Abstract
Ifosfamide blood concentrations are necessary to monitor its therapeutic response, avoiding any adverse effect. We developed and validated an analytical method by UPLC-MS/MS to quantify ifosfamide in dried blood spots (DBS). Blood samples were collected on Whatman 903® filter paper cards. Five 3 mm disks were punched out from each dried blood spot. Acetonitrile and ethyl acetate were used for drug extraction. Chromatographic separation was carried out in an Acquity UPLC equipment with a BEH-C18 column, 2.1 x 100 mm, 1.7 μm (Waters®). The mobile phase consisted in 5 mM ammonium formate and methanol:acetonitrile (40:48:12 v/v/v) at 0.2 mL/min. LC-MS/MS detection was done by ESI+ and multiple reaction mode monitoring, ionic transitions were m/z1+ 260.99 > 91.63 for ifosfamide and 261.00 > 139.90 for cyclophosphamide (internal standard). This method was linear within a 100–10000 ng/mL range and it was accurate, precise and selective. Ifosfamide samples in DBS were stable for up to 52 days at -80°C. The procedure was tested in 14 patients, ages 1 month to 17 years (9 males and 5 females), with embryonic tumours treated with ifosfamide, alone or combined, at a public tertiary referral hospital. Ifosfamide blood levels ranged from 11.1 to 39.7 μmol/L at 12 hours after the last infusion, while 24-hour levels ranged from 0.7–19.7 μmol/L. The median at 12 hours was 19.5 μmol/L (Q25 14.4–Q75 29.0) and 3.8 μmol/L (Q25 1.5–Q75 9.9) at 24 hours, p<0.001. This method is feasible to determine ifosfamide plasma levels in paediatric patients.
Highlights
Cancer is the second most common cause of death [1], and solid tumours account for 60% of all malignancies
We developed and validated a rapid and sensitive method to measure ifosfamide blood concentrations in paediatric patients, since there is still lacking a method to monitor ifosfamide levels routinely, as it is done with other antineoplastic drugs such as methotrexate, whose toxic effects are considerable
Etoposide could be extracted with the same method, it did not interfere with ifosfamide quantification
Summary
Cancer is the second most common cause of death [1], and solid tumours account for 60% of all malignancies. Ifosfamide is one of the most commonly used drugs in chemotherapy for children and adults with solid tumours [1], as it is a very effective broad-spectrum drug that can be used alone or combined [1] It has been reported, that it can cause severe systemic toxicity or even the death of the patient [1,2,3,4,5]. Knowing that 1 μM methotrexate is achieved in blood at 24 hours [2], allows the prompt implementation of rescue measures in the case this plasma concentration is overtaken, even if toxicity signs are not clinically shown. The introduction of blood collection in Whatman 9031 filter paper cards (Guthrie cards), allows the use of minimal blood volumes, which represents a great technical advantage in paediatric patients undergoing antineoplastic therapy
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