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?!!