DIACHEMO is a Euroepan project developing a platform technology for point-of-care devices for chemotherapeutics and other drugs, as Christian Siebel and Dott.ssa Bianca Posocco, medical experts of the consortium detail here
Today, the drug dose given to a patient for treatment is mainly calculated on the basis of easily accessible parameters like the body surface. This dose determination, unfortunately, does not take into consideration features such as individual metabolism and, therefore, can lead to highly different concentrations of the drugs in the blood of the patient.
The idea of treatment individualisation on the basis of drug concentration measurement, interpretation and subsequent dose adaptation was first introduced in clinical practice during the 1960s for the administration of the antiepileptic phenytoin. Since then, therapeutic drug monitoring (TDM) approaches have been progressively applied to a variety of drug classes among others antiepileptics, antidepressants, cardiovascular drugs, immunosuppressants or antibiotics. In principle, the concept of TDM aims to control for pharmacokinetic variability among patients which might otherwise lead to substantial variations in systemic drug exposure. Using plasma drug concentrations to manage the treatment regimen for each individual patient is thought to optimise the therapeutic outcome by improving treatment efficacy and/or reducing toxicity.1,2
TDM could be of particular value in anticancer therapy considering the potentially fatal consequences of inappropriate drug administration in cancer patients where under dosing might be associated with therapy failure, whereas overdosing might increase the risk of serious toxic side effects. However, though the therapeutic outcome might be improved, TDM has been rarely implemented in cancer chemotherapy. Methotrexate is the only cytostatic where TDM is routinely used to adapt the dose of the antidote leucovorin. In acute lymphoblastic leukaemia trials, the activity of asparaginase has been monitored to detect immunological silent drug inactivation.3,4 Most obviously, successful implementation of TDM requires, inter alia, an established relationship between the drug exposure and its therapeutic and/or toxic effects which then culminates in the definition of a target exposure range.
Establishing such a relationship is particularly difficult in cancer chemotherapy owing to an imperfect understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of many drugs, the long lag time between concentration measurement and therapeutic outcome or late toxicity, respectively, as well as the broad use of combination chemotherapy regimens.5,6
However, a critical limitation for obtaining meaningful PK/PD data constitutes logistical requirements as the availability of appropriate equipment, assays and trained personnel. To make TDM work, correct sample collection, sample processing, as well as highly sensitive, accurate and precise analytical methods are mandatory. The avoidance of errors during these processes is fundamental for a valid analysis and interpretation of PK/PD data.
Furthermore, analytical methods used for routine monitoring have to be fast, easy to use and widely applicable to facilitate the conduct of PK/PD studies and the transfer of TDM approaches in routine clinical practice.3,5,7 These requirements are often not satisfactorily met by current analytical procedures which are frequently laborious and may involve well-equipped laboratories, the shipment of samples and complex sample processing steps.
Doxorubicin and paclitaxel are two commonly used chemotherapeutics which exemplify some of the analytical difficulties that currently hamper drug monitoring in oncology but also underline the potential advantages arising from TDM.
The anthracycline doxorubicin has gained widespread use in the treatment of solid and haematological malignancies. Due to the induction of irreversible cardiotoxicity drug monitoring of doxorubicin has been repeatedly proposed in the past. As young children are at an increased risk to develop long-term cardiac side effects and considering the otherwise long life expectancy of childhood cancer survivors, doxorubicin drug monitoring might be of particular benefit in this patient group. Monitoring of plasma concentrations in these most vulnerable patients, however, requires reducing the number and volume of blood samples to keep the patient´s burden to a minimum.
Further, doxorubicin analysis is prone to errors arising from pre-analytical errors during blood sample collection and sample processing even if standardised sampling procedures are used.8,9 The high sensitivity for pre-analytical errors especially affecting the measurement of peak concentrations and the need for very low blood volumes would make paediatric doxorubicin monitoring clearly benefit from more advanced analytical technologies.
Paclitaxel was firstly approved by the FDA in 1992 and, since then, it has been used to treat a plethora of solid tumours. Despite its ample and long-standing use, paclitaxel dosing is still not optimised. The currently applied “one dose fits all” appears not to be an appropriate approach since it does not take into account the significant inter- and intra-patient pharmacokinetic variability, leading to the risk of severe haematological and neuropathic toxicities.10,11
Moreover, paclitaxel is used in a wide range of doses (80-225 mg/m2) and it shows a disproportionate increase in systemic exposure with higher dosages. According to some studies, the duration of paclitaxel plasma concentrations above a threshold value correlates both with toxicity and antitumor activity. However, no consensus has still been reached on this value, with a proposed concentration of 0.05 µM.11
Nowadays, paclitaxel plasma concentrations are measured with standard time-consuming techniques, requiring sample preparation and specialised personnel.12 In this scenario, an advanced technology allowing a real-time quantification of paclitaxel plasma concentrations may produce a dual benefit: to better clarify the threshold level and to promptly adjust the dose during the drug infusion. This would lead to overcome the difficulties that hinder the application of TDM in clinical practice, finally moving from the standard paclitaxel dosing to a more rational therapy personalisation.
Prospectively, refined analytical technologies could also be of substantial advantage for the safe and effective use of novel targeted therapies which show long half-lives and a high risk of accumulation.13
Thus, miniaturised, fast and easy to use bedside monitoring tests that allow obtaining reliable results from the smallest of sample volumes without error-prone sample processing would meet a so far unmet need. The gap in the technological development of adequate monitoring tests, meaning miniaturisation and delivery of the test to the point-of-care, is currently addressed by the DIACHEMO project that is funded by the EU Research and Innovation programme Horizon 2020 (Grant Agreement Number 633635).
The DIACHEMO project aims towards the development of a point-of-care analytical device that will provide a fast and reliable determination of chemotherapeutic drug concentrations, therefore, supporting the conduction of pharmacokinetic trials and the implementation of TDM approaches in daily clinical practice. To achieve this goal, three research institutions, two hospitals, two industrial partners and a professional EU project management agency joined a European partnership.
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References
1 Eadie MJ: Therapeutic drug monitoring-antiepileptic drugs. British Journal of Clinical Pharmacology 46:185–93, 1998 (3).
2 Dasgupta A, Wahed A: Therapeutic Drug Monitoring. in Dasgupta A, Wahed A (eds): Clinical Chemistry, Immunology and Laboratory Quality Control: A Comprehensive Review for Board Preparation, Certification and Clinical Practice. Burlington, Elsevier Science, 2014, pp 249–273.
3 Bardin C, Veal G, Paci A, et al: Therapeutic drug monitoring in cancer—are we missing a trick? European journal of cancer (Oxford, England 1990) 50:2005–9, 2014 (12).
4 Van der Sluis IM, Vrooman LM, Pieters R, et al: Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica 101:279–85, 2016 (3).
5 Hon YY, Evans WE: Making TDM work to optimize cancer chemotherapy: a multidisciplinary team approach. Clinical Chemistry 44:388–400, 1998 (2).
6 Alnaim L: Therapeutic drug monitoring of cancer chemotherapy. Journal of oncology pharmacy practice official publication of the International Society of Oncology Pharmacy Practitioners 13:207–21, 2007 (4).
7 Jonge ME de, Huitema ADR, Schellens JHM, et al: Individualised Cancer Chemotherapy: Strategies and Performance of Prospective Studies on Therapeutic Drug Monitoring with Dose Adaptation A Review. Clinical Pharmacokinetics 44:147–73, 2005 (2).
8 Kontny NE, Hempel G, Boos J, et al: Minimization of the Preanalytical Error in Plasma Samples for Pharmacokinetic Analyses and Therapeutic Drug Monitoring – Using Doxorubicin as an Example. Therapeutic Drug Monitoring 33:766–71, 2011 (6).
9 Krischke M, Boddy AV, Boos J: Sources of preanalytical error in pharmacokinetic analyses – focus on intravenous drug administration and collection of blood samples. Expert opinion on drug metabolism & toxicology 10:825–38, 2014 (6).
10 Andriguetti NB, Raymundo S, Antunes MV, et al: Pharmacogenetic and Pharmacokinetic Dose Individualization of the Taxane Chemotherapeutic Drugs Paclitaxel and Docetaxel. Current medicinal chemistry 24:3559–82, 2017 (33).
11 Gerritsen-van Schieveen P, Royer B: Level of evidence for therapeutic drug monitoring of taxanes. Fundamental & clinical pharmacology 25:414–24, 2011 (4).
12 Posocco B, Buzzo M, Follegot A, et al: A new high-performance liquid chromatography-tandem mass spectrometry method for the determination of paclitaxel and 6α-hydroxy-paclitaxel in human plasma: Development, validation and application in a clinical pharmacokinetic study. PloS one 13:e0193500, 2018 (2).
13 Gao B, Yeap S, Clements A, et al: Evidence for Therapeutic Drug Monitoring of Targeted Anticancer Therapies. Journal of Clinical Oncology 30:4017–25, 2012 (32).
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Dr Silke Krol
Head of the Translational
Nanotechnology Lab and Coordinator of DIACHEMO Project
IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy
Tel: +39 (0)80 5555 987
