ICH guidelines-compliant HPLC-UV method for pharmaceutical quality control and therapeutic drug monitoring of the multi-targeted tyrosine kinase inhibitor pazopanib

Abstract

In this study, an HPLC method with ultraviolet (UV) detection was developed and validated for determination of pazopanib (PAZ), a multi-targeted tyrosine kinase (TK) inhibitor in bulk drug, tablets formulation, and in human plasma. Oxamniquine (OXA) was used as internal standard (IS). The analytical column used for the separation was Nucleosil CN with dimensions (i.d. 250 × 4.6 mm and particle size 5 µm). The separation was carried out in isocratic mode with mobile phase constituting acetonitrile:100 mM sodium acetate buffer (pH 4. KEYWORDSTyrosine kinase inhibitors, pazopanib, HPLC, UV detection, quality control, therapeutic drug monitoring. IntroductionAn important role of vascular endothelial growth factor receptor (VEGF) in quite a few tumor forms has been reported.1-3 The dysregulation of platelet derived growth factor (PDGF) 4 and epidermal growth factor (EGF) 5 also play an important role in propagation of tumor cell. Pazopanib (PAZ; GW-786034) chemically known as 5-({4-[(2,3-Dimethyl-2H-indazol-6-yl) (methyl) amino]-2-pyrimidinyl}amino)-2-methylbenzene-sulfonamide (Fig. 1) is tyrosine kinase inhibitor (multi-targeted and orally active). The targets for PAZ are VEGFR-1, -2, and -3, PDGFR-a, PDGFR-b, c-Kit and act by inhibiting auto-phosphorylation of growth factor receptor (intracellular TK domain). PAZ competes with ATP to bind to the intracellular TK domain thus, blocking downstream signal transduction. 6 The recommended dose of PAZ is not more than 800 mg once daily for treatment of soft tissue sarcoma or renal cell carcinoma. Pharmacokinetic studies have revealed peak plasma concentration of 58.1 µg mL -1 and mean AUC of 1037 µg h mL -1 for PAZ after a dose of 50-2000 mg. The absorption of PAZ in cancer patients is slow and the bioavailability of 800 mg tablet in these patients is 21 %. The PAZ accumulates after continuous once daily dosing for 22 days and the drug is present in the systemic circulation as intact PAZ and not as metabolites of PAZ. PAZ is 99 % plasma protein bound and is eliminated mainly through feces and around 4 % through renal route.

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“…The data were reported as means ± standard error means of three independent analyses, and the method was validated according to the USP and ICH guidelines [11][12] . Various parameters were studied to validate the reproducibility of the method viz the effectiveness, the linearity, the limit of detection (LOD), the limit of quantitation (LOQ), the precision and the accuracy.…”

Spectrophotometric Investigations of Charge Transfer Complexes of Tyrosine Kinase Inhibitors with Iodine as a σ-Electron Acceptor: Application to Development of Universal High-Throughput Microwell Assay for Their Determination in Pharmaceutical Formulations

“…An appropriate analytical method is needed for TKI quality control (QC). Chromatographic methods including high-performance liquid chromatography (HPLC) [18][19][20][21][22][23] and high-performance thinlayer chromatography (HPTLC) [24][25][26][27] as well as other techniques such as voltammetry [28], spectrofluorimetry [29][30][31][32], and spectrophotometry [33][34][35][36][37][38][39][40][41][42][43][44] have all been reported as methodologies for the QC of TKIs in pharmaceutical formulations. Because of its simplicity, low cost, and widespread availability in QC laboratories, spectrophotometry is the most practical analytical method.…”

Development of Green and High Throughput Microplate Reader-Assisted Universal Microwell Spectrophotometric Assay for Direct Determination of Tyrosine Kinase Inhibitors in Their Pharmaceutical Formulations Irrespective the Diversity of Their Chemical Structures

“…To ensure the accurate contents of TKIs in the formulations, a proper quantitative analytical technique is required. The analytical techniques existing in the literature for the quantitative determination of TKIs in their formulations are chromatography [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], voltammetry [ 28 ], spectrofluorometry [ 29 , 30 , 31 , 32 ], and spectrophotometry [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Among these techniques, spectrophotometry is the most convenient and widely applied technique, as evident from the number of publications [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”