Abstract
PurposeFedratinib (SAR302503, TG101348) is an orally administered Janus kinase (JAK) 2-selective inhibitor that is being developed for the treatment of patients with myelofibrosis (MF). The objectives of this analysis were to develop a population pharmacokinetic (PK) model to characterize fedratinib concentration-time profiles in patients with MF, polycythemia vera (PV) and essential thrombocythemia (ET) following oral fedratinib administration; and to investigate the effects of selected covariates on fedratinib PK parameters.MethodsNonlinear mixed effects modeling was employed in developing a population PK model for fedratinib. Intensive or sparse fedratinib concentration data collected in adult subjects with MF, PV or ET from six studies were pooled, and a total of 452 subjects and 3442 plasma concentration observations were included in the final model.ResultsFedratinib PK in patients with MF/PV/ET was adequately described by a two-compartment structural PK model with first-order absorption incorporating a lag time and first-order elimination. Following oral administration, fedratinib undergoes biphasic disposition and exhibits linear, time-invariant PK at doses of 200 mg and above. Compared to MF/ET patients, PV patients had higher apparent clearance (CL/F) and apparent central volume of distribution. Creatinine clearance was a statistically significant covariate on CL/F, and patients with mild and moderate renal impairment had 10% and 37% increases in fedratinib exposure as compared to patients with normal renal function. No clinically meaningful effect on fedratinib exposure was observed regarding age, body weight, sex, race and liver function.ConclusionsThese results should serve as the basis for dose adjustment of fedratinib for special populations.
Highlights
Myeloproliferative neoplasms (MPNs) are clonal, BCRABL1 negative hematopoietic diseases of myeloid proliferation, and characterized by abnormal production of terminally differentiated functional blood cells [1, 2]
The fedratinib population PK model provided an adequate description of plasma fedratinib concentration-time data from MF, polycythemia vera (PV), or essential thrombocythemia (ET) patients receiving oral fedratinib doses of 100 mg and above
Fedratinib concentration-time data were well characterized by the structural PK model that consists of a two-compartment with first-order absorption incorporating a lag time and first-order elimination
Summary
Myeloproliferative neoplasms (MPNs) are clonal, BCRABL1 negative hematopoietic diseases of myeloid proliferation, and characterized by abnormal production of terminally differentiated functional blood cells [1, 2]. MPNs are classically categorized into three disease entities: primary. Myelofibrosis (primary MF or PMF), polycythemia vera (PV) and essential thrombocythemia (ET) [1, 2]. Patients with PV and ET are characterized by an abnormal increase in hemoglobin/hematocrit and platelet count, respectively, and PMF is more advanced subtype of MPNs, associated with bone marrow fibrosis, release of profibrotic and proinflammatory cytokines and splenomegaly due to extramedullary hematopoiesis [3]. Janus kinase (JAK)/signal transducer and activation of transcription (STAT) pathway is key to cytokine receptor signaling and plays a critical role in hematopoiesis and immune response [5].
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