4. Isentress SmPC July 2015; 5. Stribild SmPC updated June 2015); 6. Ramanathan S, et al. Clin Pharmacokinet 2011;50:229–44. Raltegravir OD vs BD QDMRK failure to achieve VL<50 mainly at high baseline VL in both arms also associated with lower Ctrough in the 800-mg-QD arm Rizk ML at al. AAC 2012: 56(6): 3101-3106 Raltegravir 600mg vs 400mg • 600mg has higher relative bioavailability vs 400 mg – likely due, at least in part, to improvements in tablet disintegration/dissolution • Once absorbed, bothONCEMRK forms show similar pharmacokinetics: – Steady-stateRAL in around 1200 twoOD daysnon-inferior – Little to no accumulationto 400 with BD multiple doses • Food had no clinically relevant effect on raltegravir exposure https://www.sps.nhs.uk/wp-content/uploads/2018/03/Raltegravir-600-mg-once-daily-Final-Feb-2018.pdf accessed 3rd October 2018 It’s not just plasma half-life…. • Once the INSTI it binds to the integrase enzyme & the speed the drug unbinds = dissociation half-life White K et al. CROI 2017 Impact of food on drug absorption • Food may have no effect or may change the rate or extent of drug absorption by following mechanisms: – Altered pH – Altered gastric emptying – Stimulation of gastro-intestinal secretions – Altered drug bioavailability – Increased blood flow – Competition for transporters – Increased viscosity of gastric contents – Complex formation between drug & food components Why is this important? • Counselling patients • Utilising data to alter exposure: – Overcoming resistance – Managing side effects???? Poster Number Effect of Food on Pharmacokinetics of Elvitegravir, Emtricitabine, Tenofovir DF and the A1-1300 Pharmacoenhancer GS-9350 as a Fixed- Dose Combination Tablet Gilead Sciences, Inc. 49th Interscience Conference on 1 1 1 1 2 1 333 Lakeside Drive Antimicrobial Agents and Chemotherapy (ICAAC) P German, D Warren, L Wei, L Zhong, J Hui, and BP Kearney Foster City, CA 94404 September 12-15, 2009 Tel: (650) 522-2990 1 2 San Francisco, CA USA Gilead Sciences, Inc., Foster City, CA, USA; Gilead Sciences, Inc., Durham, NC, USA Fax: (650) 522-5801 Introduction Methods Results (cont’d) • Gilead’s investigational HIV-1 integrase inhibitor, elvitegravir • HIV-1 uninfected healthy subjects (N=24) were randomized to Table 2. GS-9350 Plasma Pharmacokinetic Parameters Figure 1. EVG Plasma Concentration-Time Profi les Figure 4. FTC Plasma Concentration-Time Profi les (EVG), is primarily metabolized by CYP3A enzymes receive single doses of FDC fasted, with a light meal (373 kcal, C AUC AUC 20% fat), and with a high fat meal (800 kcal, 50% fat) N=24 max last inf EVG FTC • GS-9350 lacks antiretroviral activity and is in development as (ng/ml) (ng·hr/ml) (ng·hr/ml) 10000 10000 ) ) l l • Each treatment was followed by a 1-week washout m __ _ m a pharmacoenhancer (booster) to increase the systemic levels Fasted 1190 (34.5) 8290 (49.5) 8370 (49.7) / Fasted Administration; ___ / Fasted Administration; g g n 1000 ___ Light Meal (373 kcal, 20% fat); n ___ of coadministered CYP3A substrates, such as EVG and HIV • Blood was collected over 48 hours post-dosing for the evaluation ( Light Meal (373 kcal, 20% fat); ( Light Meal 1240 (35.5) 8010 (44.4) 8090 (44.5) n High Calorie/High fat (800 kcal, 50% fat n High Calorie/High fat (800 kcal, 50% fat) o 1000 o protease inhibitors (PIs) of EVG, FTC, TFV, and GS-9350 PK i HC/HF Meal 944 (43.9) 6570 (49.1) 6680 (49.5) i t t a 100 a r r • Plasma concentrations were measured by validated LC/MS/MS t • GS-9350 may be an alternative to ritonavir (R TV) as the GMR (90% CI) % t n n e e c pharmacoenhancer of EVG • PK parameters were estimated via non-compartmental analysis Light Meal vs. 10 c n 104 (93.6,114) 103 (89.6,118) 103 (89.9,117) n o 100 o using WinNonlin™ 5.2 (Pharsight Corporation, Mountain V iew, Fasted c c • Administration of a single unboosted 400 mg EVG dose results in a 1 1 subject had a measurable concentration a CA, USA) HC/HF Meal vs. m m C and AUC increases of 3.3-fold and 2.7-fold, respectively in 75.7 (68.4, 83.6) 82.4 (71.9, 94.4) 82.9 (72.5, 94.7) s value at 48 hours in HC/HF group max inf s a l 1 Fasted a l the fed (575 kcal, 33% fat) versus fasted state • Geometric least-squares means ratios and 90% CIs for p 0.1 p 10 AUC , AUC and C were estimated using ANOVA with PK HC/HF Meal vs. • The current dosing recommendation for RTV-boosted EVG is inf last max 73.1 (66.1, 80.8) 80.2 (70.0, 91.9) 80.7 (70.6, 92.2) 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 equivalence boundaries of 80-125% Light Meal time (hr) time (hr) administration with a meal to improve pharmacokinetics (PK) and Data presented as arithmetic mean (%CV); GMR: Geometric Least-Squares Means tolerability and due to its concurrent administration with R TV- Ratio; CI: Confi dence Interval; HC/HF- high calorie/high fat boosted PIs Results Figure 2. GS-9350 Plasma Concentration-Time Profi les Table 3. TFV Plasma Pharmacokinetic Parameters Conclusions Background Demographics Cmax AUClast AUCinf GS-9350 • 24 subjects enrolled and completed the study N=24 ) (ng/ml) (ng·hr/ml) (ng·hr/ml) l 10000 m ___ / F asted Administration; • EVG exposures were increased with • The fi xed-dose combination of emtricitabine (FTC)/ tenofovir DF – 12 females, 12 males g Fasted 326 (33.4) 2240 (24.4) 2580 (24.2) n ___ ( Light Meal (373 kcal, 20% fat); (TDF), is a preferred agent for the treatment of antiretroviral- naïve 1000 food vs. fasted state – Mean age: 35 years (range: 21 to 45 years) n Light Meal 386 (29.2) 2770 (17.1) 3140 (17.2) High Calorie/High fat (800 kcal, 50% fat) o 2 i HIV patients t – Mean weight: 73 kg (range: 61 to 91 kg) HC/HF Meal 356 (45.7) 2780 (19.7) 3140 (18.9) a • GS-9350 exposures were lower with high calorie/ r 100 3 t • FTC pharmacokinetics is unaffected by food n GMR (90% CI) % e high fat meal relative to light meal or fasted Safety c n 10 Light Meal vs. o administration • Tenofovir (TFV) exposure (AUCinf) is modestly increased (~ 40%) with • No Grade 3/4 adverse events or serious adverse events (AEs) 120 (104, 139) 125 (119, 131) 124 (118, 130) c 4 Fasted a a high fat meal • No discontinuations due to adverse events m 1 – Lower GS-9350 exposures with high calorie/ HC/HF Meal vs. s a 103 (89.4, 120) 125 (119, 131) 123 (117, 129) l high fat meal did not adversely affect EVG • Treatment emergent drug-related adverse events: Fasted p – 1 subject: nausea (light meal) HC/HF Meal vs. 0.1 exposures Objectives 86.1 (74.5, 99.7) 99.9 (95.2, 105) 99.7 (94.8, 105) 0 6 12 18 24 30 36 42 48 Impact– 1 subject: of headache, food on dizziness elvitegravir (high calorie/high(as fatStribild meal) ) Light Meal time (hr) • TFV and FTC PK were consistent with their Data presented as arithmetic mean (%CV); GMR: Geometric Least-Squares Means established profi les Primary: Table 1. EVG Plasma Pharmacokinetic Parameters Ratio; CI: Confi dence Interval; HC/HF- high calorie/high fat • To evaluate the pharmacokinetics of EVG, FTC, TFV and GS-9350, – FTC exposures were bioequivalent C AUC AUC administered as a fi xed-dose combination tablet (EVG/FTC/TDF/ N=24 max last inf Table 4. FTC Plasma Pharmacokinetic Parameters Figure 3. TFV Plasma Concentration-Time Profi les – TFV exposures were slightly higher with food GS-9350 [FDC]) under fasted and fed (light and high calorie/high fat) (ng/ml) (ng·hr/ml) (ng·hr/ml) C AUC AUC vs.
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