Abstract
PurposeUse of the patient’s body surface area (mg m−2) as a basis for dosing does not take individual variation in metabolic capacity and rate of clearance into account. Here, we evaluated a novel approach for individual monitoring of short-lived cytotoxic agents formed from cytostatic drugs such as cyclophosphamide (CP).MethodsThe accumulated blood dose of the cytotoxic active agent phosphoramide mustard (PAM) formed from CP was measured as a reaction product with hemoglobin (Hb adduct). This adduct, N-[2-(2-oxazolidonyl)ethyl]-valyl Hb (OzVal-Hb), was detached from Hb with the adduct FIRE procedure™, and the formed analyte was quantified using LC-MS/MS. This dose biomarker for PAM and the analytical procedure was evaluated in accordance with the guidelines on bioanalytical method validation formulated by the European Medicine Agency. The evaluated method was applied to quantify blood dose levels of PAM in female breast cancer patients (n = 12) before and after three cycles of polychemotherapy regimes containing CP.ResultsOzVal-Hb, a specific and stable biomarker, could be measured with great sensitivity (lower limit of quantification = 33 pmol g−1 Hb), high accuracy (within ±20 %) and good repeatability (CV < 20 %). The inter-individual variability in the blood level of this adduct in women with breast cancer (n = 12) who received three doses of CP in combination with one or two other cytostatic drugs was 250 % following the first dose and approximately 150 % after each subsequent dose.ConclusionsMeasurement of the biomarker OzVal-Hb can be used to quantify the short-lived cytotoxic agent PAM in a single blood sample drawn several days after therapy. This procedure may aid in individualizing doses of CP, thereby improving efficacy while both reducing the risk of and increasing the predictability of side-effects.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2524-7) contains supplementary material, which is available to authorized users.
Highlights
Dosing of cytostatic drugs is based on the patient’s body surface area (BSA, mg m−2) or weight, little evidence validates these approaches [1, 2]
Identification of a stable OzVal‐Hb adduct formed from phosphoramide mustard (PAM)
In blood samples from patients treated with CP, as well as in control blood samples incubated with 4-OOH-CP, the OzVal-Hb adduct was detected
Summary
Dosing of cytostatic drugs is based on the patient’s body surface area (BSA, mg m−2) or weight (mg kg−1), little evidence validates these approaches [1, 2]. The major concern is that such average optimal BSA dosing for a large group of patients does not take into account individual variations in metabolism and rate of clearance. The cytostatic prodrug cyclophosphamide (CP) must be metabolized to obtain the active agent. This involves hydroxylation in the liver to form the unstable precursor. Cancer Chemother Pharmacol (2014) 74:549–558 Cl N OP Cl metabolism N OP. HN O large inter individual variability HO O
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