2015 ESO ESMO EEBR Drug Drug Interactions JOERGER

DRUG-DRUG INTERACTIONS | ESO-ESMO MASTERCLASS | BRATISLAVA SLOVAKIA | 8/6/2015
Drug-drug Interactions
Markus Joerger MD-PhD ClinPharm
Dep. of Medical Oncology&Hematology

Cantonal Hospital St.Gallen
CH-9007 St.Gallen
Switzerland
markus.joerger@kssg.ch
Phone: +41-765591070
Fax: +41-714946325
President
SAKK - New Anticancer Drugs Group
| 1
Overview | Index
Definitions / Principles
Classes of drug(-drug) interactions
Epidemiology of drug interactions
Special cases of drug interactions
Food-drug interaction
Herb-drug interaction
Patient cases
Conclusions & Outlook
2
Drug Interaction | Definition

A measurable modification (in magnitude or
duration) of the action of a specific drug by prior or
concomitant administration of another substance.
Drug-Drug (drug-drug interaction, DDI)
Drug-Herbal
Drug-Over-the-counter substance
Drug-Food
Drug-Disease
Drug-Lifestile
3
Drug Interaction | Risk Categories

The risk of clinically relevant DDIs increases.
with the number of drugs taken
with the use of drugs with a small therapeutic window
in patients with pre-existing organ dysfunction (kidney, liver)
in patients with pre-existing comorbidities
in patients pertaining to special populations, e.g. the elderly,
obese, cachectic etc.
The therapeutic window reflects the relationship between the

dose at which a therapeutic effect kicks in, and the dose at
which toxicity occurs
Drug-drug Interaction | Categories

Pharmaceutical interaction
E.g. compatibility of molecules within infusion bags
Absorption after oral administration (pH conditions)
Pharmacokinetic (PK) interaction
A bsorption
D istribution (incl. protein binding)
M etabolismus (induktion, inhibition)
E limination (renal, biliary)
Pharmacodynamic (PD) interaction
A specific drug may impact on the effect of a second drug,
resulting in.
increased potency
decreased potency
longer duration of drug effect
shorter duration of drug effect 5
Risk Factors for Drug Interactions

High-risk patients
Elderly, young, very sick, multiple disease
Multiple drug therapy
Renal, liver impairment
High-risk drugs
Narrow therapeutic index drugs
Strong enzyme inhibitors/inducers
Oral antidiabetics, warfarin derivatives
Psychoactive drugs such as antidepressants, antipsychotics, antiepileptic
drugs (enzyme-inducing antiepileptic drugs, EIAED), methadon
Cytotoxic drugs, immunosuppressive drugs, digoxin, tyrosine kinase inhibitors
Nicht-steroidale Antirheumatika (NSAR)
Several herbals and lifestyle food supplementations
6
Pharmaceutical Drug Interactions

Interaction that occurs prior to systemic drug availability
E.g. incompatibility between two drugs mixed in an IV bag
These interactions can be physical (e.g. with a visible
precipitate) or chemical with no visible sign of a problem
Gastric and intestinal absorption is pH-dependent
7
Oral Anticancer Drugs | Drug Absorption
8
Pharmacokinetic Drug Interactions

One drug alters the rate or extent of ADME of another drug
A change in blood concentration causes a change in the drugs
effect
Membrane transport and metabolism
Importance of ABC drug transporter
Importance of CYP-P450 enzyme system
Enzyme/transporter induction/inhibition
Oral tyrosine kinase inhibitor
Pharmacodynamic Drug Interactions

One drug causes a change in patient response to another drug
without altering that drugs pharmacokinetics
Pharmacodynamic drug interactions can be:
At the level of receptors (usually), enzymes
Additive (e.g. combination chemo)
Synergistic
Antagonistic
10
Drug Interactions | Clinical Consequences & Relevance
Potential clinical consequences of drug interactions..

Desired effect (e.g. combination chemotherapy!)
No consequences
Increased toxicity
Decreased clinical activity
PD interactions are often used therapeutically..

Combination of antihypertensive drugs
Combination of analgesic drugs (NSAR, opiates .)
Administration of an antagonist in case of drug intoxication (z.B. Naloxon
bei Opiatintoxikation)
Combination chemotherapy, cytotoxics and mAb (Avastin-FOLFOX etc.)
11
Drug Interactions | Epidemiology

7% of all adverse events in hospitalized patients
Roughly 30% of all drug-related fatalities
Most unwanted drug interactions can be avoided
Risk for drug-interactions is 40% with the intake of between 16 and 20
drugs
Up to 80% of elderly (> 65 years) patients suffer from drug interactions
Karas 1981; Ann Emerg Med;10: 627-302 12

Special Cases of DDI | OTCs & Herbals
Herbal-drug interaction
St.Johns Wort: Strong CYP-inductor
Echinacea: Strong CYP3A4-inhibitor
Soja: Flavonoids are pro-estrogenic (beware breast cancer
patients)
Grapefruit: Strong CYP-inhibitor
refreshing but risky (Herald Tribune 2006)

Furanocoumarines 13
Special Cases of DDI | Food-drug Interaction
Particular significance with the use of oral anticancer drugs

Fat-rich food > decreased absorption of class-3 drugs, increased
absorption of class-2 drugs (tyrosine kinase inhibitors)
Class-2 drugs: Oral tyrosine kinase

inhibitors, endocrine compounds etc.
Segal et al, J Oncol Practice 2014 14

Food-Drug Interaction | Drug Transporters | Dasatinib
Ingredients of fruit juices are inhibitors of

BCRP (ABCG2)
Impaired biliary excretion of specific drugs
Increase risk of toxicity, e.g. QTc-
prolongation, Myelosuppression,
ventricular arrhythmias
CAVE citrus fruits
Fleisher et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:266275, 2015

15
Drug Interactions in Oncology:

Clinical Cases
16
Case-1 | Drug-drug | Capecitabine

66-y P with metastatic breast cancer (2006)
Oral marcoumar Januar 2007 for bilateral pulmonary embolism
Oral capecitabine in Januar 2008
Difficult marcoumar dosing, INR-peaks >3
Cephalea, unrest November 2008
Chronic subdural hematoma
Complete recovery after temporal withdrawal of marcoumar
Capecitabine inhibits CYP2C9 and catabolism of marcoumar
3.5
3
2.5
INR 2
1.5
1
0.5
18.1.07 6.8.07 22.2.08 9.9.08 28.3.09
Capecitabine (cycles)
17

62-y man with rectal cancer uT3 uN1 (July 2010)
Radiochemo (50 Gy) with capecitabine Aug-Sep 2010
Resection and protective ileostoma November 2010
Adjuvant chemo with capecitabine starting December 2010
Emergency admission in May 2011 with neutropenic fever,
diarrhea and rash
18
Prolonged and severe aplasia

Hand-foot syndrome (HFS)
Subacute renal dysfunction (GFR 27 ml/min)
Preexisting renal dysfunction
Regular intake of diclofenac for lumbalgia
Elevated cholestasis parameters, no anatomical
stenosis/compression
Staph. aureus superinfection of skin lesions on both feet
Antibiotic treatment
Avoid the combination of capecitabine/5FU and NSAR
19
Case-3 | Drug-drug | Methotrexate
63-y man with laryngeal carcinoma (August 2009)

Laryngectomy, neck dissection, radiotherapy mid 2010
Local relapse January 2011
Refractory on paclitaxel/carboplatin/cetuximab
Start MTX 60mg IV (absolute dose) 11.8.11
20
Case-3 | Drug-drug | Methotrexate

Emergency admission August 18-2011 for severe stomatitis
Prolonged and severe neutropenia
Subacute renal dysfunction (GFR 23 ml/min) (improvement to 56 ml/min)
Ulcerative exanthema
Severely compromised clearance of MTX (5.5 L/min instead of 15 L/min)
Complicating pneumonia and exitus letalis
Patient admitted temporary use of mefenacide
Joerger et al, Br J Clin Pharmacol 2006 Jul;62(1):71-80
21
Case-3 | Methotrexate | Risk Factors

Renal dysfunction (impaired elimination)
Drug-drug interactions (NSAR, penicillamin, protone pump inhibitors,
bactrim)
Third-space trapping (pleural effusions, ascites)
22
Case-4 | Drug-Drug | Erlotinib

75-y woman with metastatic adenocarcinoma of the lung in
February 2006
Stable disease on 6 cycles of paraplatin/paclitaxel
Tumor relapse in January 2007, left pleural effusion
Activating EGFR exon 19 L858R mutation
VATS pleurodesis January 2007
Start with erlotinib 2nd-line treatment in February 2007
23
Emergency hospitalisation after 6 weeks of treatment due to general

muscle pain and asthenia
Co-morbidities: Hypertension, hyperlipidemia, coronary heart disease
Co-medication: Aspirin, atenolol, amlodipin, simvastatin
Myoglobinuria, CK 17878 U/L
Acute rhabdomyolyse
.however: Simvastatin has been taken by this patient for 3 years
without similar complications
Impact of new co-medication erlotinib?
Veeraputhiran et al, Clin Lung Cancer. 2008 Jul;9(4):232-4
24

Complete remission following hydration, erlotinib withdrawal
Simvastatin was discontinued and erlotinib given without further
complications
Beware competition for CYP3A4 as a potential mechanism for drug-
drug interactions
Veeraputhiran et al, Clin Lung Cancer. 2008 Jul;9(4):232-4

25
Erlotinib | Beware these Interactions
Azoles, grapefruit, makrolides, indinavir, nelfinavir, Ca-antagonists

CYP3A4-inhibition > more toxicity
Consider dose reduction to 100(50)
Phenytoin, St.Johns Wort, dexamethasone, EIAED, rifampicin etc.
CYP3A4-induction > less activity
Close monitoring
Smoking
CYP1A2-induction > less activity
Stop smoking
Protone pump inhibitors: Only relevant with IV-use
Ter Heine et al, British Journal of Clincal Pharmacology 2011 26

Case-5 | Tamoxifen | Beware these interactions

SERM (selective estrogen receptor modulator)
Prodrug (endoxifen & OH-tamoxifen most important active metabolite)
Activation by CYP2D6 and others (CYP2C19)
PK interaction (1): SSRI (serotonin reuptake inhibitors)
PK interaction (2): Marcoumar (Tamoxifen as a CYP2C9-inhibitor)
PD interactions: High-dose soja nutrients, isoflavones (red clover) (pro-
estrogenic)
27
Case-5 | Tamoxifen and SSRI / SNRI

Strong CYP2D6 inhibitors (paroxetine, fluoxetine) and
weak inhibitors (sertraline and citalopram)
Venlafaxine does not inhibit CYP2D6
28
Case-6 | Drug-Drug | Sunitinib

76 year-old male patient with metastatic kidney cancer
Comedikation: Carbamazepin, phenytoin
Do you expect potential DDIs ?
Sunitinib is a substrate of CYP3A4, resulting in the active main
metabolite
Carbamazepin and phenytoin are strong 3A4-induktors
Recommenation: Switch to non-EIAED
If combination of sunitinib and EIAED cannot be avoided: Stepwise
increase of daily dose of Sunitinib to max. 87.5mg/die
Beware when stopping strong CYP3A4 inducers: potential dose
reduction ! 29
Case-6 | Characteristics of important EIAED
30
Case-7 | Drug-drug | Vismogedib-Marcoumar
78 year-old male patient with basal-cell carcinoma

Receiving stabile oral anticoagulation using marcoumar
Marked increase of INR 3 weeks after starting Vismodegib
Vismodegib inhibits CYP2C9, 2C19, 2C8, BCRP
Lim et al, Am J Health-Syst Pharm. 2014; 71:200-3

31
Warfarin | Metabolism, Pharmacogenetics
32
32
Warfarin | Potentially relevant DDIs
Maudlin et al, J Support Oncol 2007;5:131136 33

Case-8 | Drug-Herbal | Imatinib

75 year-old female patient with CML (first diagnosis in 2007)
Start Imatinib in Januar 2008 > MMR
Start Ginseng products in April 2009
Extraregular admission in July 2009 for abdominal pain
Ikterus, ALT/AST 1069/481 U/L, AST 481 U/L, Bilirubin 41 mol/L
Liver biopsy: subacute-lobular hepatitis, most probably toxic
34
Case-8 | Drug-Herbal | Imatinib

Stopp Imatinib and Ginseng products
Prednison 60mg/d for 1 week, subsequent tapering
Complete normalization of AST/ALT within 3 weeks
Re-start of Imatinib withou further problems
Hypothesis: PK interaction, elevated plasma concentrations of Imatinib
by adding the CYP3A4-inhibitor Ginseng
35
Case-9 | Drug-Drug | Imatinib
66 year-old male patient starting Imatinib for CML

Comedication: Simvastatin 40mg since 2000, paracetamol PRN
Do you expect DDIs ?
Imatinib inhibits CYP2C9, 2D6, 3A4
Simvastatin is a substrate of CYP3A4
Simvastatin+Imatinib > AUC (Simvastatin) >3-fach (Rabdomyolyse)
Change from Simvastatin to Pravastatin
Imatinib inhibits O-glucuronidation and inhibits hepatic elimination of
paracetamol > potential liver damage
NCCN recommendation: Maximum daily dose of paracetamol of
1300mg with the concomittant use of Imatinib; liver monitoring
36
Case-9 | Charakteristics of main Statins
37
Imatinib | PKPD - CML

25-fold variability of Cimatinib through levels (153-3910 ng/mL)1
Numerically improved PFS in P with Cmin >1000ng/L (p=0.16)1
Higher rate of MMR after 1 Jahr of treatment with Imatinib if Cmin
>1000ng/L (p=0.01)2
1 Larson et al, Blood 2008;11: 4022-28 2Takahashi et al, Clin Pharmacol Ther 2010;88: 809-13
38
Imatinib TDM | Swiss I-COME Studie

Imatinib Concentration Monitoring Evaluation
Gotta et al, I-COME Trial, Clinical Therapeutics 2013; Vol 35, Number 8S, e6, OC014
39
I-COME | Results
Gotta et al, Cancer Chemother Pharmacol (2014) 74:13071319

40
Imatinib | Major DDIs

Inhibition of PgP; Absorption Imatinib-Exposure
PPI (H2-antagonists)
Inhibition of CYP2C9 by Imatinib

Bleeding complications as a consequence of higher plasma
concentrations of vitamin K antagonists
Inhibition of CYP3A4 and PgP Imatinib-Exposure

Verapamil, Diltiazem, Statine, Amiodarone, ACE-Inhibitors,
Amprenavir, Indinavir, Nelfinavir, Saquinavir, Aprepitant, Atazanavir,
Cyclosporin, Makrolide, Azole, Fluvoxamine
Induction of CYP3A4 Imatinib-Exposure

Dexamethason, Rifampicin, Rifabutin, EIAED, Barbiturates, St. Johns
worth, Efavirenz, Nevirapine, Omeprazol
Haouala et al, Blood. 2011 Feb 24;117(8):e75-87

41
Case-10 | Alcohol-Drug | Paclitaxel
64yr male P with stage IV squamous-cell lung cancer

Bilirubin 8 mol/L, AST 67 U/L (40), ALT 86 U/L (55)
Normal total bilirubin
No evidence for (chronic) hepatitis
Moderate CRP elevation without evident infection
Nicotine 1 pack/day, 1 L red wine/day [BSA 1.8m2]
Inclusion into a TDM (paclitaxel) study
First administration of 3-weekly paclitaxel/carboplatin 15.8.11
Hospitalisation 19.8.11 for general pain, asthenia and severe
neutropenia
42

Severely impaired paclitaxel elimination
Fully recovered
Patient received 6 cycles of pac/carbo at a TDM-adapted dose
Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6

W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12 W13 W14 W15 W16 W17 W18
TAXOL 300mg
250mg
DOSE 200mg
150mg
50 hrs
40 hrs
TC>0.05 30 hrs
20 hrs
10 hrs
1.6 G/L
1.4 G/L
1.2 G/L
ANC 1.0 G/L
0.8 G/L
NADIR 0.6 G/L
0.4 G/L
0.2 G/L
0.0 G/L
4 cm
TUMOR 3 cm
DIAMETER 2 cm
1 cm
0 cm 43

Average paclitaxel elimination capacity 36 mol/h
High-level alcohol consumption (5 alcohol units/day)
associated with substantially impaired paclitaxel elimination
(25 mol/L)
Beware the use of taxanes in patients with elevated AST/ALT,
GGT, heavy alcohol consumption, chronic hepatitis
A B
Paclitaxel Vmax (mol/h)
60
60
p=0.01 p=0.02
50
50
40
40
30
30
20
20
< 5 drinks/day at least 5 drinks/day <ULN >ULN
Heavy Alcohol Consumption Aspartate Aminotransferase (AST)
C D
ax (mol/h)
Joerger et al, CESAR Annual Meeting Abstract, Tbingen (GE) 2013

60
60
p=0.0002 p=0.0008
44
50
50
Case-11 | Sun-Drug | Vandetanib
69-y man with metastatic medullary thyroid cancer Feb 2012

No treatment response to sorafenib
Start with oral vandetanib in July 2012
Emergency hospitalisation after 3 weeks of treatment
Severe bullous erythema multiforme
Caprelsa was withdrawn
Complete remission within 2 weeks
Further treatment with vandetanib without complications
45
Case-11 | Drug-Sun | Vandetanib

Sunny weather and outdoor activity
No further adverse events related to vandetanib
Beware solar dermatosis with all anticancer drugs, especially
anthracyclines, EGFR-targeting drugs, vandetanib
46
Conclusions & Outlook

Cancer patients are at high risk to experience drug interactions
Beware to stop unnecessary medication
Beware to know each patients drugs (including herbs and
special nutrients, diet)
Support patient compliance
www.cancerdrugs.ch
http://www.medscape.com/druginfo/druginterchecker

2015 ESO ESMO EEBR Drug Drug Interactions JOERGER

Transféré par

Informations du document

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

2015 ESO ESMO EEBR Drug Drug Interactions JOERGER

Transféré par

Droits d'auteur :

Formats disponibles

DRUG-DRUG INTERACTIONS | ESO-ESMO MASTERCLASS | BRATISLAVA SLOVAKIA | 8/6/2015

Markus Joerger MD-PhD ClinPharm

Dep. of Medical Oncology&Hematology

Drug Interaction | Definition

Drug Interaction | Risk Categories

The therapeutic window reflects the relationship between the

Drug-drug Interaction | Categories

Risk Factors for Drug Interactions

Pharmaceutical Drug Interactions

Oral Anticancer Drugs | Drug Absorption

Pharmacokinetic Drug Interactions

Pharmacodynamic Drug Interactions

Drug Interactions | Clinical Consequences & Relevance

Potential clinical consequences of drug interactions..

PD interactions are often used therapeutically..

Drug Interactions | Epidemiology

Karas 1981; Ann Emerg Med;10: 627-302 12

Special Cases of DDI | OTCs & Herbals

refreshing but risky (Herald Tribune 2006)

Special Cases of DDI | Food-drug Interaction

Particular significance with the use of oral anticancer drugs

Class-2 drugs: Oral tyrosine kinase

Segal et al, J Oncol Practice 2014 14

Food-Drug Interaction | Drug Transporters | Dasatinib

Ingredients of fruit juices are inhibitors of

Fleisher et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:266275, 2015

Drug Interactions in Oncology:

Case-1 | Drug-drug | Capecitabine

Case-2 | Drug-drug | Capecitabine

Case-2 | Drug-drug | Capecitabine

Prolonged and severe aplasia

Case-3 | Drug-drug | Methotrexate

63-y man with laryngeal carcinoma (August 2009)

Case-3 | Drug-drug | Methotrexate

Joerger et al, Br J Clin Pharmacol 2006 Jul;62(1):71-80

Case-3 | Methotrexate | Risk Factors

Case-4 | Drug-Drug | Erlotinib

Case-4 | Drug-Drug | Erlotinib

Emergency hospitalisation after 6 weeks of treatment due to general

Veeraputhiran et al, Clin Lung Cancer. 2008 Jul;9(4):232-4

Case-4 | Drug-Drug | Erlotinib

Veeraputhiran et al, Clin Lung Cancer. 2008 Jul;9(4):232-4

Erlotinib | Beware these Interactions

Azoles, grapefruit, makrolides, indinavir, nelfinavir, Ca-antagonists

Protone pump inhibitors: Only relevant with IV-use

Ter Heine et al, British Journal of Clincal Pharmacology 2011 26

Case-5 | Tamoxifen | Beware these interactions

Case-5 | Tamoxifen and SSRI / SNRI

Case-6 | Drug-Drug | Sunitinib

Case-6 | Characteristics of important EIAED

Case-7 | Drug-drug | Vismogedib-Marcoumar

78 year-old male patient with basal-cell carcinoma

Lim et al, Am J Health-Syst Pharm. 2014; 71:200-3

Warfarin | Metabolism, Pharmacogenetics

Warfarin | Potentially relevant DDIs

Maudlin et al, J Support Oncol 2007;5:131136 33

Case-8 | Drug-Herbal | Imatinib

Case-8 | Drug-Herbal | Imatinib

Case-9 | Drug-Drug | Imatinib

66 year-old male patient starting Imatinib for CML

Case-9 | Charakteristics of main Statins

Imatinib | PKPD - CML

Imatinib TDM | Swiss I-COME Studie

Gotta et al, Cancer Chemother Pharmacol (2014) 74:13071319