mechanistic analysis of the risk of pharmacokinetic drug ... · telotristat ethyl, its active...

Mechanistic Analysis of the Risk of Pharmacokinetic Drug-drug

Interactions with Drugs Recently Approved by the US FDA

Jingjing Yu, MD, PhDResearch Scientist

Senior Project ManagerDrug Interaction Database Program

School of PharmacyUniversity of Washington

12-3-2018 1

Why NDA Reviews?

Provide a most unique perspective on the evolution of“drug interaction science”

Provide an opportunity to observe how pharmaceuticaland regulatory scientists interpret regulatory guidances inthe context of specific therapeutic classes

Specifically, how the results of metabolism- andtransporter-mediated drug-drug interactions,physiologically based pharmacokinetic modeling andsimulations, and pharmacogentic studies, are translatedinto labeling

2

Number of Novel Drugs Approved: 2008-2017

2008 2009 20102011

20122013

20142015

20162017

20 20

15

24

33

25

30

33

15

34

46

6 6 6

2

11 12

7

12

NDAs BLAs

3

• Average: 32 drugs/year

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Outline

Scope of the evaluation

2017 New Drug Application (NDA) highlights: Represented therapeutic classes

Mechanistic drug-drug interaction (DDI) studieso Metabolism-based DDIs

o Transporter-mediated DDIs

o Clinical DDIs with AUC ratios ≥ 5 (for inhibition) or ≤ 0.2 (for induction)

Physiologically based pharmacokinetic (PBPK) modeling andsimulation examples

Pharmacogenetic studies

Overall conclusions

4

Manuscript titled “Mechanisms and Clinical Significance of Pharmacokinetic-based

Drug-drug Interactions with Drugs Approved by the U.S. Food and Drug Administration

in 2017”, uncopyedited version on DMD FastForward site:

http://dmd.aspetjournals.org/content/early/2018/11/15/dmd.118.084905

http://dmd.aspetjournals.org/content/early/2018/11/15/dmd.118.084905

Data Source Metabolism and

Transport Drug

Interaction Database®,

University of

Washington

https://www.druginteractioninfo.org/

5

https://www.druginteractioninfo.org/

Data Source NDA Reviews available at Drugs@FDA

NIH ClinicalTrials.gov

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208745Orig1s000TOC.cfm 6

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208745Orig1s000TOC.cfm

Outline








Overall conclusions

7

Therapeutic Classes for Novel Drugs Approved in 2017 (N = 34)

26%

23%

12%

12%

9%

6%

6%

3% 3%Cancer Treatments (9)

Anti-infective Agents (8)

Central Nervous System Agents (4)

Endocrinology/Metabolism DisorderTreatments (4)

Gastrointestinal Agents (3)

Cardiovascular Disease Treatments (2)

Eye Treatments (2)

Anti-inflammantory Drugs (1)

Diagnostic Agents (1)

8

Cancer Treatments (N = 9)Active Ingredient Trade Name Therapeutic Class Indications

Acalabrutinib CALQUENCE Kinase Inhibitor Mantle cell lymphoma

Copanlisib ALIQOPA Kinase Inhibitor Relapsed follicular lymphoma

Enasidenib IDHIFAIsocitrate Dehydrogenase-2

(IDH2) InhibitorRelapsed or refractory acute myeloid leukemia

(AML)

Midostaurin RYDAPT Kinase Inhibitor Acute myeloid leukemia

Abemaciclib VERZENIO Kinase InhibitorHormone receptor (HR)-positive, HER2-negative

advanced or metastatic breast cancer

Ribociclib KISQALI Kinase InhibitorHormone receptor (HR)-positive, HER2-negative

advanced or metastatic breast cancer

Neratinib NERLYNX Kinase InhibitorHuman epidermal growth factor receptor 2

(HER2)-positive breast cancer

Niraparib ZEJULAPoly ADP-ribose polymerase

(PARP) inhibitorOvarian, fallopian tube or primary peritoneal

cancer

Brigatinib ALUNBRIG Kinase InhibitorAnaplastic lymphoma kinase (ALK)-positive

metastatic non-small cell lung cancer (NSCLC)

9

Anti-infective Agents (N = 8)

Active Ingredient Trade Name Therapeutic Class Indications

Delafloxacin BAXDELA AntibacterialsAcute bacterial skin and skin structure

infections (ABSSSI)

Meropenem/vaborbactam VABOMERE Antibacterials Complicated urinary tract infections

Ozenoxaxin XEPI Antibacterials Impetigo

Secnidazole SOLOSEC Antibacterials Bacterial vaginosis

Glecaprevir/pibentasvir MAVYRET Antivirals Hepatitis C virus (HCV)

Sofosbuvir/ velpatasvir/voxilaprevir

VOSEVI Antivirals Hepatitis C virus (HCV)

Letermovir PREVYMIS Antivirals Cytomegalovirus (CMV)

Benznidazole BENZNIDAZOLE Antiparasitics Chagas disease

10

Therapeutic Classes for Drugs 2013-2016 (N = 103)

Yu. et al. (2018) Drug Metab Dispos. 46 (6): 835-845

27%

20%

16% 16%

7% 7% 7%

2%

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6

8

10

12

14

16

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30%

24%

15%

9%7% 7%

4%2% 2%

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10121416

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• Oncology (21%) and anti-infective (20%) are the most represented therapeutic areas

Oncology drugs (N = 22): 17 (78%) kinase inhibitors

Anti-infective drugs (N = 21): 10 antivirals, 6 antibacterials, 4 antifungals, and 1 anti-parasitic

• In clinically significant DDIs (AUC change in victim ≥ 2 or < 2 but triggering dose

recommendations), these two classes were also the most represented

30%

20%

15% 15%

10%

5% 5%

0

2

4

6

8

Anti

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A B

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Clinical inhibition, NME as substrate

11

Clinical inhibition, NME as inhibitor (C)

Clinical induction, NME as substrate

Novel Drugs in 2017 (N = 34)

12

NDA # Drug Name Active Ingredient DDI PGx PBPK208745 TRULANCE PLECANATIDE Y (in vitro)

208325 PARSABIV ETELCALCETIDE Y

208684 EMFLAZA DEFLAZACORT (prodrug) Y Y

208794 XERMELO TELOTRISTAT ETHYL (prodrug) Y

209092 KISQALI RIBOCICLIB Y Y

207145 XADAGO SAFINAMIDE Y

208854 SYMPROIC NALDEMEDINE Y Y

208447 ZEJULA NIRAPARIB Y

208082 AUSTEDO DEUTETRABENAZINE Y Y

209241 INGREZZA VALBENAZINE Y

207997 RYDAPT MIDOSTAURIN Y

208743 TYMLOS ABALOPARATIDE Y

208772 ALUNBRIG BRIGATINIB Y

209176 RADICAVA EDARAVONE Y

208610 BAXDELA DELAFLOXACIN Y Y

208383 BEVYXXA BETRIXABAN Y

208051 NERLYNX NERATINIB Y

209195 VOSEVI SOFOSBUVIR/VELPATASVIR/VOXILAPREVIR Y

209606 IDHIFA ENASIDENIB Y

209394 MAVYRET GLECAPREVIR/PIBRENTASVIR Y Y

209570 BENZNIDAZOLE BENZNIDAZOLE Y (in vitro)

209776 VABOMERE MEROPENEM/VABORBACTAM Y (in vitro)

209936 ALIQOPA COPANLISIB Y

209363 SOLOSEC SECNIDAZOLE Y

208716 VERZENIO ABEMACICLIB Y Y

210259 CALQUENCE ACALABRUTINIB Y Y

207795 VYZULTA LATANOPROSTENE BUNOD (prodrug) Y (in vitro)

209939 PREVYMIS LETERMOVIR Y Y

209637 OZEMPIC SEMAGLUTIDE Y

208945 XEPI OZENOXACIN Y (in vitro)

208254 RHOPRESSA NETARSUDIL Y (in vitro)

209803 STEGLATRO ERTUGLIFLOZIN Y Y Y

205598 MACRILEN MACIMORELIN Y (in vitro)

209360 ANGIOTENSIN II GIAPREZA Y (in vitro)

Outline








Overall conclusions

13

NMEs as Substrates of Enzymes:in vitro metabolism

• all NMEs were evaluated as substrates of specific drug-metabolizing enzymes

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2013-2016 NMEs (N = 107)


14

NMEs as Substrates of Enzymes:in vivo CYP3A inhibition studies (N = 11 NMEs with AUC ratios ≥ 1.25)

sensitive substrates

(FDA classification)

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Max

imu

m A

UC

Rat

ios

Ketoconazole 400 mg QD 5-10 days or N/PItraconazole 200 mg QD or BID 6.5-10 daysClarithromycin 500 my BID 4 daysRitonavir 100 mg BID 14 daysVoriconazole 200 mg BID 4 days

*P-gp substrate, #BCRP substrate; N/P, not provided

15

NMEs as Substrates of Enzymes:in vivo CYP3A induction studies (N = 11 NMEs with AUC ratios ≤ 0.8)

Inducer: rifampin 600 QD 7-14 days or not provided

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

Max

imu

m A

UC

Rat

ios

16

AUC ratios < 0.2

NMEs as Inhibitors of Enzymes:in vitro positive inhibition (N = 20 NMEs)

• 32 parents and 24 metabolites (including the active moieties of three prodrugs) were

evaluated as inhibitors of specific drug-metabolizing enzymes

• Inhibition potential on major CYPs as a post-marketing requirement (PMR)

Deflazacort (prodrug) active metabolite 6beta-hydroxydeflazocort

Telotristat ethyl (prodrug) downstream active metabolite LP-951757

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parent metabolite

2013-2016 NMEs (N = 107)


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NMEs as Inhibitors of Enzymes:In vivo positive inhibition (Max AUC ratios ≥ 1.25, N = 4)

• ~75% of the in vitro inhibitors are not considered clinically relevant

• Based on in vitro inhibition results (R > 1.1), enasidenib had possible clinical inhibitory

potency: inhibited major CYPs and UGT1A1, metabolite AGI-16903 also inhibited major

CYPs; clinical study as a PMR

Inhibitor Substrate Enzyme AUC Ratio Cmax Ratio Potency Labeling Impact

Ribociclib Midazolam CYP3A 5.20 (PBPK) 2.40 (PBPK) StrongReduce dose of sensitive CYP3A substrates with NTR

Letermovir

Midazolam CYP3A2.56-3.44 (oral)

2.48 (IV)1.83-2.10 (oral)

1.44 (IV)Moderate

Refer to the respective label for dosing of the CYP3A substrates with a moderate CYP3A inhibitor

Repaglinide CYP2C81.88 (oral) 2.47 (IV)

1.41 (oral) 1.49 (IV)

ModerateClosely monitor glucose plasma concentrations

Glecaprevir/pibentasvir

Caffeine CYP1A2 1.35 1.00 Weak None

Midazolam CYP3A 1.27 1.00 Weak None

Raltigravir UGT1A1 1.47 1.34 Weak None

Safinamide Caffeine CYP1A2 1.30 1.08 Weak None

18

NMEs as Inducers of Enzymes:in vitro positive induction (N = 16 NMEs)

• 31 parents and 15 metabolites were evaluated for induction of CYPs, phase II enzymes

(GSTs, SULTs, and UGTs), as well as regulation of nuclear receptors

• Down-regulation of major CYPs: abemaciclib and metabolites (M2 and M20)

• Induction of major CYPs as a PMR/PMC: Deflazacort (prodrug) active moiety 21-desacetyl deflazacort on major CYPs

Telotristat ethyl, its active moiety telotristat, and downstream metabolite LP-951757 (active) on

CYP1A2, CYP2B6, and UGTs

Valbenazine metabolite NBI-136110 on CYP2B6

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parent metabolite

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2013-2016 NMEs (N = 107)

19

NMEs as Inducers of Enzymes:In vivo positive induction (Max AUC ratios ≤ 0.8, N = 3)

• Based on in vitro induction results, 5 other drugs with possible clinical relevance (induction or down-

regulation):

2 drugs did not show clinical induction (delafloxacin, midostaurin; marker substrate: midazolam)

2 drugs to conduct clinical trials as a PMR/PMC (brigatinib, enasidenib)

1 drug clinical evaluation is ongoing (abemaciclib)

• Majority in vitro induction is not clinically relevant

Inducer Substrate Enzyme AUC Ratio Cmax Ratio Potency Labeling Impact

Telotristat ethyl Midazolam CYP3A, UGT0.49,

0.51 (1-OH mdz)

0.74,0.66 (1-OH

mdz)Moderate

Monitor efficacy and consider dose adjustment

Letermovir VoriconazoleCYP2C19, CYP2C9

0.56 0.61 Weak

Closely monitor the plasma concentrations of drugs that are CYP2C9 and CYP2C19 substrates; adjust dose if necessary

Safinamide Midazolam CYP3A0.81,

1.42 (1-OH mdz/mdz)

0.98 Weak None

20

Outline



Mechanistic Drug-drug interaction (DDI) studieso Metabolism-based DDIs





Overall conclusions

21

22

2013 2014 2015 2016 2017

In vitro Transport (% of NDAs)

80% (20/25)

73% (22/30)

76% (25/33)

93% (14/15)

82% (28/34)

# of Transporter experiments

~120 (6/drug)

~450 (20/drug)

~400 (16/drug)

~310 (22/drug)

~ 590(21/drug)

# of Transporters tested

16 19 21 21 20

In vitro Metabolism(% of NDAs)

88% (22/25)

100% (30/30)

91% (30/33)

93% (14/15)

100% (34/34)

• P-gp, BCRP, and OATP1B1/3 were the most frequently tested.

• Other transporters included ASBT, BSEP, MATE1, MATE2-K, MRP1, MRP2, MRP3,

MRP4, MRP5, MRP8, NTCP, OAT1, OAT2, OAT3, OAT4, OATP1A2, OATP2B1,

OCT1, OCT2, OCT3, OCTN1, OCTN2, URAT1 (transporters in bold are

recommended for consideration by the 2017 FDA DDI guidance).

Yu et al., DMD, 2014, 2016, 2017, 2018; Dr. Lei Zhang, ASCPT Conference 2017

Transporter Studies Overview 2013-2017

NMEs as Substrates of Transporters:in vitro positive studies (N = 19 NMEs)

• Transporters: 17 were studied; 8 transporters showed negative results (MATE1,

MATE2-K, MRP2, OATP2B1, OCT1, OCT2, PEPT1, and PEPT2)

• Parent drugs: 27 (out of 35) NMEs were tested; 19 positive

• Metabolites: 14 were tested; 6 positive (including active moieties of 2 prodrugs)

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P-gp BCRP OATP1B1 OATP1B3 BSEP hOATPs OAT1 OAT3 MRP4

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2013-2016 NMEs (N = 107)


23

NMEs as Substrates of Transporters:in vivo positive studies (Max AUC ratio ≥ 1.25, n = 10 NMEs)

*substrate of CYP3A (in vitro and/or in vivo); N/A, not available

**sensitive substrate of CYP3A through clinical inhibition studies with strong CYP3A inhibitors

Substrate (N = 10) PrecipitantAUC Ratio

Cmax Ratio

Transporter Possibly Affected

Labeling Impact

Inhibition DDIs

VoxilaprevirCyclosporine 9.73 14.29 OATP1B1/1B3, P-gp, BCRP Not recommended

Rifampin (SD) 7.96 8.74 OATP1B1/1B3, P-gp Contraindicated with rifampin

Glecaprevir Rifampin (SD) 8.55 6.52 OATP1B1/1B3, P-gp None (yes due to induction)

Atazanavir/ritonavir 6.53 4.05 OATP1B1/1B3, P-gp, BCRP Contraindicated with atazanavir

Acalabrutinib Itraconazole 4.96 3.90 P-gp** None (yes CYP3A)

21-Desacetyl deflazacort Clarithromycin 3.38 2.25 P-gp* None (yes CYP3A)

Betrixaban Verapamil 3.06 4.72 P-gp Reduce dose with P-gp inhibitors

Pibrentasvir Lopinavir/ritonavir 2.46 1.4 P-gp, BCRPNot recommended with lopinaviror ritonavir

Abemaciclib Verapamil 2.28 (PBPK) N/A P-gp** None

Letermovir Cyclosporine 2.10 1.48 OATP1B1/1B3 Reduce dose with cyclosporine

Naldemedine Cyclosporine 1.79 1.45 P-gp*Monitor for adverse reactions with P-gp inhibitors

Copanlisib (IV) Itraconazole 1.58 1.04 P-gp*, BCRP None (yes CYP3A)

Induction DDIs

Glecaprevir Rifampin 0.12 0.14 P-gp* Contraindicated with rifampin

Pibrentasvir Rifampin 0.17 0.21 P-gp Contraindicated with rifampin

24

NMEs as Inhibitors of Transporters: in vitro positive studies (N = 25 NMEs)

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parent metabolite

• Transporters: 19 were studied; 4 transporters showed negative results (OAT4,

OCTN2, PEPT1, and PEPT2)

• Parent drugs: 31 (out of 35) NMEs were evaluated; 25 positive

• Metabolites: 26 were evaluated; 9 positive

2013-2016 NMEs (N = 107)


25

NMEs as Inhibitors of Transporters: P-gp: from in vitro (N = 15) to in vivo

*inhibitor of BCRP in vitro; #inhibitor of OATP1B1/3 in vitro; N/A, not available; N/T, not tested

Inhibitor (N =9) [I]1/IC50 [I]2/IC50 % BoundIn vivo

SubstrateAUC Ratio Cmax Ratio Labeling Impact

Glecaprevir*#/pibrentasvir*#

2.16 (G); 2.74 (P)

4335 (G); 11978 (P)

97.5 (G); > 99.9 (P)

Dabigatran 2.38 2.05Avoid/not recommended/adjust dose of dabigatran

Digoxin 1.48 1.72Monitor digoxin concentrationsand adjust dose of digoxin

Neratinib# 0.00001 1723 > 99 Digoxin 1.32 1.54Monitor adverse reactions of NTR P-gp substrates

Valbenazine 0.09 32 > 99 Digoxin 1.33 1.87Monitor digoxin conc./adjust dose of digoxin

Betrixaban* 0.01 61 60 Digoxin no change no change None

Letermovir*#1.66 (oral);

3.62 (IV)245 99 Digoxin 0.90 (oral) 0.78 (oral) None

Telotristat ethyl* 0.01 1739 > 99 Fexofenadine 1.14 1.11 None

Abemaciclib* 1.03 2771 96.3 N/TEffects on sensitive P-gp substrates unknown

Brigatinib* 1.42 700 66 N/TPotential to increase concentrations of P-gp substrate

Enasidenib*# > 0.1 N/A 98.5 N/T; PMRPotential to alter exposure of P-gpsubstrates

Based on [I]1/IC50 (≥ 0.1) and [I]2/IC50 (≥10) ratios, 9 drugs (including 10 NMEs) had the

potential to cause clinically relevant inhibition

26

NMEs as Inhibitors of Transporters: BCRP: from in vitro (N = 17) to in vivo

*also inhibitor of P-gp in vitro; #also inhibitor of OATP1B1/3 in vitro; ^mainly by OATP1B1/1B3; N/A, not available; N/T, not tested

Inhibitor [I]1/IC50 [I]2/IC50 % BoundIn vivo

SubstrateAUC Ratio

Cmax Ratio

Labeling Impact

Glecaprevir*#/pibentasvir*#

0.31 (G); 0.01 (P)

622 (G); 31 (P)

97.5 (G); > 99.9 (P)

Rosuvastatin^ 2.15 5.62 Reduce dose of rosuvastatin

Abemaciclib* 1.84 4935 96.3 N/TEffects on sensitive BCRP substrates unknown

Acalabrutinib < 0.1 21 97.5 N/TPotential to increase exposure of BCRP substrates

Brigatinib* 0.25 122 66 N/TPotential to increase concentrations of BCRP substrates

Enasidenib*# > 0.1 N/A 98.5 N/T; PMRPotential to alter exposure of BCRP substrates

Letermovir*#0.78 (oral);

1.70 (IV)115 99 N/T

Reduce dose of rosuvastatin and monitor for myopathy and rhabdomyolysis

Ribociclib 0.14 29.7 70 N/TMay inhibit BCRP at clinically relevant concentrations

Safinamide 0.02 15 88-89 N/T; PMRMonitor for increased pharmacologic or adverse effect of BCRP substrates

Based on [I]1/IC50 (≥ 0.1) and [I]2/IC50 (≥10) ratios, 8 drugs (including 9 NMEs) had the

potential to cause clinically relevant inhibition

27

NMEs as Inhibitors of Transporters: OATP1B1/3: from in vitro (N = 9) to in vivo

*also inhibitor of P-gp in vitro; #also inhibitor of BCRP in vitro; inhibition of CYP3A may also contribute; N/T, not tested

InhibitorOATP1B1 Cmax/IC50

OATP1B3 Cmax/IC50

% Bound In vivo VictimAUC Ratio

Cmax Ratio

Labeling Impact

Glecaprevir*#/pibentasvir*#

42 (G); 0.08 (P)

11 (G);< 0.1 (P)

97.5 (G); > 99.9 (P)

Atorvastatin^ 8.28 22.00 Not recommended

Letermovir*# 7.83 21 99 Atorvastatin^ 3.28 2.16Reduce dose of atorvastatin and monitor for myopathy and rhabdomyolysis

sofosbuvir/velpatasvir/Voxilaprevir

1.22 0.31 > 99 Pravastatin 2.13 1.95 Reduce dose of pravastatin

Enasidenib*# > 0.1 > 0.1 98.5 N/T; PMRPotential to alter exposure of OATP1B1/3 substrates

Midostaurin6.83;

R ≥ 1.250.41 > 99.8 N/T None

Based on Cmax/IC50 (≥ 0.1) and R (≥1.25) values, 5 drugs (including 6 NMEs) had the potential

to cause clinically relevant inhibition

28

Outline



Mechanistic Drug-drug interaction (DDI) studieso Metabolism-based DDIs





Overall conclusions

29

Most Significant Clinical Inhibitions: max AUC ratios ≥ 5

* Substrate of P-gp in vitro

Substrate InhibitorMax AUC

RatioMax Cmax

RatioEnzyme/Transporter

Possibly AffectedLabeling Impact

NME as substrate (N= 6)

Abemaciclib* Ketoconazole 15.73 (PBPK) N/P CYP3A, P-gp Avoid with ketoconazole

Midostaurin Ketoconazole 10.42 1.83 CYP3AConsider alternative therapies that do not inhibit CYP3A; monitor for adverse reactions

Voxilaprevir Cyclosporine 9.73 14.29 OATP1B1/1B3, P-gp, BCRPVOSEVI not recommended with OATP inhibitor

Glecaprevir* Rifampin 8.55 6.52 OATP1B1/1B3, P-gp(contraindicated with rifampin due to induction)

Voxilaprevir Rifampin 7.96 8.74 OATP1B1/1B3 Contraindicated with rifampin

GlecaprevirAtazanavir/

ritonavir6.53 4.05 OATP1B1/1B3, P-gp, BCRP Contraindicated with atazanavir

Neratinib* Ketoconazole 5.16 3.63 CYP3A, P-gp Avoid with strong CYP3A inhibitors

Acalabrutinib* Itraconazole 4.96 3.90 CYP3A, P-gp Avoid with strong CYP3A inhibitors

NME as inhibitor (N = 4)

AtorvastatinGlecaprevir/pibentasvir

8.28 22.00 OATP1B1/1B3, CYP3A Not recommended with atorvastatin

Rosuvastatinsofosbuvir/velpatasvir/Voxilaprevir

7.35 17.96 BCRP, OATP1B1/1B3VOSEVI not recommended with BCRP substrates

Midazolam Ribociclib 5.20 (PBPK) 2.40 (PBPK) CYP3AReduce dose of sensitive CYP3A substrates with NTR

30

Most Significant Clinical Inductions: max AUC ratio ≤ 0.2

Substrate InducerMax AUC

RatioMax Cmax

RatioEnzyme/Transporter

Possibly AffectedLabeling Impact

NME as substrate (N = 9)

Abemaciclib Rifampin 0.05 0.08 CYP3A, P-gp Avoid with strong CYP3A inducers

21-Desacetyl deflazacort

Rifampin 0.06 0.08 CYP3A, P-gp Avoid with strong CYP3A inducers

Midostaurin Rifampin 0.06 0.27 CYP3A Avoid with strong CYP3A inducers

Ribociclib Rifampin 0.11 0.19 CYP3A, P-gp Avoid with strong CYP3A inducers

Neratinib Rifampin 0.12 0.22 CYP3A, P-gp Avoid with strong CYP3A inducers

Glecaprevir Rifampin 0.12 0.14 P-gp, CYP3A Contraindicated with rifampin

Naldemedine Rifampin 0.17 0.61 CYP3A, P-gp Avoid with strong CYP3A inducers

Pibrentasvir Rifampin 0.17 0.21 P-gp Contraindicated with rifampin

Brigatinib Rifampin 0.19 0.40 CYP2C8, CYP3A, P-gp Avoid with strong CYP3A inducers

NME as inducer (no clinical DDIs with max AUC ratio ≤ 0.2)

31

Outline


2018 New Drug Applications (NDAs) highlights: Represented therapeutic classes

Mechanistic Drug-drug interaction (DDI) studieso Metabolism-based

o Transport-mediated




Overall conclusions

32

PBPK Modeling in 2017 NDAs (N = 6 NDAs)

33

Drug NameInhibition Induction

Clinical PBPK Clinical PBPK

Abemaciclib(CYP3A)

Clarithromycin (3.4)

Ketoconazole (16) Itraconazole (7.2)Diltiazem (4.0) Verapamil (2.3)

Rifampin (95%↓)Carbamazepine (80%↓)Moderate CYP3A inducers:PMR via PBPK or clinical trial

Acalabrutinib(CYP3A)

Itraconazole (5.0)

Clarithromycin (3.3) Erythromycin (2.8)Diltiazem (2.3)Fluconazole (2.4)Fluvoxamine (1.4)

Rifampin (77%↓)Carbamazepine (61%↓)Efavirenz (61%↓)

Deflazacort(CYP3A)

Clarithromycin (3.4) Fluconazole (4.0) Rifampin (95%↓) Efavirenz (70%↓)

Naldemedine(CYP3A)

Itraconazole (2.9) Fluconazole (1.9) Rifampin (83%↓) Efavirenz (43% ↓)

Ribociclib(CYP3A)

Ritonavir (3.2)

Ketoconazole (3.1)Itraconazole (2.6)Erythromycin (1.9)Fluvoxamine (1.0)

Rifampin (89%↓)Carbamazepine (62% ↓)Efavirenz (60% ↓)

Ertugliflozin(UGT)

Mefenamic acid (1.5; UGTinhibitor)

Rifampin (39%↓; UGT and CYP inducer)

As Substrate: (▪ Strong ▪ Moderate ▪ Weak inhibitors/inducers with AUC ratios)

As Inhibitor: Ribociclib (CYP3A)

• Clinical: 400 mg QD 8 days, midazolam (AUC ratio = 3.8)

• PBPK: 600 mg QD (recommended dose), midazolam (AUC ratio = 5.2)

Outline



Mechanistic Drug-drug interaction (DDI) studieso Metabolism-based

o Transport-mediated

o Clinically significant DDIs



Overall conclusions

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Pharmacogenetic Studies

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Five drugs had pharmacogenetic data related to drug metabolism and transport:

Positive effect: Deutetrabenazine

• Extensively metabolized by carbonyl reductase to two major active metabolites, alpha-

and beta-dihydrodeutetrabenazine, which were subsequently metabolized primarily by

CYP2D6

• In CYP2D6 PMs (N = 4), IMs (N = 3), EMs (N = 13), total alpha- and beta-

dihydrodeutetrabenazine exposure in PMs was > 2-fold higher than in EMs/IMs

• In a separate PK study (N = 90), total alpha- and beta-dihydrodeutetrabenazine exposure

in subjects with impaired CYP2D6 function was > 2-fold higher than in subjects with

functional CYP2D6

• Label: adjust dose in CYP2D6 PMs

No effect:

• Delafloxacin: UGT1A1, UGT2B4, UGT2B15, P-gp, BCRP variants

• Ertugliflozin: UGT1A9 variants

• Glecaprevir: OATP1B1 variants

• Letermovir: UGT1A1, OATP1B1 variants

Overall Conclusions

• A total of 46 drugs were approved by the FDA in 2017, including 34 NDAs

• All the NDAs were systemically evaluated for metabolism- and transport-mediated DDI and similar trends were observed compared with drugsapproved 2013-2016

• CYP3A was confirmed as the predominant enzyme responsible forclinically significant drug interactions involving both inhibition andinduction

• Inhibition of OATP1B1/1B3 is emerging as a significant mechanism ofDDIs, leading to large changes in exposure of victim drugs (antivirals,statins)

• In addition to clinical trials, PBPK simulations continue to develop as aclinical tool to support dose recommendations

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UW DIDB Program Team• Scientific Team: Faculties and

Research Staff

• IT Support: Chris Kinsella

• Administrative Coordinator:

Grace Lee

Dr. Isabelle Ragueneau-Majlessi

Dr. Jingjing Yu

Dr. Tasha Ritchie

Dr. Cheryl Wu

Dr. Jessica Sontheimer

Dr. Katie Owens

Dr. Rene Levy

Dr. Catherine Yeung

Dr. Sophie Argon

Acknowledgements

Dr. Ichiko Petrie

Technology:

Chris Kinsella

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THANK YOU

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