Quantitative Determination of AZD3264, a Selective Ikb-Kinase IKK2 Inhibitor, in Dog Plasma by Solvent-Induced Phase Transition Extraction Coupled with HPLC-MS/MS and its Application to Pharmacokinetic Study in Dogs

Q4 · AGRICULTURAL & FORESTRY SCIENCE

Article

Author: Wang, Chao ; Qiao, Kesen ; Liang, Shuofu ; Li, Gang

AbstractBackgroundAZD3264 is a small molecule inhibitor of selective IkB-kinase IKK2 currently in preclinical development for the potential treatment of asthma and chronic pulmonary obstructive disorder.ObjectiveA method for the quantitative analysis of AZD3264 was established and optimized by using HPLC tandem mass spectrometry in dog plasma.MethodPlasma samples were pretreated using a solvent-induced phase transition extraction method with a methanol solution of omeprazole as the internal standard. Chromatographic separation was performed using a Thermo Hypersil GOLD-C18 (50 mm × 4.6 mm, 3 μm) column with the temperature maintained at 25°C. Mobile phase consisted of 0.1% formic acid in water and acetonitrile in a gradient mode at a flow rate of 0.6 mL/min. Mass spectrometric detection was carried out in selected reaction monitoring mode with positive electrospray ionization, and the mass transitions of AZD3264 and omeprazole were m/z 442.1 → 425.0 and m/z 346.0 → 198.0, respectively.ResultsThe intra-batch accuracy was within 95.11–105.06% and the precision was within 6.50–9.98%. The inter-batch accuracy was within 96.83–102.80% with a precision of 7.62–9.50%. The selectivity, sensitivity, linearity, dilution linearity, extraction recovery and matrix effect, stability, and carry-over met all requirements of the guidelines for bioanalytical method validation. AZD3264 showed linear pharmacokinetic characteristics following intravenous administration to dogs at 0.3–2.7 mg/kg.ConclusionsThe developed and validated method was successfully employed in pharmacokinetic studies in dogs following intravenous administration at the doses of 0.3, 0.9, and 2.7 mg/kg.HighlightsThis was the first investigation of the in vivo pharmacokinetic characteristics of AZD3264 in dogs by LC-MS/MS with SIPTE method for plasma sample preparation.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Disease, Chronic Obstructive	Discovery	GB	AstraZeneca PLC	-

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