General Background

A significant amount of scientific evidence demonstrates the high intra-patient and inter-patient variability of chemotherapeutic drugs and the correlation between dose management, toxic side effects, and clinical outcomes.1-7 When chemotherapy dosing is calculated based on current established standards (body surface area or BSA), the drug blood level variation among patients can be greater than 10-fold.1-7 This variability can lead to under- and over-dosing that impacts treatment efficacy, toxicity, and patient quality of life. Saladax Biomedical has compiled an extensive bibliography of pertinent studies that demonstrate these findings.

To confound the problem of variability, studies have shown that the current widely accepted standard of administering the maximum tolerated dose (MTD) – in hopes of achieving and maintaining an optimal therapeutic blood level – is difficult to execute in practice and is often not being followed because of oncologists’ concerns over the resulting severe toxic side effects.¹ As a consequence, many patients are not receiving adequate levels of chemotherapy while others may receive excessively high doses which are well into the toxic range.

Monitoring blood concentrations is routine in many medical disciplines for many drugs that have significant variability, a high toxicity profile, and a narrow therapeutic window that presents the potential for damaging side effects. Some anti-epileptic, cardiac, and transplantation drugs are routinely monitored, as are certain antibiotics, as well as the cancer drugs busulfan, methotrexate and carboplatin. Adoption of pharmacokinetic dose management in oncology has been somewhat limited to date because of the lack of reliable and convenient tools for incorporation into routine clinical practice.1

MyCare assays from Saladax provide clinical oncologists and pharmacologists with a tool to optimize individual patient dosing based upon measurement of actual blood drug levels. This enables you to monitor the correlation of dosing with clinical patient response on an ongoing basis.

The MyCare5-FU Assay

The MyCare5-FU Assay is the first to be offered by Saladax Biomedical and the value of pharmacokinetic dose management of this widely used drug is well established. In a recent study of colorectal cancer patients treated with 5-fluorouracil (5-FU), published in the May 2008 issue of the Journal of Clinical Oncology, BSA dosing resulted in 68% of patients being sub-therapeutic and requiring upward dose adjustments; 17% of patients were over-dosed and required downward dose adjustments and only 15% were actually in the optimal therapeutic range.8

These data were derived from a study of two arms of patients: Arm A, in which patients were dosed using standard fixed BSA dosing and Arm B, in which patients were dosed based upon measurement of blood drug levels after the initial BSA-based dose and subsequent cycle dose adjustments were made to reach the target drug blood range. The chart below shows that in Arm A (the blue bars), all patients were administered the same dose of 1500 mg/m2 and only a few patients received decreased subsequent dosing based upon presentation of toxic side effects. On the other hand, the patients in Arm B (the red bars) required a wide range of dose adjustments to achieve target 5-FU plasma levels. 

Arm B patients achieved a higher response and survival rate and lower rates of serious toxicity.  Patients in Arm B, despite the extensive incidence dose intensification illustrated above, experienced a significantly lower incidence of Grade 3 / 4 toxicities, as shown below:

Clinical outcomes were also significantly improved in the Arm B patients, with an almost doubling of positive response, i.e., at least a 50% reduction in tumor size.

 

 

Overall survival among the Arm patients showed a trend of material improvement, with a better than double increase at two years:

 

The Saladax MyCare Family of Assays

The Saladax MyCare assays will provide widespread access to chemotherapy drug blood level testing, offering physicians the opportunity to optimize cancer drug dosing for better patient management in their own practice of medicine, resulting in better treatment outcomes, lower toxicities and better quality of life for patients. Pharmacokinetic dose management with MyCare Assays may reduce medical costs by translating better treatment management into fewer medical interventions, reduced need for supportive medications (which currently comprise about 30% of all anticancer drug dollars9), fewer and shorter hospital stays, improved drug response rates, and lower rates of disease relapse.

References

1. Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol. 2003;21(24):4524-4531.
2. de Jonge ME, Huitema ADR, Schellens JHM, Rodenhuis S, Beijnen JH. Individualised cancer chemotherapy: Strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation: a review. Clin Pharmacokinet. 2005;44(2):147-173.
3. Hon YY, Evans WE. Making TDM work to optimize cancer chemotherapy: a multidisciplinary team approach. Clin Chem. 1998;44(2):388-400.
4. Undevia SD, Gomez-Abuin G, Ratain MJ. Pharmacokinetic variability of anticancer agents. Nat Rev Cancer. 2005;5(6):447-458.
5. Krynetski EY, Evans WE. Pharmacogenetics of cancer therapy: getting personal. Am J Hum Genet. 1998;63(1):11-16.
6. McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood. 2003;101(5):2043-2048.
7. Partridge AH, Avorn J, Wang PS, Winer EP. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst. 2002;94(9):652-661.
8. Gamelin E, Delva R, Jacob J, et al. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(13):2099-2104.
9. Data on file, Saladax Biomedical, Inc.