Ceritinib

Ceritinib is an orally highly selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of ALK-dependent cancer cells both in vitro and in vivo.

ALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK signaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; this generates an EML4-ALK fusion protein containing the protein kinase domain of ALK fused to the N-terminal part of EML4. Ceritinib was demonstrated to be effective against EML4-ALK activity in a NSCLC cell line (H2228), resulting in inhibition of cell proliferation in vitro and regression of tumours in H2228-derived xenografts in mouse and rat.

Absorption

Peak plasma levels (C_max) of ceritinib are achieved approximately 4 to 6 hours after a single oral administration in patients. Oral absorption was estimated to be ≥25% based on metabolite percentages in the faeces. The absolute bioavailability of ceritinib has not been determined.

Systemic exposure of ceritinib was increased when administered with food. Ceritinib AUC_inf values were approximately 58% and 73% higher (C_max approximately 43% and 41% higher) in healthy subjects when a single 500 mg ceritinib dose was administered with a low fat meal (containing approximately 330 kcalories and 9 grams of fat) and a high fat meal (containing approximately 1000 kcalories and 58 grams of fat), respectively, as compared with the fasted state.

In a dose optimisation study A2112 (ASCEND-8) in patients comparing ceritinib 450 mg or 600 mg daily with food (approximately 100 to 500 kcalories and 1.5 to 15 grams of fat) to 750 mg daily under fasted conditions (dose and food condition of administration initially authorised), there was no clinically meaningful difference in the systemic steady-state exposure of ceritinib for the 450 mg with food arm (N=36) compared to the 750 mg fasted arm (N=31), with only small increases in steady-state AUC (90% CI) by 4% (-13%, 24%) and C_max (90% CI) by 3% (-14%, 22%). In contrast, the steady-state AUC (90% CI) and C_max (90% CI) for the 600 mg with food arm (N=30) increased by 24% (3%, 49%) and 25% (4%, 49%), respectively, compared to the 750 mg fasted arm. The maximum recommended dose of ceritinib is 450 mg taken orally once daily with food.

After single oral administration of ceritinib in patients, plasma exposure to ceritinib, as represented by C_max and AUC_last, increased dose-proportionally over the 50 to 750 mg dose range under fasted conditions. In contrast with single-dose data, pre-dose concentration (C_min) after repeated daily dosing appeared to increase in a greater than dose-proportional manner.

Distribution

Binding of ceritinib to human plasma proteins in vitro is approximately 97% in a concentration independent manner, from 50 ng/ml to 10,000 ng/ml. Ceritinib also has a slight preferential distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35. In vitro studies suggest that ceritinib is a substrate for P-glycoprotein (P-gp), but not of breast cancer resistance protein (BCRP) or multi-resistance protein 2 (MRP2). The in vitro apparent passive permeability of ceritinib was determined to be low.

In rats, ceritinib crosses the intact blood brain barrier with a brain-to-blood exposure (AUC_inf) ratio of about 15%. There are no data related to brain-to-blood exposure ratio in humans.

Biotransformation

In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib.

Following a single oral administration of radioactive ceritinib dose at 750 mg fasted, ceritinib was the main circulating component in human plasma. A total of 11 metabolites were found circulating in plasma at low levels with mean contribution to the radioactivity AUC of ≤2.3% for each metabolite. Main biotransformation pathways identified in healthy subjects included mono-oxygenation, O-dealkylation, and N-formylation. Secondary biotransformation pathways involving the primary biotransformation products included glucuronidation and dehydrogenation. Addition of a thiol group to O-dealkylated ceritinib was also observed.

Elimination

Following single oral doses of ceritinib under fasted conditions, the geometric mean apparent plasma terminal half-life (T_1⁄2) of ceritinib ranged from 31 to 41 hours in patients over the 400 to 750 mg dose range. Daily oral dosing of ceritinib results in achievement of steady-state by approximately 15 days and remains stable afterwards, with a geometric mean accumulation ratio of 6.2 after 3 weeks of daily dosing. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 litres/hour) after 750 mg daily oral dosing than after a single 750 mg oral dose (88.5 litres/hour), suggesting that ceritinib demonstrates non-linear pharmacokinetics over time.

The primary route of excretion of ceritinib and its metabolites is in the faeces. Recovery of unchanged ceritinib in the faeces accounts for a mean 68% of an oral dose. Only 1.3% of the administered oral dose is recovered in the urine.

Special populations

Hepatic impairment

The effect of hepatic impairment on the single-dose pharmacokinetics of ceritinib (750 mg under fasted conditions) was evaluated 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 AUC inf (unbound AUC_inf) 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 AUC_inf (unbound AUC_inf) of ceritinib was increased by 66% (108%) in subjects with severe hepatic impairment compared to subjects with normal hepatic function. 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 ceritinib.

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 ceritinib. Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of ceritinib on the QT interval in 925 patients treated with ceritinib 750 mg once daily fasted. A central 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 ceritinib 750 mg fasted. A pharmacokinetic analysis suggested that ceritinib causes concentration-dependent increases in QTc.

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 with ceritinib.

Reproductive toxicology studies (i.e. embryo-foetal development studies) in pregnant rats and rabbits indicated no foetotoxicity or teratogenicity after dosing with ceritinib during organogenesis; however, maternal plasma exposure was less than that observed at the recommended human dose. Formal non-clinical studies on the potential effects of ceritinib on fertility have not been conducted.

The principal toxicity related to ceritinib administration in rats and monkeys was inflammation of the extra-hepatic bile ducts accompanied by increased neutrophil counts in the peripheral blood. Mixed cell/neutrophilic inflammation of the extra-hepatic ducts extended to the pancreas and/or duodenum at higher doses. Gastrointestinal toxicity was observed in both species characterised by body weight loss, decreased food consumption, emesis (monkey), diarrhoea and, at high doses, by histopathological lesions including erosion, mucosal inflammation and foamy macrophages in the duodenal crypts and submucosa. The liver was also affected in both species, at exposures that approximate clinical exposures at the recommended human dose, and included minimal increases in liver transaminases in a few animals and vacuolation of the intra-hepatic bile duct epithelium. Alveolar foamy macrophages (confirmed phospholipidosis) were seen in the lungs of rats, but not in monkeys, and the lymph nodes of rats and monkeys had macrophage aggregates. Target organ effects showed partial to complete recovery.

Effects on the thyroid were observed in both rat (mild increases in thyroid stimulating hormone and triiodothyronine/thyroxine T3/T4 concentrations with no microscopic correlate) and monkey (depletion of colloid in males in 4-week study, and one monkey at high dose with diffuse follicular cell hyperplasia and increased thyroid stimulating hormone in 13-week study). As these non-clinical effects were mild, variable and inconsistent, the relationship between ceritinib and thyroid gland changes in animals is unclear.