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Review
. 2023 Jan 10;15(1):239.
doi: 10.3390/pharmaceutics15010239.

Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces-A Review

Zoltán Köllő  1 , Miklós Garami  2 , István Vincze  1 , Barna Vásárhelyi  1 , Gellért Balázs Karvaly  1
Affiliations
Review

Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces-A Review

Zoltán Köllő et al. Pharmaceutics. .

Abstract

Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets (OACD) have revolutionized oncological pharmacotherapy. Nevertheless, the differences in exposure to these drugs in the systemic circulation and extravascular fluid compartments have led to several cases of therapeutic failure, in addition to posing unknown risks of toxicity. The therapeutic drug monitoring (TDM) of OACDs in therapeutically relevant peripheral fluid compartments is therefore essential. In this work, the available knowledge regarding exposure to OACD concentrations in these fluid spaces is summarized. A review of the literature was conducted by searching Embase, PubMed, and Web of Science for clinical research articles and case reports published between 10 May 2001 and 31 August 2022. Results show that, to date, penetration into cerebrospinal fluid has been studied especially intensively, in addition to breast milk, leukocytes, peripheral blood mononuclear cells, peritoneal fluid, pleural fluid, saliva and semen. The typical clinical indications of peripheral fluid TDM of OACDs were (1) primary malignancy, (2) secondary malignancy, (3) mental disorder, and (4) the assessment of toxicity. Liquid chromatography-tandem mass spectrometry was most commonly applied for analysis. The TDM of OACDs in therapeutically relevant peripheral fluid spaces is often indispensable for efficient and safe treatments.

Keywords: cerebrospinal fluid; imatinib; oncology; oral anticancer drugs; precision pharmacotherapy; therapeutic drug monitoring.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of the search strategy and the article selection process. WoS, Web of Science.
Figure 2
Figure 2
Summary of the results of the literature search. (A) Types of studies, (B) indications of monitoring, (C) monitored peripheral fluid spaces, (D) evaluation of clinical interest: number of manuscripts discussing the substance normalized to the number of years on the market, (E) marketed small-molecule, orally taken anticancer drugs with cellular protein targets without any example of being monitored in a peripheral fluid space. CSF, cerebrospinal fluid.
Figure 3
Figure 3
Relationships of the concentrations of various orally administered, small-molecule anticancer drugs with specific cellular protein targets in serum/plasma and in cerebrospinal fluid (CSF). (A) Erlotinib in plasma and in CSF, trough samples were drawn. (B) O-desmethyl-erlotinib (OSI-420) in plasma and in CSF, trough samples were drawn. (C) Unbound alectinib in plasma and in CSF. (D,E) Gefitinib in plasma and in CSF. (F) Unbound lorlatinib in plasma and in CSF. (G,H) Erlotinib in plasma and in CSF. (I) Gefitinib in plasma and in CSF, a Michaelis–Menten equation has been fitted to the data. (J) Icotinib in plasma and in CSF [50,61,62,63,64,70,77,83]. Licenses or permissions to reproduce the graphs have been granted by the copyright holders.
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