Monoclonal Antibodies & Tyrosine-Kinase Inhibitors

Transcription

1 Monoclonal Antibodies & Tyrosine-Kinase Inhibitors Charlotte Capstick Clinical Pharmacist Oncology Weston Park Hospital Sheffield Teaching Hospitals NHS Trust

2 Contents Background Dosing Renal impairment Hepatic impairment Drug Interactions Supportive Medications HCP Assessments Summary

3 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

4 Blinotumomab Nilotinib Crizotinib Bevacizumab Vemurafenib Atezolizumab Pembrolizumab Imatinib Gefitinib Sorafenib Cetuximab Sunitinib Vandetanib Erlotinib Axitinib Trastuzumab Dabrafenib Carfilzomib Afatinib Regorafenib Denosumab Ceritinib Nintedanib Rituxumab Lapatinib Ipilimumab Vismodegib Cabozantinib Pazopanib Nivolumab Trametinib Alemtuzumab

5 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!

6 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

7 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

8 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

9 Dosing in Hepatic Impairment MABs Mild Moderate Severe Pembrolizumab No dose adjustment Not studied Not studied Ipilimumab No dose adjustment No recommendations No recommendations At baseline caution if Bili>3xULN Transaminases> 5xULN Nivolumab No dose adjustment No recommendations No recommendations

10 Dosing in Hepatic Impairment TKIs TKIs mostly metabolised by the liver Mild Moderate Severe Debrafenib No dose adj. Caution: limited data Vemurafenib No dose adj. Caution: risk of exposure Caution: limited data Caution: risk of exposure Regorafenib No dose adj. Limited date: no recommendations Axitinib No dose adj. Dose reduction e.g. start at 2mg BD NOT recommended as no data Not recommended as no data

11 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

12 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

13 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

14 Supportive Medications MABs Loperamide 4mg at 1 st onset then 2mg PRN max 16mg/24hrs Pembrolizumab Domperidone 10mg TDS PRN Nivolumab Loperamide 4mg at 1 st onset then 2mg PRN max 16mg/24hrs Ipilmumab

15 Supportive Medications TKIs Dependent upon side-effect profile of the individual TKI In general Loperamide: 4mg at 1 st onset, then 2mg after each loose motion, max.16mg/24hrs Diprobase: apply PRN Metoclopramide/Domperidone: 10mg TDS PRN

16 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

17 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?!!