Pharmacokinetics and Safety of Intravenous Ferric Pyrophosphate Citrate: Equivalence to Administration via Dialysate.

Ferric pyrophosphate citrate (FPC) is indicated to maintain hemoglobin in patients with stage 5 hemodialysis-dependent chronic kidney disease on chronic hemodialysis by addition to the dialysate. An intravenous (IV) FPC presentation containing 6.75 mg of iron in 4.5 mL was developed. The objective was to establish the equivalence of iron delivery via dialysate and IV infusion using a pharmacokinetic approach. An open-label, randomized, multiple-period, single-dose, crossover study was conducted in 27 patients with CKD-5HD. Each patient received (1) a basal iron profile over 12 hours, (2) FPC 6.75 mg Fe IV predialyzer, (3) FPC 6.75 mg Fe IV postdialyzer, and (4) FPC 2 µM (110 µg Fe/L of hemodialysate). Serum and plasma iron was analyzed for total Fe and transferrin bound iron (TBI). Equivalence was determined by comparing maximum observed concentration and area under the concentration-time curve from time 0 to the last observation of 110 µg Fe/L of hemodialysate (reference) and test treatments Fe predialyzer and postdialyzer iron profiles. The main outcome measure was the measurement of bioequivalence between the reference and test treatments. Bioequivalence parameters showed that infusion of FPC iron IV, predialyzer and postdialyzer delivered equivalent iron as via hemodialysate. The increment in serum total Fe from predialysis to postdialysis was the same as observed in the long-term clinical studies of FPC. FPC IV was well tolerated. IV infusion of 6.75 mg iron as FPC during 3 hours of HD delivers an equivalent amount of iron as when Triferic is delivered via hemodialysate. The IV presentation of FPC extends the ability to provide FPC iron to all patients receiving hemodialysis or hemodiafiltration.

Inductively coupled plasma-MS in drug development: bioanalytical aspects and applications.

The vast majority of today's modern bioanalytical methods for pharmacokinetic, pharmacodynamic and immunogenicity purposes are based on LC-MS/MS and immunoanalytical approaches. Indeed, these methodologies are suitable for a wide range of molecules from small to large. For a smaller but not insignificant group of compounds, LC-MS/MS is not suitable - or in some cases much less suitable - as a reliable bioanalytical methodology, and inductively coupled plasma (ICP)-MS is a more appropriate methodology. ICP-MS is one of these less widely used techniques in drug development. This methodology is predominantly used for elemental bioanalysis for pharmacokinetics, for imaging purposes, for mass-balance, food-effect and biomarker studies. In addition, in the last couple of years an increasing number of applications has been published, where ICP-MS and its various hyphenations (LC-ICP-MS, CE-ICP-MS) have been used for speciation/metabolism and proteomics studies. Here, the analytical potential, the quantitative bioanalytical aspects, the various modes of operation and the challenges of the application of ICP-MS in life sciences applications are given. This includes an overview of recent applications in this area in scientific literature, the various hyphenation possibilities and their application areas and the analysis of the various sample matrices applicable to these fields. It also provides a brief outlook of where the potential of this technique lies in the future of regulated bioanalysis and drug development.

High temperature liquid chromatography hyphenated with ESI-MS and ICP-MS detection for the structural characterization and quantification of halogen containing drug metabolites.

In this paper we describe the hyphenation of high temperature liquid chromatography with ICP-MS and ESI-MS for the characterization of halogen containing drug metabolites. The use of temperature gradients up to 200°C enabled the separation of metabolites with low organic modifier content. This specific property allowed the use of detection methods that suffer from (significant) changes in analyte response factors as a function of the organic modifier content such as ICP-MS. Metabolites of two kinase inhibitors (SB-203580-Iodo and MAPK inhibitor VIII) produced by bacterial cytochrome P450 BM3 mutants and human liver microsomes were identified based on high resolution MS(n) data. Quantification was done using their normalized and elemental specific response in the ICP-MS. The importance of these kinds of quantification strategies is stressed by the observation that the difference of the position of one oxygen atom in a structure can greatly affect its response in ESI-MS and UV detection.