Talazoparib has no clinically relevant effect on QTc interval in patients with advanced solid tumors.

The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia's (QTcF) and Bazett's (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from -3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization.

A preliminary investigation into the action of anagrelide: thrombopoietin-c-Mpl receptor interactions.

OBJECTIVE: Many studies have validated the clinical efficacy of anagrelide to reduce platelet counts in thrombocythemic conditions. With the ability to support human megakaryopoiesis in vitro using thrombopoietin (TPO), specific investigation of changes in platelet levels can be carried out in human systems. Using CD34(+) stem cells and murine BaF3 cells transfected with the human or murine TPO receptor, c-Mpl (BaF3mpl), the effect of anagrelide on cell differentiation, proliferation, and signaling was examined in the presence of TPO. METHODS: Inhibition of TPO-mediated cell differentiation by anagrelide was evaluated by fluorescein-activated cell sorting analysis. Cell proliferation was monitored by 3-(4,5-dimethylthiazol-2-yl)-5-3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays. Effect of anagrelide on TPO-mediated phosphotyrosine (pTyr) activity was examined by Western analysis of whole cell lysates. RESULTS: In the presence of TPO, anagrelide reduced the number of CD41(+) cells without a reduction in the total mononuclear cell number in a dose-dependent manner. Growth inhibition was also observed in BaF3 cells transfected with human c-Mpl. Anagrelide also reduced TPO-specific pTyr activity in a species-specific manner. No inhibitory effect could be demonstrated with interleukin-3 stimulation. CONCLUSION: Parallel dose-response effects were found in both CD41(+) number and TPO-specific pTyr activity. These results suggest that anagrelide reduces TPO-mediated megakaryocyte proliferation of CD34(+) cells through a mechanism that leads to inhibition of intracellular signaling events. Furthermore, data also suggest that it is a species-specific effect, with no inhibitory activity against the murine receptor. Because there is a less than 10% difference in DNA sequence homology between human and murine receptors, the difference in sequence-specific activity must reside in these amino acid differences.