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 a high fat meal Fasted a • 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. fasted state conditions Fasted 1490 (40.3) 15600 (40.2) 16400 (38.6) max last inf TFV
N=24 1000 ) Light Meal 1760 (31.5) 20400 (28.0) 21100 (27.5) (ng/ml) (ng·hr/ml) (ng·hr/ml) l • EVG/FTC/TDF/GS-9350 FDC should be
m ___ Secondary: / Fasted Administration; HC/HF Meal 2230 (27.1) 28000 (22.6) 28800 (21.6) Fasted 1910 (29.1) 11000 (21.8) 11300 (21.0) g
n ___ Light Meal (373 kcal, 20% fat); administered with food to provide desired EVG (
• To evaluate the safety and tolerability of administration of the
GMR (90% CI) % Light Meal 1810 (28.8) 10300 (19.6) 10700 (18.6) n High Calorie/High fat (800 kcal, 50% fat)
o exposures
i 100
EVG/FTC/TDF/GS-9350 fi xed-dose combination tablet under fed and t
Light Meal vs. HC/HF Meal 1820 (26.5) 10400 (19.1) 10800 (18.8) a r fasted conditions 122 (108, 138) 136 (121, 154) 134 (119, 151) t
Fasted GMR (90% CI) % n
e c
HC/HF Meal vs. Light Meal vs. n 156 (138, 176) 191 (170, 216) 187 (166, 210) 95.4 (86.5, 105) 94.3 (90.3, 98.6) 95.3 (91.2, 99.6) o 10
c References
Fasted Fasted
a m
HC/HF Meal vs. HC/HF Meal vs. s 1. Internal Gilead Data on fi le.
128 (114, 145) 140 (124, 158) 139 (123, 157) 96.2 (87.2, 106) 95.6 (91.5, 99.9) 95.7 (91.6, 100) a l
Light Meal Fasted p 1 2. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and HC/HF Meal vs. Adolescents. January 29, 2008 . Data presented as arithmetic mean (%CV); GMR: Geometric Least-Squares Means 101 (91.4, 111) 101 (97.0, 106) 100 (96.1, 105) 0 6 12 18 24 30 36 42 48 Ratio; CI: Confi dence Interval; HC/HF- high calorie/high fat Light Meal time (hr) 3. Truvada US Prescribing Information. May 2005. German P. 49th ICAAC 2009; poster A1-1300 Data presented as arithmetic mean (%CV); GMR: Geometric Least-Squares Means 4. Viread US Prescribing Information. October 2003. Ratio; CI: Confi dence Interval; HC/HF- high calorie/high fat Impact of food on elvitegravir (as Stribild)
Standard breakfast Fasted Protein rich drink
Shiomi M et al. Journal of Clinical Pharmacology. 2014;54(6):640-648. Food effect on dolutegravir
In the presence of integrase resistance, DTG should preferably be taken with food to enhance exposure (particularly with Q148)
1. Song I et al. Antimicrobial Agents and Chemotherapy. 2012;56(3):1627-1629. 2. Tivicay SPC accessed 2nd October 2018 Food effect may vary with formulation: example of bictegravir
1 0 0 Food Effect ↑84% 8 0 BIC can be taken with 6 0 or without food
4 0 ↑24%
2 0 % Increase in BIC Exposure in BIC Increase %
0 BIC BIC/FTC/TAF Single Agent STR
Zhang H, et al, CROI, 2017. Forgiveness
• Tail studies very informative • Achieve steady state, stop then monitor drug levels • Dolutegravir & elvitegravir in healthy volunteers: – [DTG] > IC90 in 100% of subjects after 36 & 48 h and in 94% after 60 & 72 h – [EVG] > IC95 in 100% of subjects at 24 h, 65% at 36 h, 0% after 48 h Renal transporters May result in reduced uptake from blood
May result in reduced excretion Yombi JC et al. AIDS 2014, 28:621–632 Two main consequences?
• Impact on creatinine secretion • Impact on drug secretion Renal Transporters and Creatinine Clearance Inhibition by: Renal tubular Rilpivirine cell Dolutegravir Bictegravir Creatinine OCT2
Inhibition by: Dolutegravir Creatinine MATE1 Trimethoprim Ritonavir Cobicistat Bictegravir Raltegravir
Blood Active Tubular Secretion Urine
Slide courtesy of Marta Boffito; adapted from Lepist EI, et al. 51st ICAAC 2011. Abstract A1-1724 DRUG-DRUG INTERACTIONS Mechanisms of drug interactions
HEPATIC RENAL ABSORPTION CLEARANCE CLEARANCE
• Chelation • Enzymes/transporters • Renal transporters • pH effects • Liver disease • Renal disease • Gut enzymes & • Pharmacogenetics transporters
UGT1A1*28 polymorphism increases [RAL] which correlates with fatigue Pharmacokinetic consequences of drug- drug interactions 1. Increased exposure to one/both drugs – Risk of toxicity
2. Decreased exposure to one/both drugs – Lack of efficacy Inhibition of hepatic CYP: increased systemic exposure
Drug
A. Drug alone 10 AUC 2
CYP 1 Concentration
Time B. Drug + inhibitor Drug AUC 5 10
Inhibitor blocks the Cobicistat & function of the CYP CYP 1
enzyme ritonavir Concentration
Time Perpetrator vs victim
• Any individual drug can be one or the other, or both • Example = dolutegravir – Perpetrator: increased metformin concentrations – Victim: concentrations reduced by cations – Victim: of strong enzyme inducers
Adapted from Back DJ & Kiser J. ICAAC September 2014. Effect of DTG on metformin Dose adjustment of metformin may be considered
Regimen Cmax (μg/mL) AUC0– (µgh/mL) t1/2 (h) Metformin + DTG (50 mg q24h) vs 1.66 (1.53, 1.81) 1.79 (1.65, 1.93) 1.09 (0.954, 1.24) metformin alone Metformin + DTG (50 mg q12h) vs 2.11 (1.91, 2.33) 2.45 (2.25, 2.66) 1.14 (1.00, 1.29) metformin alone
Values shown are GLS mean ratio (90% CI) Zong et al 2014 Chelation of InSTI by polyvalent cations
2.0 DTG alone 1.8 DTG + antacid 1.6 DTG + antacid 2 hours later
1.4 Mg2+
1.2 Mg2+ 1.0 0.8 InSTI 0.6 0.4
Mean DTG concentration (µg/mL) DTG concentration Mean 0.2 0 0 10 20 30 40 50 60 70 80
Time (h)
Patel et al 2011 Impact of moderate/strong UGT1A1 and/or CYP3A4 inducers on DTG
DTG C or C DTG dose 24 Co-administered drug n GLS mean ratio (90% CI) Recommendation studied Ratio of 1 = no impact
FPV/r 700/100 mg BID 12 50 mg QD 0.51 (0.41–0.63) DTG 50 mg BID should be given TPV/r 500/200 mg BID 16 50 mg QD 0.24 (0.21–0.27) DTG 50 mg BID should be given DRV/r 600/100 mg BID 15 30 mg QD 0.62 (0.56–0.69) No DTG dose adjustment required EFV 600 mg QD 12 50 mg QD 0.25 (0.18–0.34) DTG 50 mg BID should be given
ETR 200 mg BID 15 50 mg QD 0.12 (0.09–0.16) DTG 50 mg BID should be given
Rifampin 600 mg QD 11 50 mg BID 0.28 (0.23–0.34) DTG 50 mg BID should be given Rifabutin 300 mg QD 9 50 mg QD 0.70 (0.57–0.87) No DTG dose adjustment required CBZ 100 mg BID 14 50 mg QD 0.274 (0.24–0.31) DTG 50 mg BID should be given
The GLS ratio values in red signify that in these cases, C for DTG is reduced significantly below 75% (the lower boundary of a clinically significant alteration in DTG exposure)
Tivicay SPC; Song et al 2011; Song et al 2011; Dooley et al 2013 ARVs and interaction potential
Higher potential Moderate Potential Low Potential
Boosted PIs (r or cobi) Rilpivirine Raltegravir Perpetrators – enzyme and Victim of enzyme inhibition Victim of few induction transporter Inhibition and induction. Also and absorption Victim - absorption (ATV); absorption. interactions induction EVG/cobi Maraviroc Most NRTIs Perpetrators – enzyme and Victim of enzyme inhibition Some transporter transporter inhibition and induction. mediated Victim - absorption; induction Efavirenz, nevirapine, Dolutegravir etravirine Perpetrators –transporter Inhibition Perpetrators – enzyme and Victim of enzyme transporter induction inhibition/induction and absorption interactions
Slide courtesy of Marta Boffito www.hiv-druginteractions.org BIC Drug–Drug Interaction Profile
• Perpetrator? Low potential (OCT2/metformin) • Victim? Low potential (or moderate?) – INSTIs are affected by cation-containing antacids • BIC administration with antacids should be staggered (± 2 hours) • Fasted administration 2 hours before or 2 hours after antacid resulted in a decrease in BIC exposures of 13% and 52%, respectively – BIC is a substrate of CYP3A4 and UGT1A1 • Inhibition of both CYP3A4 and UGT1A1 needed for substantial increase in exposure • Potent induction reduces exposure to a clinically significant extent
Zhang, et al. CROI 2017 Acid-reducing drugs & cations
RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR (ISENTRESS) (Stribild & Genvoya) (TIVICAY, TRIUMEQ & JULUCA) ANTACIDS e.g. Do not take aluminium or Take your HIV meds 2 Rennie, Gaviscon magnesium antacids. hours before or 6 Calcium antacids are OK hours after antacids, if you are on TWICE A multivitamins or DAY raltegravir & do not calcium need to be spaced Can be taken if at supplements. MULTIVITAMINS Can only be taken if you least 4 hours apart are on TWICE A DAY from your HIV meds If you have any raltegravir & at least 6 resistance to hours apart dolutegravir you should NOT take Calcium Can only be taken if you these – your clinician supplements are on TWICE A DAY will advise you raltegravir & at least 4 hours apart https://www.hiv-druginteractions.org/checker accessed 21st May 2018 ART & contraception Coloured boxes: European SPC advice; grey boxes: my opinion NR = not recommended)
Oral DMPAa Implanonb RAL No dose adjustment No dose No dose adjustment adjustment DTG No dose adjustment* Likely fine Likely fine Stribild & NG: AUC ↑126%, Cmin ↑167%, Genvoya Cmax ↑ 108% EE: AUC ↓25%, Cmin ↓44%, Likely fine Likely fine Cmax At least 30mcg EE. If prog other than norgestimate, use alternativec BIC Small increases in ethinyl Likely fine Likely fine oestradiol & norgestimate
a) DMPA: clearance = hepatic blood flow, inducers unlikely to impact efficacy b) Implanon: failures on EFV & AED; SPC says efficacy may be affected by enzyme inducers *no impact on LH or FSH c) Long-term effects of substantial increases in progesterone exposure are unknown COMMUNICATION Dear Doctor,
RE: Mr X
I saw this gentlemn with HIV…..he is on Stribild. Please note there is a risk of drug interactoins (see footer). He needs anual flu vaccination and a pneumococcal vaccine.
Your sincerely
Dr L Waters
Blurb about vaccinations and drug interactions in general – I’m sure no- one actually bothers to read it so that’s why I type important interactions in myself. I wonder if you’ll read this? Will you?? What we do now
• GP and referral letter templates a section at the top of the letter which we delete as appropriate: – Please note there is a significant risk of drug-drug interactions between HIV therapy and other drugs, e.g: – Ritonavir/cobicistat is a potent inhibitor of CYP3A4; important interactions include simvastatin (risk of rhabdomyolysis) and several inhaled/intranasal/injected steroids such as fluticasone and triamcinolone (risk of iatrogenic Cushing’s) – Rilpivirine has significant interactions with acid-reducing agents; PPI are contra-indicated; H2A and antacids require careful dose spacing Patient information
• If you find yourself repeating the same messages
Make an information card!! Patient information card: handed out in consultations, website Conclusions
• Understanding pharmacology important • The main clinical implications: – Food advice – Advice about late/missed doses – Drug-drug interactions • Ensure advice to patients and other health care professionals is: – Clear – Accessible – Relevant Acknowledgements
• Marta Boffito – Queen of PGP Carluccio’s Thank you! ? [email protected] @drlaurajwaters