Critical review of the literature

Transcription

1 Critical review of the literature Sophie Argon, Pharm D Drug Interaction Database Program Senior Editor, Drug Interactions e-pkgene Project Manager 18 th International Conference on Drug-Drug Interactions Seattle, June 29 th July 1 st Outline 1-DDI Publications: What is new in ? Publications: updates and trends Most pronounced drug interactions Transporter-based clinical DDIs Highlight: Case study: Grapefruit juice-clopidogrel interaction 2 1

2 Number of publications entered in DIDB Number of Publications Top 10 journals make up 47% of the published articles Journals Number of Articles Overall Percentage Main focus Drug Metab Dispos in vitro Xenobiotica in vitro J Clin Pharmacol in vivo Int J Clin Pharmacol Ther in vivo Br J Clin Pharmacol in vivo Cancer Chemother Pharmacol in vivo Clin Ther in vivo Antimicrob Agents Chemother in vitro/in vivo Drug Metab Pharmacokinet in vitro/in vivo Clin Drug Investig in vivo 4 2

3 Types of publications* ( ) Number of publications in vivo in vitro metabolism in vitro transport *publications can contain both in vitro and in vivo studies 5 Publications publications in vivo: 46% publications in vitro: 54% publications Enzymes (58%) Transporters (42%) Metabolism 34% CYPs (31%) UGTs (8%) Inhibition 47.4% CYPs (43%) UGTs (9%) Activation 1.3% UGTs (3%) CYPs (2%) Induction 17.3% CYPs (23%) UGTs (3%) Substrates 47.2% P-gp(25%) OATs (19%) OATPs (10%) Inhibition 52.8% P-gp(36%) OATs (19%) OATPs (8%) 6 3

4 Publications publications in vivo: 46% publications in vitro: 54% publications inhibition (52%) induction (15%) single drug PK (33%) including organ impairment food-effect studies Negative Studies 56.5% Positive Studies 43.5% Positive Studies 67.3% Negative Studies 32.7% Inhibitors: 11% Antibiotics 10% Antivirals 9.5% Antifungals Inducers: 39.4% Antibiotics (rifampin) 25.7% Antivirals 18.2% Anticonvulsant (carbamazepine) 7 38 case reports of toxicity victims involved 18.4 Percentage Therapeutic classes Immunosuppressants: cyclosporine, tacrolimus most represented: Anticoagulants: warfarin Cancer treatments: methotrexate 8 4

5 38 case reports of toxicity perpetrators involved Percentage Therapeutic classes Anticonvulsants: phenytoin most represented: Cardiovascular drugs: various Antibiotics: rifampin 9 Outline 1-DDI Publications: What is new in ? Publications: updates and trends Most pronounced drug interactions Transporter-based clinical DDIs Highlight: Case study: Grapefruit juice-clopidogrel interaction 10 5

6 TOP 10 inhibitory interactions Victims Inhibitors Enzymes/ Victim Transporters AUC ratio Reference dextromethorphan fluoxetine CYP2D Sager, 2014 voclosporin ketoconazole CYP3A, P-gp 18.1 Ling, 2014 asunaprevir rifampin (SD, P.O) OATP1B1, OATP2B Eley, 2015 dextromethorphan quinidine CYP2D Bosilkovska, 2014 almorexant ketoconazole CYP3A Dingemanse, 2014 maraviroc telaprevir CYP3A, P-gp, 9.3 Vourvahis, 2014 OATP1B1 omeprazole fluvoxamine and CYP2C19, 3A4 7.8 Bosilkovska, 2014 voriconazole omeprazole fluoxetine CYP2C Sager, 2014 pitavastatin rifampin (SD, IV) OATP1B1 6.5 Prueksaritanont, 2014 nebivolol paroxetine CYP2D6 6.2 Briciu, 2014 All perpetrators are potent inhibitors of CYPs enzymes and/or transporters. All victims are sensitive substrates or probes 11 TOP 10 induction interactions Victims Inducers Enzymes VictimAUC ratio Reference midazolam rifampin CYP3A Bosilkovska, 2014 bosutinib rifampin CYP3A Abbas, 2015 omeprazole rifampin CYP2C Bosilkovska, 2014 voclosporin rifampin CYP3A Ling, 2014 erlotinib rifampin CYP3A4, 1A2, 2C Hamilton, 2014 apremilast rifampin CYP3A Liu, 2014 pretomanib rifampin CYP3A, other 0.32 Dooley, 2014 etonogestrel efavirenz CYP3A Vieira, 2014 bupropion rifampin CYP2B Bosilkovska, 2014 dolutegravir tipranavirand ritonavir CYP3A4, UGT 0.41 Song, 2014 The most pronounced inductions are almost all due to rifampin. 12 6

7 Outline 1-DDI Publications: What is new in ? Publications: updates and trends Most pronounced drug interactions Transporter-based clinical DDIs Highlight: Case study: Grapefruit juice-clopidogrel interaction 13 In vivo articles discussing the role of transporters in DDI (128 studies) Percent of studies OATP1A2 2% MATE2-K 2% OATP 2% OAT1 5% MATE1 6% OATP2B1 5% BCRP 3% OCT 3% OAT3 6% MRP2 OCT2 2% OCT1 1% OCTN1 2% 1% OATP1B3 8% OATP1B1 13% P-gp 40% OATPs: 30% OATs: 11% MATE1/2-K: 8% OCTs: 7% BCRP: 3% 14 7

8 P-gp related inhibition Victim Precipitant Precipitant Dose Victim AUC ratio Reference voclosporin(also CYP3A S) ketoconazole 400 mg QD[10 days] Ling, 2014 maraviroc(also CYP3A S) telaprevir 750 mg TID [10 days] 9.32 Kim, 2014 domperidone(also CYP3A S) milk thistle 500 mg BID [6.5 days] 4.88 Yamsani, 2014 ticagrelor(also CYP3A S) cyclosporine 600 mg SD 2.85 Teng, 2014 voclosporin(also CYP3A S) verapamil 80 mg TID [10 days] 2.68 Ling, 2014 loperamide quinidine 600 mg SD 2.18 Kim, 2014 fexofenadine* quinidine 200 mg SD 2.14 Bosilkovska, 2014 teneligliptine ketoconazole 400 mg QD [6 days] 1.5 Nakamaru, 2014 digoxin* ivacaftor 150 mg BID [9 days] 1.32 Robertson, 2015 lenvatinib rifampin 600 mg SD 1.3 Shumaker, 2014 canagliflozin cyclosporine 400 mg SD 1.25 Devineni, 2015 loperamide HM30181** 180 mg SD Kim, 2014 afatinib ritonavir 200 mg BID [3 days] Wind, 2014 digoxin* voclosporin 0.4 mg/kg BID [11 days] 1.25 Ling, 2014 colchicine (also CYP3A S) atorvastatin 40 mg QD [14 days] 1.24 Davis, 2014 digoxin* vandetanib 300 mg SD 1.22 Johansson, 2014 ethinyl estradiol ledipasvir 90 mg QD [14 days] 1.2 German, 2014 * Regulatory agencies recommended P-gp probe substrates ** HM30181 is a third generation P-gp inhibitor 15 Hepatic OATP-related inhibition Victim Perpetrator Perpetrator Dose Victim AUC ratio Transporter(s) involved Reference asunaprevir rifampin 600 mg SD 14.8 OATP, OATP1B1, OATP2B1 Eley, 2015 maraviroc* telaprevir 750 mg TID [10 days] 9.32 P-gp, OATP1B1 Vourvahis, 2014 pitavastatin rifampin 600 mg SD (IV) 600 mg SD (PO) OATP1B1 rosuvastatin rifampin 600 mg SD (PO) 4.08 OATP1B1 Prueksaritanont, 2014 Prueksaritanont, 2014 bosentan clarithromycin 500 mg BID [4 days] 3.73 OATP1B1, OATP1B3 Markert, 2014 rosuvastatin rifampin 600 mg SD (IV) 3.03 OATP1B1 Prueksaritanont, 2014 (S)-fexofenadine* rifampin 450 mg QD [7 days] 2.99 P-gp, OATPs, OATP1B3 Akamine, 2015 (R)-fexofenadine* rifampin 450 mg QD [7 days] 2.98 P-gp, OATPs, OATP1B3 Akamine, 2015 empagliflozin gemfibrozil 600 mg BID [5 days] 1.6 OATP1B1, OATP1B3, OAT3 Macha, 2014 rosuvastatin asunaprevir 200 mg BID [11 days] 1.4 rosuvastatin elvitegravir and cobicistat 150/150 mg QD [10 days] OATP1B1, OATP2B1, OATP1B3 Eley, BCRP, OATP1B1, OATP1B3 Custodio, 2014 empagliflozin rifampin 600 mg SD 1.35 OATP1B1, OATP1B3 Macha, 2014 *Also a P-gp substrate Maraviroc and telaprevir: interplay between inhibition of CYP3A/P-gp and OATP1B1 by telaprevir 16 8

9 Intestinal OATP-related inhibition Victim Perpetrator Perpetrator Dose Victim AUC Transporter(s) ratio involved Reference nadolol green tea 700 ml [14 days] 0.15 OATP1A2 Misaka, 2014 (S)-fexofenadine apple juice 400 ml SD 0.35 OATP2B1 Akamine, 2014 (R)-fexofenadine apple juice 400 ml SD 0.47 OATP2B1 Akamine, 2014 talinolol quercetin 20 mg BID, 6 days Day 7: 1500 mg with talinolol talinolol quercetin 500 mg TID,6 days Day 7: 1500 mg with talinolol 0.76 P-gp, OATP2B1, OATP1A P-gp, OATP2B1, OATP1A2 Nguyen, 2014 Nguyen, DDI publications : conclusion Most pronounced interactions Inhibition: various CYP and transporters involved Induction: mostly due to rifampin Case reports of toxicity Victim drugs: immunosuppressants, anticoagulants, cancer treatments Perpetrators: anti-infective agents, anticonvulsants, cardiovascular drugs Transporter-based DDIs P-gp and OATPs are the main transporters involved. 18 9

10 Outline 1-DDI Publications: What is new in ? Publications: updates and trends Most pronounced drug interactions Transporter-based clinical DDIs Highlight: Case study: Grapefruit juice-clopidogrel interaction 19 Case study: Grapefruit juiceclopidogrel interaction Clin Pharmacol Ther Mar;95(3):

11 Grapefruit juice-clopidogrel interaction Study Design & Drug Administration Study design & subjects: Random crossover 14 healthy volunteers (CYP2C19: 7 EMs; 5 IMs; 2 PMs), non-smokers Victim: clopidogrel (P2Y 12 platelet inhibitor) 600 mg single dose, administered in the morning on Day 3 of grapefruit juice or water administration (fasting state) Perpetrator: grapefruit juice (food) 200 mlof normal-strength grapefruit juice three times a day for 3 days (8 am, 12 pm, and 8 pm). PK measurements at 0-3h, 0-12h and 0-inf PD measurements: platelet inhibition at 0-12 hours Clin Pharmacol Ther Mar;95(3): Grapefruit juice-clopidogrel interaction impact on pharmacokinetics clopidogrel active cis-metabolite (R ) No significant effect on clopidogrel 16.7% increase in AUC 0-inf Clin PharmacolTher Mar;95(3): % decrease in AUC 0-3h 83.8% decrease in AUC 0-inf 88.6% decrease in AUC ratio m/p t max and t 1/2 unaffected 22 11

12 Grapefruit juice-clopidogrel interaction impact on pharmacodynamics (n=2) Subject 1: CYP2C19*1/*1 Subject 2: CYP2C19*2/*2 WATER Subject 1: CYP2C19*1/*1 Subject 2: CYP2C19*2/*2 GFJ Average inhibition of P2Y12-mediated platelet aggregation: -subject 1 (EM): decrease from 90% (with water) to 20% (with GFJ) -subject 2 (PM): decrease from 47% (with water) to 12% (with GFJ) Clin PharmacolTher Mar;95(3): Authors conclusion New type of grapefruit juice drug interaction: grapefruit juice is able to impair the bioactivationof a prodrug Possible mechanism proposed: inhibition of both CYP3A4-and CYP2C19-mediated metabolism of clopidogrel Recommendation: avoid the concomitant use of clopidogrel and grapefruit juice 24 12

13 Victim: clopidogrel Intestinal absorption of clopidogrelis limited by the intestinal efflux pump P-gp. Clopidogrel undergoes an extensive and complex metabolism in the liver. ~15% is bioactivated in the liver CYP2C19 (45%) CYP3A4 (40%), 2B6 (33%) CYP1A2 (36%) CYP2C19 (21%), 2C9 (6.8%) clopidogrel 2-oxo-clopidogrel active cis-metabolite (prodrug) CYP2B6 (19%) (inactive) paraoxonase (R ) ~85% carboxylesterases (CES1>CES2>>BChE) CES1>CES2>>BChE CE1>CES2 clopidogrel 2-oxo-clopidogrel R carboxylic acid carboxylic acid carboxylic acid (inactive) (inactive) (inactive) (In vitro fractions metabolized) Expert Opin Pharmacother Apr;13(5): Perpetrator/ Genetic variant Clopidogrel in vivo metabolism (effect of CYP inhibitors and Pharmacogenetics) Enzymes investigated ketoconazole CYP3A4(+++) CYP2C9 (+) prodrug % AUC active metabolite Perpetrator dose Effect of platelet inhibition References mg q.d, 10 d Yes Farid, 2007 fluoxetine CYP2C19 (+++) mg q.d, 5 d Yes Delavenne, 2013 omeprazole CYP2C19 (++) mg q.d, 9 d 80mg q.d, 14 d 80mg q.d, 10 d 20 mg q.d, 7d Yes Frelinger, 2012 Andersson, 2014 Angiolillo, 2011 Funck-Brentano, 2013 *0/*0 CYP2C19-29; ; -43 Not Applicable Yes Kim, 2014 Simon, 2011 *1/*3; *2/*2; *2/*3 CYP2C Not Applicable Yes Brandt, 2007 grapefruit CYP3A4 (++) juice CYP2C19? +++: potent; ++: moderate; +: weak ml t.i.d, 3 d Yes Holmberg, 2014 The individual inhibition studies of CYP2C19 and CYP3A4, as well as genetic variation with null or limited activity do not reach the extent of the DDI observed between GFJ and clopidogrel

14 Clopidogrelas a substrate of transporters? In vitro: limited transport data available in the literature In vivo: clopidogrelis a P-gpsubstrate. Aspirin induced intestinal P-gplowering the oral bioavailability of clopidogrel(oh et al, 2014) Pharmacogenetics:subjects homozygous variant ABCB1c.3435TT vs. 3435CC+CT clopidogrel active metabolite Max % AUC -80 to to -76 Taubert, 2006; Karazniewicz-Lada, Case study results: Prodrug clopidogrel Cmax and AUC were unchanged by grapefruit juice administration Conclusion:intestinal inhibition of uptake transporters (OATP1A2 and/or 2B1) and/or activation/induction of efflux transporter P-gp are two mechanisms not involved in this interaction

15 Grapefruit juice as a perpetrator in vitro IC 50 (µm) -Data summarized from DIDB Constituents Content in juice Naringin ng/ml Naringenin ng/ml GF-I ng/ml GF-I ng/ml GF-I ng/ml DHB ng/ml GF-I-5 GF-I-6 CYP3A4 CYP2C19 CYP2C9 CYP1A2 178 (felodipine) 1349 (quinidine) (depending on substrate) (nifedipine) (omeprazole) (nifedipine) (omeprazole) 1; Ki: 2.24 (midazolam) (nifedipine) 15; Ki: (midazolam) 0.65(nifedipine) (testosterone) (testosterone) 2 (MFC) (flurbiprofen) 2.6 (MFC) 12 (diclofenac, flurbiprofen) GF-I-1 and GF-I-4: furanocoumarin dimer; GF-I-2: bergamottin; DHB: 67-dihydroxybergamottin; GF-I-5: (R)-bergamottin-67-epoxide; Furanocoumarins are potent inhibitors of CYP3A4, CYP2C19, CYP2C9 and CYP1A2 enzymes, 29 all involved to some extent in the bioactivation of clopidogrel. Grapefruit juice as a perpetrator in vivo Effect of GFJ on CYP probe disposition (Data summarized from DIDB) Enzyme Probes GFJ dose % AUC CYP3A4 midazolam (oral) midazolam (IV) 240 ml regular-s QD, 4 days 240 ml double-s QD, 3days 250 ml regular-s, twice CYP2C19 lansoprazole 200 ml SD 20.9 CYP1A2 caffeine 300 ml, 1.5 days (no inhibition) CYP2C9 (others) warfarin* 1 grapefruit each morning, 1 week INR of L of GFJ per day, 10 days INR of 6.29 GFJ is a moderate-to-potent intestinal CYP3A inhibitor GFJ weakly inhibits CYP2C19 (and maybe CYP1A2) Effect of GFJ on CYP2B6 and CYP2C9 probes were not evaluated in vivo. *Bodiford, 2013: Elevated international normalized ratio with the consumption of grapefruit and use of warfarin *Am J Health Syst Pharm.1999 Apr 1;56(7):

16 Grapefruit juice as a perpetrator: transporter data In vitro: IC 50 (µm) -Data summarized from DIDB GFJ components Naringin Naringenin GF-I-2 DHB OATP1A2 (int) OATP2B1 (int) 4.63 I 1 /IC 50 : 350 P-gp (int/hep) 2409 I 1 /IC 50 : 0.62 BCRP (int/hep) I 1 /IC 50 < 10-3 I 1 /IC 50 < % at 10µM Limited evidence for the potential inhibition of hepatic uptake of clopidogrelpreventing its bioactivation. (K. Manderyet al. European Journal of Pharmaceutical Sciences 46 (2012) 79 85) 5.2 I 2 /IC 50 : 17.1 R> 1.25: FDA cut-off for potential in vivo DDI In vivo: GFJ has no significant effect on digoxin disposition (Clin Pharmacol Ther Oct;70(4):311-6; Pharmacotherapy Aug;23(8):979-87) OATP1B1 (hep) OATP1B3 (hep) MATE1 (ren/hep) I 1 /IC 50 : I 1 /IC 50 : 1.54 I 1 = Cmax I 1 /IC 50 : I 1 /IC 50 : I 1 /K I < I 2 = dose (mol)/250ml IC 50 C max /IC 50 R OATP1B µm OATP1B µm Evidence: Grapefruit juice as perpetrator GFJ affects CYP3A4 substrates undergoing extensive firstpass metabolism Effect on P-gpappears to be minimal Possible other mechanisms: Inhibition of CYP3A4, 2C19, and 1A2: does not explain the dramatic decrease in exposure of clopidogrelactive metabolite Inhibition of hepatic OATP1B1 and OATP1B3 and possibly other hepatic transporters: no strong evidence supporting this hypothesis Drug Metab Dispos Nov;25(11): J Clin Invest May 15;99(10):

17 GFJ-clopidogrel DDI loss of efficacy (not published presented in clinicaltrials.gov ) Effect of grapefruit juice (two small cans [11 oztotal] of regular strength GFJ in the morning) on platelet-inhibitory effect of clopidogrel. Clopidogreldosage regimen % Platelet Inhibition (measured by Verify Now) without GFJ with GFJ 300 mg single dose loading dose (n=15) 75 mg for 7days maintenance dose (n=17) No statistical analysis provided for % platelet inhibition 41.2 (19.1) 23.4 (14.2) : -43.2% 59 (22.5) 24.6 (24.2) : -58.3% GFJ decreases the efficacy of clopidogrelon platelet inhibition clinicaltrials.gov, identifier: NCT Conclusion First case of non-intestinal GJF-drug interaction Mechanism not fully elucidated but potentially involving inhibition of multiple enzymes including CYP3A4 and CYP2C19 as well as hepatic transporters Avoid drinking GFJ during clopidogrelchronic treatment 34 17

18 Acknowledgments Dr. Isabelle RAGUENEAU-MAJLESSI Dr. Jingjing YU Dr. Tasha RITCHIE Dr. Cathy YEUNG Dr. Katie OWENS Dr. Zhu ZHOU Dr. Jessica SONTHEIMER Dr. Nina ISOHERRANEN Marjorie IMPERIAL Grace LEE Chris KINSELLA 35 Thank you! 36 18

19 Additional slides 37 Naringenin and Hepatic OATPs IC 50 C max /IC 50 R OATP1B µm OATP1B µm C max µg/ml = 7.38 µm, with 135 mg dose (approx241 mg naringenin/l grapefruit juice, so ~560 ml of grapefruit juice) I in,max 40.4 µm (calculated by authors) R = 1 + (f u * I in,max )/IC 50, assuming f u = 0.2 (moderately protein bound) If R 1.1: clinical significance is very unlikely. K. Mandery et al. European Journal of Pharmaceutical Sciences 46 (2012)

20 Clopidogrel as a victim Marketed in 1997 Irreversible P2Y12 platelet inhibitor Indications: acute coronary syndrome, recent MI, recent stroke, or established peripheral arterial disease Extensively metabolized: no unchanged clopidogrel in urine Drug Metab Rev. 2009;41(2): Grapefruit juice as precipitant Naringin typical and abundant ingredient in GFJ: ng/ml (hand squeezed) Naringenin aglycone of naringenin: ng/ml (hand squeezed) Furanocoumarins (psoralens/bergaptens) Bergamottin(GF-I-2) (R)- 6,7 -dihydrobergamottin (DHB) (R)-bergamottin-6,7 -epoxide (GF-I-5) Paradisin A (GF-I-1) Paradisin B (GF-I-4) Paradisin C (GF-I-6) 40 20

21 Grapefruit juice as precipitant Comparison of naringin, naringeninand bergaptencontents in different brands of fresh grapefruits. Grapefruit juices Naringin(mg/L) Naringenin bergaptens Fresh (squeezed) Fresh (by blender) McCOY Sun Valley Ocean Spray (pink) ND Ocean Spray (ruby red) ND Keri Robinson Brothers ND DewDrop Pharm Acta Hely Apr;74(4): (PMID ) 41 21