Fosfomycin single- and multiple-dose pharmacokinetics in patients undergoing prolonged intermittent renal replacement therapy

Background Fosfomycin is used increasingly in the treatment of MDR bacteria. It is eliminated by renal excretion, but data regarding dosing recommendations for patients undergoing modern means of renal replacement therapies are scarce. Objectives Evaluation of the pharmacokinetics (PK) of fosfomycin in patients undergoing prolonged intermittent renal replacement therapy (PIRRT) to guide dosing recommendations. Methods Fosfomycin was given in 11 (7 female) patients with severe infections undergoing PIRRT. Plasma levels were measured at several timepoints on the first day of fosfomycin therapy, as well as 5–6 days into therapy, before and after the dialyser, to calculate its clearance. Fosfomycin was measured in the collected spent dialysate. Results The median (IQR) plasma dialyser clearance for fosfomycin was 183.4 (156.9–214.9) mL/min, eliminating a total amount of 8834 (4556–10 440) mg of fosfomycin, i.e. 73.9% (45.3%–93.5%) of the initial dose. During PIRRT, the fosfomycin half-life was 2.5 (2.2–3.4) h. Data from multiple-dose PK showed an increase in fosfomycin Cmax from 266.8 (166.3–438.1) to 926.1 (446.8–1168.0) mg/L and AUC0–14 from 2540.5 (1815.2–3644.3) to 6714 (4060.6–10612.6) mg·h/L. Dialysis intensity during the study was 1.5 L/h. T>MIC was 100% in all patients. Conclusions Patients undergoing PIRRT experience significant fosfomycin elimination, requiring a dose of 5 g/8 h to reach adequate plasma levels. However, drug accumulation may occur, depending on dialysis frequency and intensity.

Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors

SummaryBackground: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics. Methods: The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100–400 mg/m2, and 600–800 mg) once daily with food in continuous 28-day cycles. In the ADME study, volunteers received a single oral dose of [14C]entrectinib 600 mg. In the third study, volunteers received single doses of entrectinib 600 mg as the research and marketed formulations in the fasted state (Part 1), and the marketed formulation in the fed and fasted states (Part 2). Entrectinib and its major active metabolite M5 were assessed in all studies. Results: Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics. Conclusions: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food.