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Galunisertib is an anti-cancer drug currently evaluated in phase I and II clinical trials. This study describes the development and validation of a bioanalytical assay to quantify galunisertib in human plasma using HPLC-MS/MS. Stable isotope labelled galunisertib was added as internal standard and the analyte and internal standard were extracted from the matrix by protein precipitation using acetonitrile-methanol (50:50, v/v). Final extracts were injected onto a C18 column, gradient elution was applied for chromatographic separation and detection was performed using a triple quadrupole mass spectrometer operating in the positive ion mode. The assay was linear over the range 0.05-10 ng/mL, with acceptable accuracy (bias ranging from -6.1 to 3.1%) and precision (below 5.7% C.V.) values. The applicability of the assay was demonstrated in a pharmacokinetic experiment in mice.

PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi. METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC). RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces. CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.

INTRODUCTION: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo. PURPOSE: Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (Fpo) of this novel compound, which is the aim of this study. METHODS: Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg14C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography-tandem mass spectrometry method, whereas the total14C-radioactivity and14C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS. RESULTS: The Fpoof niraparib was determined to be 72.7% in humans.

The article ''Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a14C-microtracer and therapeutic dose in cancer patients'', written by L. van Andel, H. Rosing, Z. Zhang, L. Hughes, V. Kansra, M. Sanghvi, M. M. Tibben, A. Gebretensae, J. H. M. Schellens and J. H. Beijnen, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17th October 2017 without open access.

Niraparib (MK-4827) is a novel poly(ADP-Ribose) polymerase (PARP) inhibitor currently investigated in phase III clinical trials to treat cancers. The development of a new drug includes the characterisation of absorption, metabolism and excretion (AME) of the compound. AME studies are a requirement of regulatory agencies and for this purpose bioanalytical assays are essential. This article describes the development and validation of a bioanalytical assay for niraparib and its carboxylic acid metabolite M1 in human plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sample pre-treatment involved protein precipitation for plasma and dilution of urine samples using acetonitrile-methanol (50:50, v/v). Final extracts were injected onto a SunFire C18 column and gradient elution using 20mM ammonium acetate (mobile phase A) and formic acid:acetonitrile:methanol (0.1:50:50, v/v/v) (mobile phase B) was applied. Detection was performed on an API5500 tandem mass spectrometer operating in the positive electrospray ionisation mode applying multiple reaction monitoring (MRM). The assay was successfully validated in accordance with the Food and Drug Administration and latest European Medicines Agency guidelines on bioanalytical method validation and can therefore be applied in pharmacological clinical studies.

Cyclophosphamide (CP) is widely used in high-dose chemotherapy regimens in combination with thioTEPA. CP is a prodrug and is activated by cytochrome P450 to 4-hydroxycyclophosphamide (HCP) which yields the final cytotoxic metabolite phosphoramide mustard (PM). The metabolism of CP into HCP exhibits autoinduction but is inhibited by thioTEPA. The aim of this study was to develop a population pharmacokinetic model for the bioactivation route of CP incorporating the phenomena of both autoinduction and the drug-drug interaction between CP and thioTEPA. Plasma samples were collected from 34 patients who received high-dose CP, thioTEPA and carboplatin in short infusions during 4 consecutive days. Elimination of CP was described by a noninducible route and an inducible route leading to HCP. The latter route was mediated by a hypothetical amount of enzyme. Autoinduction leads to a zero-order increase in amount of this enzyme during treatment. Inhibition by thioTEPA was modeled as a reversible, competitive, concentration-dependent inhibition. PM pharmacokinetics were described by first-order formation from HCP and first-order elimination. The final models for CP, HCP, and PM provided an adequate fit of the experimental data. The volume of distribution, noninducible and initial inducible clearances of CP were 31.0 L, 1.58 L/hr and 4.76 L/hr, respectively. The enzyme amount increased with a zero-order rate constant of 0.041 amount * hr-1. After each thioTEPA infusion, however, approximately 80% of the enzyme was inhibited. This inhibition was reversible with a half-life of 6.5 hr. The formation and elimination rate constants of PM were 1.58 and 0.338 hr-1, respectively. The developed model enabled the assessment of the complex pharmacokinetics of CP in combination with thio TEPA. This model provided an adequate description of enzyme induction and inhibition and can be used for treatment optimization in this combination

To study the population pharmacokinetics of thioTEPA and its main metabolite TEPA in patients receiving high-dose chemotherapy consisting of thioTEPA (80-120 mg x m(-2) x day(-1)), cyclophosphamide (1000-1500 mg x m(-2) x day(-1)) and carboplatin (265-400 mg x m(-2) x day(-1)) for 4 days. ThioTEPA and TEPA kinetic data were processed with a two-compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The influence of patient characteristics on the pharmacokinetics was also determined. A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of thioTEPA (CL) was 34 l x h(-1) with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of thioTEPA was 47 l (IIV = 7.5%; IOV = 19%). The fraction of thioTEPA converted to TEPA divided by the volume of distribution of TEPA was 0.030 l-1 (IIV = 39%; IOV = 32%) and the elimination rate constant of TEPA was 0.64 h(-1) (IIV = 27%; IOV = 32%). CL of thioTEPA was correlated with alkaline phosphatase and serum albumin. The volume of distribution of thioTEPA and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively. A model for the description of the pharmacokinetics of thioTEPA and TEPA was developed. Factors involved in the interpatient variability of thioTEPA and TEPA pharmacokinetics were identified. Since, IOV of both thioTEPA and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model