Background and purpose: Purinoceptors containing the P2X3 subunit (P2X3 homotrimeric and P2X2/3 heterotrimeric) are members of the P2X family of ion channels gated by ATP and may participate in primary afferent sensitization in a variety of pain-related diseases. The current work describes the in vitro pharmacological characteristics of AF-353, a novel, orally bioavailable, highly potent and selective P2X3/P2X2/3 receptor antagonist. Experimental approach: The antagonistic potencies (pIC50) of AF-353 for rat and human P2X3 and human P2X2/3 receptors were determined using methods of radioligand binding, intracellular calcium flux and whole cell voltage-clamp electrophysiology. Key results: The pIC50 estimates for these receptors ranged from 7.3 to 8.5, while concentrations 300-fold higher had little or no effect on other P2X channels or on an assortment of receptors, enzymes and transporter proteins. In contrast to A-317491 and TNP-ATP, competition binding and intracellular calcium flux experiments suggested that AF-353 inhibits activation by ATP in a non-competitive fashion. Favourable pharmacokinetic parameters were observed in rat, with good oral bioavailability (%F = 32.9), reasonable half-life (t1/2 = 1.63 h) and plasma-free fraction (98.2% protein bound).
Conclusions and implications:The combination of a favourable pharmacokinetic profile with the antagonist potency and selectivity for P2X3 and P2X2/3 receptors suggests that AF-353 is an excellent in vivo tool compound for study of these channels in animal models and demonstrates the feasibility of identifying and optimizing molecules into potential clinical candidates, and, ultimately, into a novel class of therapeutics for the treatment of pain-related disorders.
Purpose
Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib.
Methods
Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1000 mg/m2 on days 1 and 8), cisplatin (70 mg/m2) or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12 and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3+3 dose escalation rules.
Results
Fourteen patients with advanced solid tumors were enrolled, 5 to the cisplatin arm and 9 to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of 2 cycles of treatment (range, 1-5) and patients enrolled in the carboplatin arm received a median of 1 cycle of treatment (range, 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia) and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort and the study was closed. No patients achieved an objective response to treatment.
Conclusions
Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression.
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