A simple and fast LC-MS/MS method for the routine measurement of cabozantinib, olaparib, palbociclib, pazopanib, sorafenib, sunitinib and its main active metabolite in human plasma

Targeted therapies such as cabozantinib (CABO), pazopanib (PAZO), sorafenib (SORA), sunitinib (SUNI) and its main active metabolite N-desethyl-sunitinib (DST-SUNI), olaparib (OLA) and palbociclib (PALBO) display large pharmacokinetics variability impacting their responses in terms of efficacy or toxicity. For the monitoring of these drugs, an analytical method allowing to routinely measure their concentrations in human plasma is needed. Such a method has been developed and validated and is presented here. The chromatographic separation is achieved on a Zorbax Bonus-RP analytical column using an isocratic elution of 92% V/V of acetonitrile and 8% of water in 0.1% formic acid at a flow rate of 500 mu l/min for 0.5 min and then 300 mu l/min for 2 min. After a liquid-liquid extraction of plasma samples, a step of filtration is performed. This method was validated based on the EMA and French committee of accreditation guidelines. The analysis time is 2.5 min per run, and all analytes eluted within 0.53-1.61 min. The standard curves are linear over the range from 1 to 380 ng/ml for SUNI; from 4.3 to 450 ng/ml for DST-SUNI; from 6 to 1000 ng/ml for PALBO; from 75 to 5000 ng/ml for CABO, from 0.17 to 20 mu g/ml for OLA; from 0.35 to 40 mu g/ml for SORA and from 1.7 to 200 mu g/ml for PAZO. The method also showed satisfactory results in terms precision (below 9.5% for within-run and below 13% for between-run) and accuracy (below 13.5% for within-run and below 14% for between-run). After sampling, all the compounds are stable in whole blood at ambient temperature at least for 6 h and plasma are stable for 48 h at ambient temperature or 4 degrees C. The method presented here allows to measure the concentrations of 7 targeted therapies in a routine setting. We moreover present here a method that is, to our knowledge, one of the first detailed method aimed at the measurement of palbociclib in human plasma in a routine setting, together with data useful for the management of samples in routine hospital practice.