Quantitation of unbound sunitinib and its metabolite N‐desethyl sunitinib (SU12662) in human plasma by equilibrium dialysis and liquid chromatography–tandem mass spectrometry: application to a pharmacokinetic study

Abstract

A rapid, selective, and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of unbound sunitinib and its active metabolite N-desethyl sunitinib in plasma. Plasma and post-dialysis buffer samples were extracted using a liquid-liquid extraction procedure with acetonitrile/n-butylchloride (1:4, v/v). Chromatographic separation was achieved on a Waters X-Terra® MS RP18 column with a mobile phase consisting of acetonitrile and water (60:40, v/v) containing formic acid (0.1 %, v/v) using an isocratic run, at a flow rate of 0.2 mL/min. Analytes were detected by electrospray tandem mass spectrometry in the selective reaction monitoring mode. Linear calibration curves were generated over the range of 0.1–100 ng/mL and 0.02–5 ng/mL for sunitinib and 0.2–200 ng/mL and 0.04–10 ng/mL for N-desethyl sunitinib in plasma and in phosphate buffered solution, respectively. The values for both within day and between day precision and accuracy were well within the generally accepted criteria for analytical methods. The analytical range was sufficient to determine the unbound and total concentrations of both analytes. The method was applied for measurement unbound concentrations in addition to total concentrations of sunitinib and its metabolite in plasma of a cancer patient receiving 50 mg daily dose.

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

“…Similarities in pharmacokinetics and pharmacodynamics, including metabolism through CYP3A4 for venetoclax and the 3 KIs, 48,[75][76][77][78] would necessitate careful coadministration in vivo. Importantly, in combination with sunitinib, venetoclax was effective at 10 nM, a concentration well below the clinically tolerated dose 9 which indeed may allow a dose adaption.…”

A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus‐positive patients with cancer: AIDS Malignancy Consortium trial AMC 061

“…Serial blood samples for pharmacokinetic analysis were collected during cycle 1 on day 1, in addition to weekly trough samples through day 29, with an optional half‐life assessment to day 42. Total and unbound plasma concentrations of sunitinib and N‐desethyl sunitinib were determined using a validated liquid chromatography‐tandem mass spectrometry method . Individual pharmacokinetic parameters were estimated by standard noncompartmental analysis using WinNonlin Professional software (version 5.3; Pharsight Corporation, Mountain View, Calif).…”

Recent developments in the chromatographic bioanalysis of approved kinase inhibitor drugs in oncology

“…Whilst concomitant administration of an CYP3A4 inhibitor would put patients at a higher risk of development of these toxicities, the use of an inducer might lower sunitinib toxicity without diminishing potency [9]. For sunitinib, multiple assays that focus on the active metabolite as well as the parent compound have been published [24,57,65,104,114,130,134]. The active O-desmethyl-metabolite of erlotinib, OSI420, is in most literature noted as the most abundant metabolite, while in fact the peak described as OSI420…”

“…The downside of UF and ultracentrifugation is the nonspecific binding of drugs to membranes and devices, giving false-low results. Equilibrium dialysis is the most commonly used since non-specific adsorption of drugs to the device and membrane has less impact than other techniques, provided that an equilibrium is reached [103,104]. In TKI bioanalysis, ultracentrifugation is used for the determination of unbound imatinib [102] and erlotinib, imatinib, sunitinib, sorafenib, and lapatinib [105].…”

“…52 axitinib -sulfoxide* [191] bosutinib oxydechloro-*, N-desmethyl-*, -N-oxide* [192] cabozantinib -N-oxide* [193] Decyclopropyl-, Dimethyl-, -N-oxide O-dearyl- [138] nilotinib -N-Oxide*, Hydroxy-* [195,196] nindetanib O-demethyl- [159] osimertinib N-desmethyl-* [197] pazopanib Hydroxy-*, N-demethyl-* [198] ponatinib N-desmethyl-* [199] regorafenib N-oxide-(BAY757495), N-oxide-O-desmethyl-(BAY818752) [163] ruxolitinib Hydroxy-* [200] sorafenib -N-oxide [2,114] sunitinib N-desethyl-N,N-didesethyl- [24,57,65,104,114,130,134] trametinib N-deacetyl-(M5)* [201] …”