Fedratinib

Fedratinib is a kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2. Fedratinib reduced JAK2-mediated phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited malignant cell proliferation in vitro and in vivo.

Fedratinib inhibits cytokine induced signal transducer and activator of transcription (STAT)3 phosphorylation in whole blood from myelofibrosis patients. A single dose administration of 300, 400, or 500 mg of fedratinib resulted in maximal inhibition of STAT3 phosphorylation approximately 2 hours after dosing, with values returning to near baseline at 24 hours. Similar levels of inhibition were achieved at steady state PK on cycle 1 day 15, after administration of 300, 400 or 500 mg of fedratinib per day.

Cardiac Electrophysiology

The potential for QTc prolongation with fedratinib was evaluated in 31 patients with solid tumors. No large mean increase in the QTc interval (>20 ms) was detected with daily dosing of fedratinib 500 mg (1.25 times the recommended dose) for 14 days.

Absorption

Fedratinib at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose of 400 mg) results in a dose proportional increase in geometric mean fedratinib C_max and the area under the plasma concentration time curve over the dosing interval (AUCtau). The mean steady state levels are achieved within 15 days of daily dosing. The mean accumulation ratios are similar in adult patients with primary MF, post-PV MF or post-ET MF, ranging from 3- to 4-fold.

At the dose of 400 mg once daily, the geometric mean (coefficient of variation, CV) fedratinib C_max,ss is 1804 ng/mL (49) and AUCtau,ss is 26870 ng.hr/mL (43%) in patients with myelofibrosis.

Following 400 mg once daily oral administration, fedratinib is rapidly absorbed, achieving C_max at steady-state in 3 hours (range: 2 to 4 hours). Based on a mass balance study in humans, oral absorption of fedratinib is estimated to be approximately 63-77%.

A low-fat, low-calorie (total 162 calories: 6% from fat, 78% from carbohydrate and 16% from protein) or a high-fat, high-calorie (total 815 calories: 52% from fat, 33% from carbohydrate and 15% from protein) meal increased AUC_inf up to 24% and C_max up to 14% of a single 500 mg dose of fedratinib. Thus, fedratinib can be taken with or without food since no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with food. Administration with a high fat meal may reduce the incidence of nausea and vomiting and thus fedratinib is recommended to be taken with food.

Distribution

The mean apparent volume of distribution of fedratinib at steady-state is 1770 L in patients with myelofibrosis at 400 mg once daily dose suggesting extensive tissue distribution. The human plasma protein binding of fedratinib is approximately 95%, mostly to α1-acid glycoprotein.

Biotransformation

Fedratinib is metabolized by multiple CYPs in vitro, with the predominant contribution from CYP3A4, and with a lesser contribution from CYP2C19 and FMOs.

Fedratinib was the predominant entity (approximately 80% of plasma radioactivity) in systemic circulation after oral administration of radiolabelled fedratinib. None of the metabolites contribute greater than 10% of total parent substance-related exposure in plasma.

Elimination

Following a single oral dose of radiolabelled fedratinib, elimination was primarily through metabolism with approximately 77% of radioactivity excreted in faeces and only approximately 5% of the excreted in urine. Unchanged parent substance was the major component in excreta, accounting on average for approximately 23% and 3% of the dose in faeces and urine, respectively. Fedratinib pharmacokinetics is characterised by a biphasic disposition with an effective half-life of 41 hours, a terminal half-life of approximately 114 hours, and apparent clearance (CL/F) (CV) of 13 L/hr (51) in patients with myelofibrosis.

Special populations

Age, body weight, gender and race

In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with regard to age (analysis including 170 patients with age 65-74 years, 54 with age 75-84 years and 4 with age 85+ years), body weight (40 to 135 kg), gender (analysis including 249 males and 203 females) and race (analysis including 399 White, 7 Black, 44 Asian and 2 other).

Renal impairment

Following a single 300 mg dose of fedratinib, the AUC_inf of fedratinib increased by 1.5-fold in subjects with moderate renal impairment (CLcr 30 mL/min to 59 mL/min by C-G) and 1.9-fold in subjects with severe renal impairment (CLcr 15 mL/min to 29 mL/min by C-G), compared to that in subjects with normal renal function (CLcr ≥90 mL/min by C-G).

In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with regard to mild renal impairment (defined as 60 ≤CLcr <90 mL/min).

Hepatic impairment

The safety and pharmacokinetics of a single oral 300 mg dose of fedratinib were evaluated in a study in subjects with normal hepatic function and with mild hepatic impairment (Child-Pugh class A). No clinically meaningful effect on the pharmacokinetics of fedratinib was observed in subjects with mild hepatic impairment compared to that in subjects with normal hepatic function.

In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with regard to mild (defined as total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST increase; n=115) or moderate (defined as total bilirubin >1.5 to 3 times ULN and any AST; n=17) hepatic impairment.

Fedratinib pharmacokinetics has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C)

Fedratinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity studies and in a carcinogenicity study. Fedratinib was not genotoxic and not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model. Preclinical studies have demonstrated that at clinically relevant doses, fedratinib does not inhibit thiamine transport in the gastrointestinal tract or the brain.

In repeat-dose toxicity studies of up to 9 months in length, in mice, rats and dogs, the main toxicities observed included bone marrow hypoplasia; bile duct hypertrophy, necrosis and proliferation; lymphoid atrophy/depletion; renal tubular degeneration/necrosis; gastrointestinal tract inflammation; degeneration/necrosis of skeletal and cardiac muscle; histiocytic infiltration of the lung; and evidence of immunosuppression including pneumonia and/or abscesses. The highest plasma exposures achieved in the repeat-dose toxicology studies were associated with significant toxicity, including mortality, and were below the tolerated plasma exposures in patients at the highest recommended dose of 400 mg, suggesting humans are less sensitive than preclinical species to the toxicities of fedratinib. Clinically relevant exposures were not attained in the species used in the toxicology studies, therefore these studies have a limited value in producing clinically relevant safety data on fedratinib.

Fertility and early embryonic development

Fedratinib had no effect on the oestrous cycle parameters, mating performance, fertility, pregnancy rate or reproductive parameters in male or female rats. The exposure (AUC) was approximately 0.10 to 0.13 times the clinical exposure at the recommended dose of 400 mg once daily. In a repeat-dose toxicity study, at exposures approximately equivalent to human clinical exposure, fedratinib caused aspermia, oligospermia and seminiferous tubule degeneration in male dogs.

Embryo-foetal development

Fedratinib administered to pregnant rats during organogenesis (gestation days 6 to 17) was associated with adverse embryo-foetal effects including post-implantation loss, lower foetal body weights, and skeletal variations. These effects occurred in rats at approximately 0.1 times the clinical exposure at the recommended human daily dose of 400 mg/day. In rabbits, fedratinib did not produce developmental toxicity at the highest dose level tested (exposure approximately 0.08 times the clinical exposure at the recommended human daily dose).