epatic impairment on the single-dose pharmacokinetics of ceritinib (750 mg under fasted conditions) was eva luated in subjects with mild (Child-Pugh class A; N=8), moderate (Child-Pugh class B; N=7), or severe (Child-Pugh class C; N=7) hepatic impairment and in 8 healthy subjects with normal hepatic function. The geometric mean AUCinf (unbound AUCinf) of ceritinib was increased by 18% (35%) and 2% (22%) in subjects with mild and moderate hepatic impairment, respectively, compared to subjects with normal hepatic function.
The geometric mean AUCinf (unbound AUCinf) of ceritinib was increased by 66% (108%) in subjects with severe hepatic impairment compared to subjects with normal hepatic function (see section 4.2). A dedicated pharmacokinetic study under steady-state in patients with hepatic impairment has not been conducted.
Renal impairment
A dedicated pharmacokinetic study in patients with renal impairment has not been conducted. Based on available data, ceritinib elimination via the kidney is negligible (1.3% of a single oral administered dose).
Based on a population pharmacokinetic analysis of 345 patients with mild renal impairment (CLcr 60 to <90 ml/min), 82 patients with moderate renal impairment (CLcr 30 to <60 ml/min) and 546 patients with normal renal function (≥90 ml/min), ceritinib exposures were similar in patients with mild and moderate renal impairment and normal renal function, suggesting that no dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment (CLcr <30 ml/min) were not included in the clinical studies of Zykadia (see section 4.2).
Effects of age, gender, and race
Population pharmacokinetic analyses showed that age, gender and race had no clinically meaningful influence on ceritinib exposure.
Cardiac electrophysiology
The potential for QT interval prolongation of ceritinib was assessed in seven clinical studies with Zykadia. Serial ECGs were collected following a single dose and at steady-state to eva luate the effect of ceritinib on the QT interval in 925 patients treated with Zykadia 750 mg once daily fasted. A categorical outlier analysis of ECG data demonstrated new QTc >500 msec in 12 patients (1.3%). There were 58 patients (6.3%) with a QTc increase from baseline >60 msec. A central tendency analysis of the QTc data at average steady-state concentration from Study A2301 demonstrated that the upper bound of the 2-sided 90% CI for QTc increase from baseline was 15.3 msec at Zykadia 750 mg fasted. A pharmacokinetic analysis suggested that ceritinib causes concentration-dependent increases in QTc (see section 4.4).
5.3 Preclinical safety data
Safety pharmacology studies indicate that ceritinib is unlikely to interfere with vital functions of the respiratory and central nervous systems. In vitro data show that the IC50 for the inhibitory effect of ceritinib on the hERG potassium channel was 0.4 micromolar. An in vivo telemetry study in monkeys showed a modest QT prolongation in 1 of 4 animals after receiving the highest dose of ceritinib. ECG studies in monkeys after 4- or 13-weeks of dosing with ceritinib have not shown QT prolongation or abnormal ECGs.
The micronucleus test in TK6 cells was positive. No signs of mutagenicity or clastogenicity were observed in other in vitro and in vivo genotoxicity studies with ceritinib. Therefore, genotoxic risk is not expected in humans.
Carcinogenicity studies have not been performed wit |
