Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects

Abstract

Crizotinib (Xalkori®) is an orally administered, selective, small-molecule, ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) and mesenchymal epithelial transition factor/hepatocyte growth factor receptor tyrosine kinases, and has recently been approved for the treatment of ALK-positive non-small cell lung cancer. The absolute bioavailability of crizotinib, effect of a high-fat meal on crizotinib pharmacokinetics (PK), and bioequivalence of several oral formulations (powder in capsule [PIC], immediate-release tablet [IRT], and commercial formulated capsule [FC]) were evaluated in two phase I clinical studies involving healthy volunteers who received single doses of crizotinib. PK parameters for crizotinib and its metabolite, PF-06260182, were determined using non-compartmental methods. The absolute oral bioavailability of crizotinib was approximately 43%, with a slight decrease in crizotinib exposures (area under the plasma concentration-time profile and maximum plasma concentration) following a high-fat meal that was not considered clinically meaningful. The FC was bioequivalent to the clinical development IRT and PIC formulations. No serious adverse events were observed during either study and the majority of adverse events were mild, the most common being diarrhea. Single-dose crizotinib could be safely administered to healthy subjects.

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model

“…In the single-dose oral bioavailability study, crizotinib oral bioavailability was estimated to be 0.43 with an F a  F g value of 0.96 in healthy subjects at an oral dose of 250 mg relative to an intravenous dose of 50 mg, assuming linear pharmacokinetics (Xu et al, 2015). Using the model-predicted F g value of 0.94, F a was calculated to be ;0.9 in this study.…”

“…Crizotinib hepatic microsomal intrinsic clearance (CL int,hep ) was back-calculated from the clinically observed plasma clearance (CL) using a retrograde model implemented in Simcyp version 13.1 (Jamei et al, 2009). Crizotinib intravenous and oral plasma CL estimates (geometric mean) were 46.8 and 108 l/h, respectively, in the single-dose oral bioavailability study (Xu et al, 2015). In the crizotinib single-dose DDI studies with ketoconazole and rifampin, crizotinib oral plasma CL estimates in the control groups (crizotinib alone) were 123 and 119 l/h, respectively (Xu et al, 2011a(Xu et al, , 2011b.…”

First-dose and steady-state pharmacokinetics of orally administered crizotinib in children with solid tumors: a report on ADVL0912 from the Children’s Oncology Group Phase 1/Pilot Consortium

“…The pharmacokinetics of crizotinib in adults has been studied after a single dose and at steady state (≥15 days) in patients with NSCLC using 250-mg formulated capsules and after a single 50-mg dose of an experimental intravenous formulation or a single 250-mg dose of three oral formulations [formulated capsules (FC), powder in capsules (PIC) and immediate-release tablets (IRT)] in healthy volunteers [8, 9]. The mean (C.V.) clearance (CL) of crizotinib was 47 (18%) L/h, the volume of distribution at steady state was 1770 (18%) L and the half-life ( T 1/2 ) was 39 (16%) h, following the intravenous dose.…”

Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib

“…administration and 250 mg oral administration with the assumption that hepatic clearance was identical. [23] No data has been reported on the bioavailability of ceritinib. Although the specific cytochrome-P (CYP) enzymes for ceritinib are unknown, both drugs are metabolized by CYP3A enzymes, with crizotinib primarily by CYP3A4/5.…”

“…If we assume these numbers are correct, at least twice as much ceritinib is needed to reach the *Calculated by comparing I.V. and oral administration with the assumption that hepatic clearance was identical [23] optimal concentration in plasma, considering ceritinib has a V d twice as large as crizotinib. However, ceritinib is 6 times more potent in inhibiting the growth of Ba/F3 ALK-positive cell lines than crizotinib, implying that a 6-fold lower concentration is as effective in vitro in ALKinhibition as crizotinib.…”