Clinical pharmacology of anti-angiogenic drugs in oncology

Abstract

Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate -pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring.

Drug‐induced peripheral oedema: An aetiology‐based review

“…Increased capillary permeability through elevated VEGF signalling induced by HGF/MET inhibition 43 BCR-Abl: 44 imatinib, dasatinib, nilotinib bosutinib, ponatinib -increased capillary permeability through endothelial Abl kinases inhibition 45 and by off-target inhibition of PDGFRβ and Src kinases 46,47 -decreased hydrostatic interstitial pressure through PDGFRβ inhibition 46,48 -heart failure (imatinib) 4 BTK: ibrutinib 49 Unknown PI3K/AKT: idelalisib, 50 alpelisib 51 Lymphedema 52 through PI3K/AKT inhibition that prevents VEGFR-3/VEGFC-dependant lymphangiogenesis 53 VEGF: sunitinib 32,54 -off-target inhibition of PDGFRβ 55,56 increases capillary permeability and decreases hydrostatic interstitial pressure 46,48 -proteinuria 57 -heart failure 4…”

“…‐ off‐target inhibition of PDGFRβ 55,56 increases capillary permeability and decreases hydrostatic interstitial pressure 46,48 …”

Optimal Scheduling of Bevacizumab and Pemetrexed/cisplatin Dosing in Non-Small Cell Lung Cancer

“…There are currently several other antiangiogenics regularly used in combination with cytotoxics which could potentially benefit from sequential administration (i.e. antiangiogenic then cytotoxic)(48,49). Of note, bevacizumab is currently only approved for concomitant administration with chemotherapy in all of its indications e.g.…”

Major pitfalls of protein kinase inhibitors prescription: A review of their clinical pharmacology for daily use

“…Most antiangiogenic PKIs prescribed in oncology have a wide kinase spectrum activity and inhibit kinase that could be responsible for off-target effects (Gougis et al, 2017). Therefore the efficacy dose is close to the toxic dose and they have a narrow therapeutic index.…”