Critical review of the 2015-2016 literature on drug interactions Katie Owens, BPharm PhD Research Scientist II Drug Interaction Database (DIDB) Program Dept. of Pharmaceutics University of Washington 19 th International Conference on Drug-Drug Interactions Seattle, June 20 th June 22 nd 2016 1
Outline DDI Publications: What is new in 2015-2016? The year in numbers Most pronounced metabolism-based DDIs Case study 1: Influence of CYP2D6 activity on ibogaine PK Transporter-based clinical DDIs Case study 2: Asunaprevir as a substrate and inhibitor of OATP 2
Number of publications Number of Articles Entered in the DIDB 800 700 600 500 464 434 510 472 522 547 504 463 460 487 623 638 714 730 780 738 868 400 300 200 100 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 130 Year Jan Mar 2016 3
in vivo in vitro Top 10 Journals Journals Number of Articles 2015-16 Overall Percentage Drug Metab Dispos 102 13.8 Xenobiotica 54 7.3 J Pharm Sci 24 3.2 Biochem Pharmacol 23 3.1 Biopharm Drug Dispos 21 2.8 J Clin Pharmacol 43 5.8 Br J Clin Pharmacol 30 4.0 Clin Pharmacol Drug Dev 28 3.8 Cancer Chemother Pharmacol 24 3.2 Clin Ther 21 2.8 70% of the articles entered in the DIDB 4
Number of publications Types of Articles (2010-2015) 800 600 333 344 340 342 355 317 302 313 399 410 446 421 400 200 0 2010 2011 2012 2013 2014 2015 262 263 271 142 155 191 In vivo In In vitro metabolism In In vitro transport 2010 2011 2012 2013 2014 2015 A delay in appearance in PubMed has been seen in some journals An increasing number of articles include the results from multiple DDI studies 5
2015-2016 Articles 868 articles Covering >7,700 studies 27 articles have both in vitro and in vivo studies 371 articles (43%) >1,200 in vivo studies (16%) Enzymes 61% 529 articles (61%) >6,500 in vitro studies (84%) Transporters 39% Metabolism 29% CYPs (51%) UGTs (9%) Inhibition 58% CYPs (25%) UGTs (18%) Induction 12% CYPs (41%) UGTs (0%) Activation 1% CYPs (16%) UGTs (26%) Substrates 25% P-gp (11%) OATs (13%) OATPs (12%) Inhibitors 75% OCTs (16%) OATs (13%) P-gp (9%) 6
2015-2016 Articles 27 articles have both in vitro and in vivo studies 868 articles Covering >7,700 studies 371 articles (43%) >1,200 in vivo studies (16%) 529 articles (61%) >6,500 in vitro studies (58%) Inhibition 52% Induction 12% Single drug PK 37% incl. organ impairment & food-effect Negative studies 60% Positive studies 40% Negative studies 29% Positive studies 71% Inhibitor therapeutic classes: 18% Antifungals 14% Antivirals 7% Antibiotics Inducer therapeutic classes: 27% Antibiotics 20% Non-Nucleoside Reverse Transcriptase Inhibitors 14% Anticonvulsants 7
Number of cases Case Reports of DDIs (N = 40) Victim drugs involved 10 7 5 4 4 4 2 1 1 1 1 Most represented therapeutic classes: Central nervous system agents: anticonvulsants (n = 7), antipsychotics (n = 3) Cardiovascular drugs: anticoagulants (n = 4), statins (n = 3) Anti-infective agents: antifungals (n = 3), antibiotics (n = 2) 8
Number of cases Case Reports of DDIs (N = 40) 19 Perpetrator drugs involved 6 4 3 3 1 1 1 1 1 Most represented therapeutic classes: Anti-infective agents: antibiotics (n = 10), antifungals (n = 5), antivirals (n = 4) Depression treatments: SSRIs (n = 4), SNRIs (n = 1), NDRIs (n = 1) 9
Outline DDI Publications: What is new in 2015-2016? The year in numbers Most pronounced metabolism-based DDIs Case study 1: Influence of CYP2D6 activity on ibogaine PK Transporter-based clinical DDIs Case study 2: Asunaprevir as a substrate and inhibitor of OATP 10
Top 10 Pronounced Clinical Inhibitions CYP2D6 sensitive substrate & natural product Victims Inhibitors Enzymes/ Transporters possibly involved Victim AUC Ratio Reference Ibogaine Paroxetine CYP2D6 (EM/IMs) 66.2 Glue, 2015 Tacrolimus Paritaprevir, Ritonavir, Ombitasvir and Dasabuvir CYP3A, OATP1B1 55.8 Badri, 2015 Midazolam Ketoconazole CYP3A 17.1 Boulenc, 2016 Asunaprevir Rifampin (SD * ) OATP 14.8 Eley, 2015 CYP2C8 sensitive substrate Midazolam Ritonavir CYP3A 14.5 Greenblatt, 2015 Omeprazole Fluconazole CYP2C19, CYP3A 13.5 Derungs, 2016 Midazolam Ketoconazole CYP3A 11.5 Greenblatt, 2015 Investigational drugs Dasabuvir Gemfibrozil CYP2C8 11.3 Menon, 2015 Alisporivir Ketoconazole CYP3A, P-gp 7.9 Barve, 2015 Simvastatin Grapefruit Juice CYP3A 7.7 Park, 2015 All perpetrators are potent inhibitors of CYP enzymes and/or transporters All victims are sensitive substrates or probe substrates of the respective enzyme and/or transporter *Single dose 11
Top 10 Pronounced Clinical Inhibitions Victims Inhibitors Enzymes/ Transporters possibly involved Victim AUC Ratio Reference Ibogaine Paroxetine CYP2D6 (EM/IMs) 66.2 Glue, 2015 Tacrolimus Paritaprevir, Ritonavir, Ombitasvir and Dasabuvir CYP3A, OATP1B1 55.8 Badri, 2015 Midazolam Ketoconazole CYP3A4 17.1 Boulenc, 2016 Asunaprevir Rifampin (SD) OATP 14.8 Eley, 2015 Midazolam Ritonavir CYP3A 14.5 Greenblatt, 2015 Omeprazole Fluconazole CYP2C19, CYP3A 13.5 Derungs, 2016 Midazolam Ketoconazole CYP3A 11.5 Greenblatt, 2015 Dasabuvir Gemfibrozil CYP2C8 11.3 Menon, 2015 Alisporivir Ketoconazole CYP3A4, P-gp 7.9 Barve, 2015 Simvastatin Grapefruit Juice CYP3A4 7.7 Park, 2015 All perpetrators are potent inhibitors of CYP enzymes and/or transporters All victims are sensitive substrates or probe substrates 12
Paul Glue, MD, FRCPsych, Helen Winter, PhD, Kira Garbe, MSc, Hannah Jakobi, MSc, Alexander Lyudin, MBChB, Zoe Lenagh-Glue, BBiomedSci, and C. Tak Hung, PhD The Journal of Clinical Pharmacology 2015, 55(6) 680 687 the Tabernanthe Iboga shrub 13
Main Characteristics Ibogaine is a naturally occurring psychoactive product derived from the bark and roots of the central African rainforest native plant Tabernanthe iboga Previously marketed in France as Lambarène between 1940-1970 at doses of 21-28 mg/day Unregulated but used by alternative therapists and drug users for the treatment of drug (opioids, stimulant and cocaine, nicotine and polysubstance) and alcohol addiction Noribogaine is under development by Demerx, Inc. for the treatment of pain and drug addiction Paroxetine is a potent CYP2D6 inhibitor 14
Main Characteristics Ibogaine CYP2D6 CYP2C9, CYP3A4 noribogaine Ibogaine + noribogaine = active moiety Terminal half-life: Ibogaine: 7.45 ±0.81 h in CYP2D6 EMs Noribogaine: 28-49 h across doses from 3, 10, 30, and 60 mg Pharmacodynamics: 15 Table extracted from Litjens et al. 2016; Clin Toxicol Obach; et al. 1998; Drug Metab Dispos Mash et al. 2001; Drug Metab Dispos
Ibogaine and Paroxetine DDI: Methods Population 21 healthy male volunteers All subjects were CYP2D6 EMs, except one PM (excluded from analysis) Design CYP2D6 phenotype determined by urinary dextromethorphan:dextrorphan ratio Parallel, double-blind, placebo-controlled Drug administration Victim: ibogaine, 20 mg single dose on Day 8 of paroxetine or placebo administration Perpetrator: paroxetine (n=9) or placebo (n=11), 20 mg once daily on Days 2-15 (starting with 10 mg QD on Days 3-4) PK investigation The effect of CYP2D6 inhibition on ibogaine exposure PD investigation A pharmacodynamic assessment sensitive to µ-opioid agonist effects was assessed by pupillometry 16
Results solid symbols: placebo phase (n=9) open symbols: paroxetine phase (n=11) 66-fold ibogaine AUC 1.1-fold noribogaine AUC 1.9-fold active moiety AUC ibogaine placebo paroxetine AUC 0-t (ng/ml*h) Cmax (ng/ml) Mean ± SD 3.6 ± 7.2 238.2 ± 202.1 P = 0.0028 1.1 ± 1.8 29.5 ± 16.8 P < 0.0001 t 1/2 (h) 2.5 ± 0.9 10.2 ± 7.8 P = 0.009 noribogaine placebo paroxetine AUC 0-t (ng/ml*h) Cmax (ng/ml) 277.4 ± 116.9 304.1 ± 127.9 P = 0.64 18.7 ± 7.3 12.7 ± 5.3 P = 0.05 t 1/2 (h) 13.0 ± 4.7 20.1 ± 10.2 P = 0.07 AUC ratio m/p 77.1 1.28 ibogaine + noribogaine AUC 0-t (nmol/ml*h) placebo 948 ± 407 paroxetine 1793 ± 695 Figure extracted from Glue et al. 2015-98.3% 17
Ibogaine and Paroxetine DDI Ibogaine is sensitive to CYP2D6 inhibition by paroxetine No correlations between ibogaine, noribogaine, or active moiety exposure and safety or PD (changes in pupil diameter, VAS scores) Clinical cases of cardiac abnormalities after ibogaine ingestion have been reported 1 Pharmacogenetic considerations: One PM subject had a 2.6-fold increased ibogaine AUC at baseline vs. EM subjects Mash et al. 2 found that CYP2D6 PMs had a 2.9-fold ibogaine exposure and 75% lower noribogaine AUC compared to EMs Authors conclusions: A single 20 mg dose of ibogaine (low dose) is safe and well tolerated Patients that are co-medicated with CYP2D6 inhibitors, or are CYP2D6 poor metabolizers, are at risk of increased exposure to ibogaine 1 Litjens and Brunt 2016; Clin Toxicol 2 Mash et al. 2001; Drug Metab Dispos 18
Top 10 Pronounced Inductions 4 Kinase Inhibitors Victims Inducers Enzymes/Transporters possibly involved Victim % AUC remaining Reference Omeprazole Rifampin CYP2C19, CYP3A 7.0 Derungs, 2016 Bosutinib Rifampin CYP3A, P-gp 7.6 Abbas, 2015 Alisporivir Rifampin CYP3A, P-gp 9.6 Barve, 2015 Ritonavir Carbamazepine CYP3A 13.0 Menon, 2015 Potent CYP3A4 Inducer Tasimelteon Rifampin CYP1A2, CYP3A 13.9 Ogilvie, 2015 Midazolam Enzalutamide CYP3A 14.1 Gibbons, 2015 Midazolam Rifampin CYP3A 15.8 Derungs, 2015 Investigational Drug Crizotinib Rifampin CYP3A 18.1 Xu, 2015 Cabozantinib Rifampin CYP3A 22.8 Nguyen, 2015 Idelalisib Rifampin CYP3A, UGT1A4 23.9 Jin, 2015 The most pronounced inductions are almost all due to rifampin 19
Outline DDI Publications: What is new in 2015-2016? The year in numbers Most pronounced metabolism-based DDIs Case study 1: Influence of CYP2D6 activity on ibogaine PK Transporter-based clinical DDIs Case study 2: Asunaprevir as a substrate and inhibitor of OATP 20
In vivo DDI Articles with Transporters (50 articles, 117 studies) OATP2B1, 4% MATE1, 2% MRP2, 3% OAT3, 4% OCT2, 4% BCRP, 9% MATE2-K, 2% OAT1, 1% OATP1B1/1B3, 19% OATP1A2, 1% P-gp, 38% Transporters listed in regulatory guidance documents FDA 1 EMA 2 NIHS 3 P-gp P-gp P-gp BCRP BCRP BCRP OATP1B1 OATP1B1 OATP1B1 OATP1B3 OATP1B3 OATP1B3 OCT2 OCT2 OCT2 OAT1 OAT1 OAT1 OAT3 OAT3 OAT3 OCT1 MATE1 MATE1 MATE1 MATE2 MATE2 MATE2 MRPs BSEP MRPs BSEP 1 FDA Draft Guidance for Industry: Drug Interaction Studies 2012 2 EMA Guideline on the Investigation of Drug Interactions 2012 3 Japanese NIHS Draft Drug Interaction Guideline 2014 21
P-gp-Related Inhibition P-gp inhibitors Victims Sofosbuvir Sofosbuvir Inhibitors Paritaprevir, Ritonavir, Ombitasvir and Dasabuvir Paritaprevir, Ritonavir and Ombitasvir Enzymes/Transporters possibly involved Victim AUC Ratio Reference CES1, P-gp & BCRP 2.13 King, 2015 CES1, P-gp & BCRP 1.93 King, 2015 Digoxin Lapatinib P-gp 1.63 Smith, 2015 Erythromycin Bitopertin CYP3A, P-gp 1.41 Boetsch, 2016 P-gp substrate Digoxin Fostamatinib P-gp 1.37 Martin, 2015 Digoxin Paritaprevir, Ritonavir and Ombitasvir P-gp 1.35 Badri, 2015 Digoxin Ivacaftor P-gp 1.32 Robertson, 2015 VIEKIRA PAK Canagliflozin Cyclosporine P-gp & MRP2 1.26 Devineni, 2015 P-gp probe substrate 22
OATP-Related Inhibition Victims Inhibitors Transporters possibly involved Victim AUC Ratio Reference Hepatic OATP inhibitor Asunaprevir Rifampin OATP1B1/3 & OATP2B1 14.8 Eley, 2015 Eluxadoline Cyclosporine OATP1B1 4.18 Davenport, 2015 Rosuvastatin Paritaprevir, Ritonavir, Ombitasvir and Dasabuvir OATP1B1/3, BCRP 2.59 Menon, 2015 Pravastatin Paritaprevir, Ritonavir, Ombitasvir and Dasabuvir OATP1B1/3 1.82 Menon, 2015 OATP substrates Pravastatin Danoprevir Paritaprevir, Ritonavir and Ombitasvir Cyclosporine OATP1B1/3 1.74 Badri, 2015 OATP1B1/3, P-gp, MRP2 1.73 Brennan, 2015 Rosuvasatin Asunaprevir OATP1B1/3, OATP2B1 1.41 Eley, 2015 VIEKIRA PAK Rosuvastatin Intestinal Paritaprevir, Ritonavir and Ombitasvir OATP1B1/3, BCRP 1.34 Badri, 2015 (R)-/(S)-fexofenadine Grapefruit juice OATP2B1 0.43-0.59 Akamine, 2015 23
OATP-Related Inhibition Victims Inhibitors Transporters possibly involved Victim AUC Ratio Reference Hepatic Asunaprevir Rifampin OATP1B1/3 & OATP2B1 14.8 Eley, 2015 Eluxadoline Cyclosporine OATP1B1 4.18 Davenport, 2015 Rosuvastatin Pravastatin Pravastatin Danoprevir Paritaprevir, Ritonavir, Ombitasvir and Dasabuvir Paritaprevir, Ritonavir, Ombitasvir and Dasabuvir Paritaprevir, Ritonavir and Ombitasvir Cyclosporine OATP1B1/3, BCRP 2.59 Menon, 2015 OATP1B1/3 1.82 Menon, 2015 OATP1B1/3 1.74 Badri, 2015 OATP1B1/3, P-gp, MRP2 1.73 Brennan, 2015 Rosuvasatin Asunaprevir OATP1B1/3, OATP2B1 1.41 Eley, 2015 Rosuvastatin Intestinal Paritaprevir, Ritonavir and Ombitasvir OATP1B1/3, BCRP 1.34 Badri, 2015 (R)-/(S)-fexofenadine Grapefruit juice OATP2B1, P-gp 0.43-0.59 Akamine, 2015 OATP probe substrates 24
T Eley, Y-H Han, S-P Huang, B He, W Li, W Bedford, M Stonier, D Gardiner, K Sims, AD Rodrigues and RJ Bertz Clin Pharmacol Ther. 2015 Feb;97(2):159-66. Rosuvastatin 10 mg Rifampin 600 mg Chemical structure of asunaprevir (BMS-650032) 25
Asunaprevir PK Profile Approved in Japan in 2014 for the treatment of hepatitis C virus (HCV) genotype 1 in combination with daclatasvir (as DAKLINZA + SUNVEPRA ) Currently under investigation in the US as a new HCV NS3 protease inhibitor Primarily eliminated by CYP3A4 and fecal excretion Demonstrated preferential distribution to the liver, suggesting active transport (preclinical animal models) Highly protein bound: > 99.5% 1 Has low potential to perpetrate DDIs via CYP3A4, P-gp and OATP but is a moderate CYP2D6 inhibitor 2 1 Eley et al. 2014; Antivir Ther 2 Eley et al. 2015; Clin Pharmacokinet 26
Asunaprevir as a Substrate of OATP in vitro Studies Initial preclinical evaluation of asunaprevir at standard uptake assay concentrations ( 1 µm) did not suggest active uptake by OATPs Uptake of asunaprevir by cryopreserved human hepatocytes at clinically relevant concentrations (5 nm to 1 µm) showed saturable nonlinear kinetics indicative of a transporter-mediated process Km = 0.685 µm OATP involvement was confirmed by uptake of asunaprevir (10 nm) in HEK293 cells overexpressing OATP1B1 and OATP2B1, but not OATP1B3 27 Figures extracted from Eley et al. 2015; Clin Pharmacol Ther
Asunaprevir as a Substrate of OATP in vivo Study Effect of single-dose rifampin on single-dose asunaprevir disposition Population: 20 healthy Asian male volunteers Design: Fixed-sequence Drug administration: Asunaprevir 200 mg single dose, alone and with a single dose of rifampin (600 mg) Results: 14.8-fold increase in AUC Safety: No adverse events reported 14.8-fold increase in asunaprevir exposure The large and highly variable increase in single dose exposure to asunaprevir seen under rifampin co-administration provided clear evidence of active hepatic OATP transport Intersubject variability was high: asunaprevir AUC: 5- to 67-fold 28 Figure extracted from Eley et al. 2015; Clin Pharmacol Ther
Asunaprevir as an Inhibitor of OATP in vitro Studies Asunaprevir inhibited the OATP-mediated uptake of probe substrates in HEK293 cells over-expressing human OATP1B1, OATP2B1 and OATP1B3 HEK-1B1 (IC 50 = 0.30 µm) HEK-2B1 (IC 50 = 0.27 µm) Therapeutic C max from previous study was 52.5 ng/ml = 0.0768 µm HEK-1B3 C max /IC 50 ratios: OATP1B1: 0.256 OATP2B1: 0.284 OATP1B3: 0.0256 C max /IC 50 > 0.1 (IC 50 = 3.00 µm) Conclusion: In vivo drug interactions between asunaprevir and OATP substrates were anticipated Figure extracted from Eley et al. 2015; Clin Pharmacol Ther 29
Asunaprevir as an Inhibitor of OATP in vivo Study Effect of steady-state asunaprevir on single-dose rosuvastatin PK Population: 20 healthy volunteers (19 Caucasian) Design: Fixed-sequence Drug administration: Rosuvastatin 10 mg single dose, alone and on Day 11 of asunaprevir administration (200 mg twice daily on Days 4-16) Results: 1.4-fold increase in rosuvastatin AUC 1.4-fold increase in rosuvastatin exposure Consistent with preclinical data, asunaprevir is a weak OATP inhibitor in vivo Rosuvastatin is also a BCRP substrate, but asunaprevir has minimal BCRP inhibitory potential (IC 50 >50 µm) 30 Figure extracted from Eley et al. 2015; Clin Pharmacol Ther
Asunaprevir and OATP: Conclusion Asunaprevir is a sensitive substrate of OATP transporters (OATP1B1 and OATP2B1) Asunaprevir is highly sensitive to OATP inhibition by rifampin (single dose), and according to the authors, could be used to detect OATP inhibition Clinically, the co-administration of strong OATP inhibitors with asunaprevir may result in reduced hepatic uptake and efficacy of asunaprevir The potential impact on hepatic concentrations warrants further investigation Asunaprevir is a weak inhibitor of OATPs in vivo 31
Conclusions 868 articles were published in 2015 and early 2016 Including over 7,700 DDI studies Most pronounced interactions Inhibition: various CYPs and transporters involved Induction: mostly due to rifampin Case reports of DDIs Victim drugs: central nervous system agents Transporter-based DDIs OATP-mediated DDIs yield greater AUC changes than P-gp 32
Acknowledgments Dr. Isabelle Ragueneau-Majlessi Dr. Sophie Argon Dr. Jingjing Yu Dr. Tasha Ritchie Dr. Cathy Yeung Dr. Zhu Zhou Dr. Jessica Sontheimer Chris Kinsella Grace Lee 33