Pharmacotherapy

and drug interactions

Jordi Rodon
 Old versus New drugs
Examples of
Old drugs New drugs new drugs

New formulations of old drugs

Etirinotecan, Nab-
New formulations of old drugs with Paclitaxel
Chemotherapy
new mechanisms of action Endo-TAG

Antibody drug conjugates

New generations of hormone

Hormone therapy Enzalutamide
therapy
New immunological approaches ARGX-110,
IFN, IL-2 Trastuzumab,
(monoclonal antibodies, vaccines )
Sunitinib,
Molecular targeted agents (small
Sorafenib,
molecules, ) Vismodegib,

Other biotech drugs (cell therapy,

Oblimersen,
peptides, proteins, nucleic acids) Sipuleucel-T
 What Happens When Your Patient Takes a
Drug?
Potential Therapeutic Outcomes

Efficacy without toxicity

Efficacy with toxicity
Treatment, potentially curative
Toxicity without efficacy
Poison
Neither toxicity nor efficacy
Alternative medicine
Sources of variability

Mathijssen, R. H. J. et al. Nat. Rev. Clin. Oncol. 2014

Sources of variability: the problem
Incidence of P450 phenotypes (pe CYP2D6) varies among ethnic
populations
Genetics can account for 20-95% of variability in therapeutic
response.
60% of cancer patients are 65 years or over
Older age leads to lower ADME resulting in higher exposure
85% of cancer patients>65 y/o have comorbid conditions
Decreased clinical performance leads to lower ADME, resulting in higher
exposure
Decreased liver function leads to decreased elimination, resulting in
higher exposure
78% of patients >65 y/o are taking prescription medications
39% take more than 5 drugs
90% over-the-counter medications
51% of patients take complementary alternative medicines
Basic concepts of Pharmacotherapy
 Pharmacology = Four different topics

Interaction of anticancer agent with body organs or tumor

Pharmacokinetics (body)
Pharmacogenetics (SNP, body)

Pharmacodynamics (body, tumor)

Pharmacogenomics (tumor)
SNP: single nucleotide polymorphism
 ADME

Distribution

Absorption

Metabolism
Excretion

Lullman H, et al. Color Atlas of Pharmacology 1996

 ADME :Absortion
PO

IV

Potential factors in cancer

patient that affect absorption

Drug design
Gastrectomy/ feeding tube
Food
PH
Concomitant medications
Lullman H, et al. Color Atlas of Pharmacology 1996
Pharmacokinetic analysis of Vismodegib
(Hedgehog inhibitor)

Increasing the dose from 150 mg to 270 mg did not

result in higher steady-state plasma levels
Vismodegib 150 mg = recommended dose

Von Hoff et al, NEJM, 2009

 ADME: Distribution
Potential factors in
cancer patient that
affect distribution
Protein binding
Hypoalbuminemia
Concomitant
Molecule size and solubility
medications
BBB in brain mets
Blood-Tissue Barriers Intratumoral
interstitial pressure
Membrane Permeation Edema, pleural
effusion, ascites

Active transport

Lullman H, et al. Color Atlas of Pharmacology 1996

 ADME: Metabolism

Liver function

Potential factors in
cancer patient that
affect metabolism:

Liver metastasis
Cirrhosis and
steatosis
Concomitant
medications

Lullman H, et al. Color Atlas of Pharmacology 1996
 Myelotoxicity and UGT genetic
polymorphisms
Irinotecan
o 350 mg/m2
o 90 min infusion, q3w
o n = 66

SN-38 metabolism
dependent on UGT
variant
Grade 4
Identification of patients
predisposed to severe
irinotecan toxicity

Innocenti et al. J Clin Oncol 22:1382-1388 (2004)

 Examples of genetic polymorphisms that have an
impact on drug metabolism and their clinical
consequences
Drug Genetic Variation Mechm Outcome
5FU/analogue DPD PK Toxicity
6MP and AZA TPMT PK Toxicity
Irinotecan UGT1A1 PK Toxicity
Aromatase Inhibitors TCL1 PD? Toxicity

Warfarin CYP2C9 & VKORC1 PK & PD Toxicity

Cisplatin TPMT and COMT Unclear Toxicity
Tamoxifen CYP2D6 PK Efficacy
5FU/analogue TS PK Toxicity
5FU/analogue MTHFR PK Toxicity
Cyclophosphamide CYPs PK Eff & Tox
MoAbs Fc-gamma-RII & III PD Efficacy
EGFR TKIs EGFR, ABCG2 PD Eff & Tox
Cisplatin DNA repair SNPs PD Eff & Tox
Dasatinib CYP3A4/3A5 PK Eff & Tox
Coate et al, JCO, 2010
 ADME: Excretion

Liver function

Potential factors in
cancer patient that
affect metabolism:

Liver metastasis
Cirrhosis and
steatosis
Renal insufficiency
Dehydration
Concomitant
medications

Lullman H, et al. Color Atlas of Pharmacology 1996
 Paclitaxel (Taxol)
o 6 hr infusion, q 21d
Cremaphor formulation
Premedication
Non-linear kinetics (saturation of
275 mg/m2
excretion)
250 mg/m2 J Clin Oncology 9:1261-1267 (1991)
175 mg/m2

paclitaxel (NabPaclitaxel)
o nanoparticles
o 30 min infusion, q 21d
No cremaphor
No premeds
Linear kinetics

Clin Cancer Res 8:1038-1044 (2002)

Stratton Clin Pharm AACR/ASCO Vail 2005

Basic concepts of Pharmacotherapy

Pharmacokinetics
 Pharmacokinetics
Quantitative analysis of the process of drug
absorption, distribution, metabolism, and elimination
through measurements of drug concentration in
accessible compartments over time

What happens to the drug between administration

and elimination

What the body does to the agent

 Per os administration
Intravenous administration

Lullman H, et al. Color Atlas of Pharmacology 1996

PK Terms- Speaking the Language (I)
 PK Terms- Speaking the Language (II)
Bioavailability-The proportion of the dose
that reaches the systemic circulation
(not the same as exposure)

Exposure- A measure for the amount of

drug that an organism has interacted
with

Volume of Distribution- A measure of the

theoretical volume that an agent
distributes to.

Clearance- A measure of the elimination of

a compound from the blood given as
volume cleared/time
PK Terms- Speaking the Language (III)
Sources of variation in cancer patient
 The reality
TheofIdeal
cancer
PK patient
Properties
and therapy

Consistent Plasma Concentrations

No variability in interpatient metabolism
Excretion uncompromised by liver or renal
dysfunction
Predictable and rapid onset of action
No accumulation with repeated dosing
Rapid clearance- minimize exposure if there are
troublesome side effects
No interactions with other co-administered drugs
o Low protein binding-
o Lack of P450 induction/inhibition
o Excretion interference

Mathijssen, R. H. J. et al. Nat. Rev. Clin. Oncol. 2014

 PK Variability in Ovarian Cancer
Patients
Paclitaxel 250 mg/m2, 24 hr infusion, 22-23 hr sample, n = 48

Cancer Chemother Pharmacol 33:48-52 (1993)

Sorafenib AUC0-12 preceeding grade 3/4 toxicity was
significantly higher than that observed in patients
without grade 3/4 toxicity

Boudou-Rouquette et al, The Oncologist, 2012

Changes in elimination kinetics in the course of drug therapy

Renal or liver
impairment,
(development of liver
metastasis, renal
dysfunction, DDI)

Drug-drug
interaction
Decreasing sorafenib dose-normalized Incidence of hypertension and
12-hour AUC over time in 25 patients HFSR significantly decreased
treated at fixed dose over time

Boudou-Rouquette et al, The Oncologist, 2012

 Drug interactions

Absorption: food, chelation, G.I. motility, pH

Distribution: transport, protein binding
Metabolism: Phase I (CYP450), Phase II (conjugation)
Elimination: Renal (glomerular filtration); transport
 Drug-Disease Interactions
Liver disease
Renal disease
Cardiac disease (hepatic blood
flow)
Acute viral infection?
Hypothyroidism or hyperthyroidism?
Standard chemotherapeutic dosing schedules
are often developed in studies that exclude
patients with organ dysfunction.
European J Cancer 1998; 34: 33-46
Number of cancer patients with impaired
hepatic or renal function eligible for protocols
evaluating organ dysfunction is limited.
Takimoto C and and Mita A. J Clin Oncol 2006, 24: 3509-10

PK will be affected by:

-organs altered metabolic capacity.
-altered excretion pursuant to altered blood flow.
-production of toxic compounds that damage organs
 Drug-Food Interactions

Administration with food

Decreased rate of absorption; not extent (AUC):

Common for many drugs; take without regard to meals

Decreased extent of absorption ( AUC):

Indinavir AUC decreased by 77% with high calorie meal; take on an empty
stomach

Increased extent of absorption ( AUC):

Itraconazole (capsules)
Effect of food on the
bioavailability

Principles of Anticancer Drug development 2011

 Implication of Food-drug interaction
(Abiraterone)
Prescribing guidelines recommend that abiraterone acetate be taken orally on an
empty stomach with no food consumed at least 2 hours before and 1 hour after
dosing

The cost of the drug to the NHS
would have been 2,930 per
patient per month.
Prostate Cancer UK said it could
delay a patient having to undergo
chemotherapy by more than two
years.
Given with a high fat meal, one
could save 1,465 per patient per
month.
2,930/2 per month x 12m x 2years
= 35,160 = 49,886
Big Mac= 4,64 (Euro area)

High-fat meals can increase total systemic exposure (AUC) 2-10-fold

 Drug-Herbal Interactions
St. Johns Wort with:
o Indinavir
o Cyclosporine
o Digoxin
o Tacrolimus
o Irinotecan: Due to changes in hepatic metabolism
caused by St. Johns wort, levels of irinotecan metabolite
SN-38 may be lowered by as much as 40%.
o Imatinib: Increased clearance.
o Docetaxel: Subtherapeutic docetaxel concentrations may
result when docetaxel is administered
o Methotrexate: Increases exposure and toxicity of
Methotrexate

About Herbs Database. https://www.mskcc.org/cancer-care/treatments/symptom-management/integrative-medicine/herbs#

 Drug-Drug interaction
Interaction: an alteration in PK/ or PD caused by concomitant drug
treatment, dietary factors or social habits (alcohol, tobacco).

EMA Investigation of Drug interactions

 Drug-Drug interactions and TKIs
Cytotoxics are frequently given iv and for a short period of time.
TKI and other biologicals are frequently given orally and
chronically.
Strong inhibitor of CYPs: increases AUC of a substrate more than 5-
fold, or more than 80% decrease in Clearance (CL).
Strong inducer of CYPs: decreases the AUC of a substrate more
than 80%.
Co-prescription of drugs that affect TKI:
o 25-60% drugs that may decrease TKI effectiveness
o 25-75% drugs that may increase TKI toxicity
TKI are victims of DDI in 61% cases, and perpetrators in 39%.
Cytochomes P450 are responsible for 65% of DDI; Transporters in
22%.
CYP3A4 in 62% and Pgp in 14%
 Interactions in Drug
Metabolism
Phase I
o Oxidation Nearly always due to interaction with Phase
o Reduction I enzymes, rather than Phase II
o Hydrolysis Commonly due to cytochrome P450
enzymes which have highly variable activity
Phase II and, in some cases, are genetically absent
o Conjugation or over-expressed
Potent inhibition or induction of CYP3A4 significantly
alters Lapatinib systemic exposure.

Lapatinib (100mg) w pretreatment with Ketoconazole (CYP3A4 inh)

Lapatinib (250mg)

Lapatinib (100mg)
Lapatinib (250mg) w pretreatment with Carbamazepine (CYP3A4 sustrate)
 Antiviral brivudine and capecitabine drug-drug
interaction

Brivudine inhibits the breakdown of 5 fluoropyrimidines such as 5-fluorouracil

and 5-FU prodrugs such as capecitabine and it can therefore lead to a
potentially fatal accumulation of 5-FU

Rtz Bravo AE et al. Acta Oncol. 2009;48(4):631-3

Conditions under which drug interactions are likely
to be clinically significant

Scripture C & William D. Figg, Nat Rev Cancer 2006

Studies of potential DDIs found that approximately one-third of patients are
exposed to dangerous drug doublets
No. of drugs used per patient 10 (125)
van Leeuwen RWF, Annals of Oncology 26: 992997, 20

A. Thomas-Schoemann et al. Critical Reviews in

Oncology/Hematology, 2014
http://medicine.iupui.edu/clinpharm/ddis/
 Summary
Drugs in Oncology frequently have a narrow
therapeutic index and a significant inter-patient
variability.
Comorbidities and concomitant medications are
frequent sources of variability together with
constitutional variables (age, body mass index,
genetics) and life style.
Drug/disease/food-drug interactions are frequent in
Oncology and a source of ineffective or toxic
treatments.
An oncologist needs to be familiar with basic PKs
parameters and the pharmacology of the drugs that
are used.