Preface to Precision Dosing of Targeted Anti-Cancer Drugs

Small molecule protein kinase inhibitors (KIs) and anti-neoplastic monoclonal antibodies (mAbs) are rapidly expanding classes of non-cytotoxic or ‘targeted’ antineoplastic drugs that are effective at treating numerous malignancies, including previously difficult to treat forms of cancers. However, variability in disposition causes inter-individual variability in drug exposure that is inadequately addressed by the standard fixed-dose schedule of administration (1). Accordingly, precision dosing has great potential to maximise therapeutic response, minimise adverse drug reactions (ADRs), and improve cost-effectiveness of these expensive drugs.

Multiple studies have demonstrated the benefit of using therapeutic drug monitoring (TDM) to individualise KI dosing on the basis of plasma-KI concentration and therapeutic concentration ranges have been established for erlotinib, gefitinib, imatinib, nilotinib, pazopanib and sunitinib (2-4). However, a major barrier to the routine clinical translation of TDM is the preclusive cost and logistical complexity required to develop high quality prospective studies to confirm clinical utility (5,6).

Given these limitations, novel and practical complementary strategies are required to facilitate the clinical application of precision dosing for targeted anti-cancer drugs. Such strategies, which may include the application of population pharmacokinetic (PopPK) and physiological-based pharmacokinetic (PBPK) modelling and simulation (7,8), development of clinical prediction models based on routinely available clinical data (9), or the tracking of early novel markers of response or toxicity in diagnostically amenable tissues (10), may facilitate earlier dose optimisation and identify patients for whom TDM is most critical. However, such strategies rely on a sound understanding of the physiological and molecular characteristics driving variability in exposure. As such, fundamental clarification of the importance of factors known to contribute to between subject variability (BSV) such as genotype (11) and ethnicity (12) remains critical.

Notably, given the major role of cytochrome P450 (CYP) 3A4 in KI elimination (13), and limited capacity of existing strategies, such as genetic testing, to account for variability in CYP3A4 activity, novel diagnostic approaches are required to provide clinically actionable insights regarding the activity of this enzyme. Such insights may facilitate the more rational use of these drugs, and re-open the potential for applications such as combination with certain cytotoxic chemotherapies (14) that were previously considered unfeasibly due to unacceptable toxicities.

The manuscripts included in this Precision Dosing of Targeted Anti-Cancer Drugs focussed issue of Translational Cancer Research evaluate the evidence for precision dosing in this field, describe some of the key challenges to clinical translation, and describe novel strategies to facilitate the clinical translation of precision dosing for targeted anti-cancer drugs.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research for the series “Precision dosing of targeted anticancer drugs”. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2017.11.23). The series “Precision dosing of targeted anticancer drugs” was commissioned by the editorial office without any funding or sponsorship. AR and MJS served as the unpaid Guest Editors of the series and serves as the unpaid editorial board members of Translational Cancer Research. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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Andrew Rowland

Michael J. Sorich