Drug-Drug Interactions Associated with Anti-Cancer Drugs - Overview of Clinical Pharmacology

Factors influencing absorption have little effect on the pharmacokinetic behaviour of intravenously-administered anti-cancer drugs,¹ as a result, their bioavailability is generally 100%.¹ In contrast, factors influencing drug absorption, such as drug interactions, can lead to reduced bioavailability of orally-administered anti-cancer agents.¹ In addition, some orally-administered anti-cancer agents are prodrugs (e.g. tamoxifen and capecitabine), and therefore require metabolic activation for therapeutic activity through metabolism in the gastrointestinal tract and/or liver¹ As a result, factors altering the absorption of orally-administered anti-cancer drugs have large effects on their pharmacokinetic characteristics.¹

Factors that can influence absorption of some orally-administered drugs include:²

1. A change in stomach pH
2. Activity of drug transporters and drug metabolising enzymes within the intestine, liver and kidney
3. Formation of insoluble complexes
4. Inhibition or induction of P glycoprotein
5. Substrates of intestinal CYP3A4

Pharmacodynamic drug-drug interactions can also occur when the effect of one drug is changed by another by acting on mechanisms associated with the same physiological process or effect (e.g. QTc-DDI).²

Major gastrectomies can also reduce the absorption of kinase inhibitors such as imatinib, nilotinib and sunitinib, which may be partially due to lack of gastric acid secretion.^3-5

Importance of patient variability

Variability in response to targeted drugs is influenced by inter-patient variability in metabolic enzyme pathways (such as variability in cytochrome P450s enzymatic activities) and drug transporter pathways (such as polymorphisms in ABC drug transporters).^6-8 In addition, drug interactions with modulators of intestinal and hepatic cytochrome P450s are a particular concern with oral targeted therapies as they are often metabolised through these pathways. As a result, there is often a very wide spread of plasma concentrations of an oral drug following standard dosage regimens.^6-8

Therapeutic window

The therapeutic window of a drug is the range of drug concentration (driven by the dose administered) that is associated with the optimal clinical benefit-risk ratio which can treat a disease effectively, with minimal side effects.⁷ The therapeutic window of many cytotoxic drugs and kinase inhibitors is narrow, with a small change in drug concentration leading to lower therapeutic effect or higher toxicity:^6,7

Footnote: In this model, the drug is less effective below a threshold drug concentration, and above the upper threshold concentration toxic effects emerge.⁷ For kinase inhibitors, while the type of adverse effects observed may differ to that of classic cytotoxic agents, the therapeutic window may also be considered narrow as the associated toxicities may be severe, dose-limiting and potentially life-threatening.

References

1. Scripture CD, Figg WD. Drug interactions in cancer therapy. Nat Rev Cancer 2006; 6: 546-558.
2. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315-326.
3. Yoo C, Ryu MH, Kang BW et al. Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib. J Clin Oncol 2010; 28: 1554-1559.
4. Kim KP, Ryu MH, Yoo C et al. Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability. Cancer Chemother Pharmacol 2011; 68: 285-291.
5. de Wit D, van Erp NP, Khosravan R et al. Effect of gastrointestinal resection on sunitinib exposure in patients with GIST. BMC Cancer 2014; 14: 575.
6. Bardin C, Veal G, Paci A et al. Therapeutic drug monitoring in cancer--are we missing a trick? Eur J Cancer 2014; 50: 2005-2009.
7. Mathijssen RH, Sparreboom A, Verweij J. Determining the optimal dose in the development of anti-cancer agents. Nat Rev Clin Oncol 2014; 11: 272-281.
8. Widmer N, Bardin C, Chatelut E et al. Review of therapeutic drug monitoring of anti-cancer drugs part two--targeted therapies. Eur J Cancer 2014; 50: 2020-2036.