monoclonal antibodies & tyrosine-kinase inhibitors
TRANSCRIPT
Monoclonal Antibodies & Tyrosine-Kinase
Inhibitors
Charlotte Capstick Clinical Pharmacist Oncology
Weston Park Hospital Sheffield Teaching Hospitals NHS Trust
Contents
Background Dosing
Renal impairment Hepatic impairment
Drug Interactions Supportive Medications HCP Assessments Summary
Background Monoclonal Antibodies & Tyrosine Kinase Inhibitors
Numerous new drugs coming on the market across the all disease
sites
Many of these are monoclonal antibodies (MABs) and Tyrosine-Kinase Inhibitors (TKIs)
The information available regarding newly licensed drugs not always complete – not always black or white!
Different mechanism of action and side-effect profiles in comparison to traditional chemotherapy esp. MABs
Side-effects of MABs require careful management
Gefitinib
Imatinib
Pazopanib
Erlotinib
Sunitinib
Regorafenib
Axitinib
Vemurafenib Dabrafenib
Nivolumab
Ipilimumab
Nilotinib
Cetuximab
Rituxumab
Sorafenib
Ceritinib Nintedanib
Afatinib
Lapatinib
Carfilzomib
Trastuzumab
Bevacizumab
Atezolizumab
Cabozantinib
Crizotinib
Trametinib Vismodegib
Vandetanib Blinotumomab
Alemtuzumab
Denosumab Pembrolizumab
Adverse Events/Side-effects
Monoclonal antibodies
Usually immune related
◦ Colitis ◦ Hepatitis ◦ Pneumonitis ◦ Skin ◦ Endocrinopathies
Infusion reactions
◦ Management depends on severity & local guidelines
◦ Severe: stop infusion
Tyrosine-Kinase Inhibitors Skin Thyroid Diarrhoea Fatigue Oedema Cardiac/vascular Hypertension Not an exclusive list!
Dosing in Renal/Hepatic Impairment
Can be problematic due to lack of information from manufacturers
Drugs not always studied in patients with renal or hepatic impairment
Decisions about dosing in renal/hepatic impairment can be tricky
Dosing in Renal Impairment MABs
Mild-Moderate Severe
Pembrolizumab No dose adjustment Not studied
Ipilimumab No dose adjustment No recommendations
Nivolumab No dose adjustment No recommendations
Dosing in Renal Impairment TKIs
Drug specific (many TKIs!)
Check manufacturers SPC (or pharmacy)
May require clinical judgement
Mild Moderate Severe
Debrafenib No dose adj. No dose adj. Caution: no data
Vemurafenib No dose adj. No dose adj. Caution: no data
Regorafenib No dose adj. No dose adj. No dose adj.
Axitinib No dose adj. No dose adj. CrCl<15ml/min: no data available
Dosing in Hepatic Impairment MABs
Mild Moderate Severe
Pembrolizumab No dose adjustment
Not studied Not studied
Ipilimumab At baseline caution if Bili>3xULN Transaminases> 5xULN
No dose adjustment
No recommendations
No recommendations
Nivolumab No dose adjustment
No recommendations
No recommendations
Dosing in Hepatic Impairment TKIs
Mild Moderate Severe
Debrafenib No dose adj. Caution: limited data
Caution: limited data
Vemurafenib No dose adj. Caution: risk of exposure
Caution: risk of exposure
Regorafenib No dose adj. Limited date: no recommendations
NOT recommended as no data
Axitinib No dose adj. Dose reduction e.g. start at 2mg BD
Not recommended as no data
TKIs mostly metabolised by the liver
Pharmacokinetics & Interactions MABs
Lack of formal studies
MABs are not metabolised by cP450 enzyme system
◦ therefore less potential to interact with other drugs
Systemic corticosteroids before starting MABs should be avoided
◦ potential interference with the pharmacodynamic activity/efficacy
Pharmacokinetics & Interactions TKIs
Metabolised by cP450 enzyme system ◦ Many sub-systems e.g. CYP3A4, CYP1A2, CYP2D6,
CYP2C8..
HERBALS can also be metabolised by this
system
CAUTION: drugs that induce or inhibit these enzymes may or plasma levels of TKIs
◦ St Johns Wort can decrease Imatinib levels ◦ Clarithromycin can increase Gefitinib levels ◦ Grapefruit/pomegranate (whole & juice) can increase levels
Pharmacokinetics & Interactions TKIs
Some TKIs are themselves inducers/inhibitors of these enzymes so may affect levels of other drugs
◦ Pazopanib can increase Simvastatin levels ◦ Vemurafenib can increase Theophylline levels
Agents that increase gastric pH might
decrease the bioavailability of TKIs ◦ E.g Dabrafenib
SPC good source of information for potential
interactions but can be hard to decipher
Supportive Medications MABs
• Loperamide 4mg at 1st onset then 2mg PRN max 16mg/24hrs
Pembrolizumab
•Domperidone 10mg TDS PRN
Nivolumab
• Loperamide 4mg at 1st onset then 2mg PRN max 16mg/24hrs
Ipilmumab
Supportive Medications TKIs
Dependent upon side-effect profile of the individual TKI
In general ◦ Loperamide: 4mg at 1st onset, then 2mg after each
loose motion, max.16mg/24hrs
◦ Diprobase: apply PRN
◦ Metoclopramide/Domperidone: 10mg TDS PRN
HCP Assessments
Know the drug – SPCs/protocol
Be aware of the common side-effects
Follow local guidelines & use HCP protocols
Know your limitations & understand when to refer
Summary
New drug therapies constantly coming onto the market
Prescribing these drugs is not always easy due to the lack of information/data
TKIs: watch for interactions with other drugs metabolised by cP450 enzyme system
MABs: watch for immune-related adverse events Many of these are black triangle drugs so report
side-effects/adverse events Ensure HCP protocols are in place for new drugs Find a friendly pharmacist who might be able to
help?!!