Lapatinib development

ErbB inhibitors in development differ in several aspects, including potency, selectivity, and mechanism of inhibition. Fortunately, there are data that compare erlotinib, gefitinib, lapatinib, canertinib, HKI-272, and BIBW 2992 directly in enzymatic and cellular studies, as shown in Tables 2 and 3 [89,95]. 

GERMLINE PHARMACOGENETICS IN ONCOLOGY DRUG DEVELOPMENT LEARNING FROM LAPATINIB... 

Lapatinib had been shown ex vivo to be primarily metabolized by CYP3A4/5 with a minor contribution from CYP2C19, and to be a substrate of the transporters MDRl(ABCBl) and BCRP(ABCG2). A hypothesis was proposed whereby polymorphisms in these genes would be associated with a propensity to develop rash and/or diarrhea. 

Burris HA, 3rd, Hurwitz HI, Dees EC et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW5720I6), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. JCfiri Oncol2005 23 5305-5313. Zaks T, Akkari A, Briley L et al. Role of pharmacogenetic studies in early clinical development Phase I studies with lapatinib. JCfiW Oncol 2006 24 3029. 

The determination of sorafenib plasma concentrations was performed by HPLC onto a C8 column (4 min run time) [115] and C18 column (6 min run time) [116]. Similarly, HPLC C18 columns have been used for the quantification in plasma of lapatinib [117], vatalanib [119] (3 and 8 min run time, respectively), and also for bosutinib [88], whereas UPLC was used for the TKI in development of axitinib (1.2 min run time) [120],... 

In general, triple stage quadrupole mass spectrometer with ESI in positive ion mode is perceived as the most appropriate MS technique available at present for small—mostly basic—molecules and was used for the assay of nilotinib [112], sorafenib [115,116], lapatinib [117], sunitinib [113,114], bosutinib [88], vatalanib [119] axitinib [120], vandetanib [118] neratinib [87], and crizotinib [125], The latter assay for crizotinib was developed for preclinical experiments and does not contain... 

At about the same time, our laboratory has reported the development and validation of an LC tandem MS assay for as much as six TKIs simultaneously. The proposed LC-MS/MS method allows the simultaneous determination of clinically relevant ranges of concentrations for the six major TKIs currently in use imatinib, dasatinib, nilotinib, sunitinib, sorafenib, and lapatinib [122], Plasma is purified by acetonitrile protein precipitation followed by reversed-phase chromatographic separation. Analyte quantification is performed by electrospray ionization-triple quadrupole mass spectrometry by selected reaction monitoring (SRM) detection using the positive mode. This was the first broad-range LC-MS/MS assay covering the major currently in-use TKIs. 

Roche S et al (2009) Development of a high-performance liquid chromatographic-mass spec-trometric method for the determination of cellular levels of the tyrosine kinase inhibitors lapatinib and dasatinib. J Chromatogr B Analyt Technol Biomed Life Sci 877 3982-3990... 

The synthesis of lapatinib involves a Suzuki-Miyaura coupling of a (5-formylfuran-2-yl)boronic derivative and an aryl iodide and was studied in detail by several teams. " In a recent patent,researchers from Zentiva noticed that in their own attempts to use commercial boronic acid, the excess of this reagent required for optimal conversions and purity was dependent on the source (a common issue with boronic acids, which are often contaminated with anhydrides and borinic acid). Thus, they turned to cyclic boronic esters as a more reliable intermediate, allowing correct control of the amount of boron reagent. Transposition of a process originally developed for the coupling of (5-formylfuran-2-yl)boronic acid was successful. The authors compared... 

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