Overestimation of the effect of (fos)aprepitant on intravenous dexamethasone pharmacokinetics requires adaptation of the guidelines for children with chemotherapy-induced nausea and vomiting.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking.

A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children.

Introduction: Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment.

ABCB1 and ABCG2 limit brain penetration and, together with CYP3A4, total plasma exposure of abemaciclib and its active metabolites.

Abemaciclib is the third cyclin-dependent kinase (CDK) 4/6 inhibitor approved for the treatment of breast cancer and currently under investigation for other malignancies, including brain cancer. Primarily CYP3A4 metabolizes abemaciclib, forming three active metabolites (M2, M20 and M18) that are likely relevant for abemaciclib efficacy and toxicity. We investigated the impact of ABCB1 (P-gp), ABCG2 (BCRP) and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its metabolites using genetically modified mice.

Simultaneous quantification of abemaciclib and its active metabolites in human and mouse plasma by UHPLC-MS/MS.

Abemaciclib is the third cyclin-dependent kinase 4 and 6 inhibitor approved for the treatment of advanced or metastatic breast cancer. In humans, abemaciclib is extensively metabolized by CYP3A4 with the formation of three active metabolites: N-desethylabemaciclib (M2), hydroxyabemaciclib (M20) and hydroxy-N-desethylabemaciclib (M18). These metabolites showed similar potency compared to the parent drug and were significantly abundant in plasma circulation.

Development and validation of a combined liquid chromatography tandem-mass spectrometry assay for the quantification of aprepitant and dexamethasone in human plasma to support pharmacokinetic studies in pediatric patients.

A pharmacokinetic study was set up to investigate the pharmacokinetics of the anti-emetic agents aprepitant and dexamethasone and the drug-drug interaction between these drugs in children. In order to quantify aprepitant and dexamethasone, a liquid chromatography-tandem mass spectrometry assay was developed and validated for the simultaneous analysis of aprepitant and dexamethasone. Protein precipitation with acetonitrile-methanol (1:1, v/v) was used to extract the analytes from plasma.

Development and validation of an LC-MS/MS method for the quantitative analysis of milciclib in human and mouse plasma, mouse tissue homogenates and tissue culture medium.

Milciclib is a promising cyclin-dependent kinase inhibitor currently in phase II clinical trials to treat several types of cancer. The first bioanalytical method for the quantitative analysis of milciclib in several biomatrices using liquid chromatography-tandem mass spectrometry is described here. This method was fully validated in human plasma according to FDA and EMA guidelines, and partially validated in mouse plasma, homogenates of mouse brain, kidney, liver, small intestine, spleen, and tissue culture medium.

A phase 0 clinical trial of novel candidate extended-release formulations of capecitabine.

Purpose: To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients.

Methods: In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2.

A sensitive assay for the quantitative analysis of vinorelbine in mouse and human EDTA plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry.

A sensitive, specific and fast high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) assay for the determination of vinorelbine in mouse and human plasma is presented. A 200 microL aliquot was extracted with solid-phase extraction (SPE) using Bond-Elut C(2) cartridges. Dried extracts were reconstituted in 100 microL 1 mM ammonium acetate pH 10.

Determination of ruthenium originating from the investigational anti-cancer drug NAMI-A in human plasma ultrafiltrate, plasma, and urine by inductively coupled plasma mass spectrometry.

We present a highly sensitive, rapid method for the determination of ruthenium originating from the investigational anti-cancer drug NAMI-A in human plasma ultrafiltrate, plasma, and urine. The method is based on the quantification of ruthenium by inductively coupled plasma mass spectrometry and allows quantification of 30 ng L(-1) ruthenium in plasma ultrafiltrate and urine, and 75 ng L(-1) ruthenium in human plasma, in 150 microL of matrix. The sample pretreatment procedure is straightforward and only involves dilution with appropriate diluents.

Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions.

The antifolate drug methotrexate (MTX) is transported by breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated protein1-4 (MRP1-4; ABCC1-4). In cancer patients, coadministration of benzimidazoles and MTX can result in profound MTX-induced toxicity coinciding with an increase in the serum concentrations of MTX and its main metabolite 7-hydroxymethotrexate. We hypothesized that benzimidazoles interfere with the clearance of MTX and/or 7-hydroxymethotrexate by inhibition of the ATP-binding cassette drug transporters BCRP and/or MRP2, two transporters known to transport MTX and located in apical membranes of epithelia involved in drug disposition.

Quantitative analysis of D-24851, a novel anticancer agent, in human plasma and urine by liquid chromatography coupled with tandem mass spectrometry.

The development of a liquid chromatography/tandem mass spectrometric assay for the quantitative analysis of the novel tubulin inhibitor D-24851 in human plasma and urine is described. D-24851 and the deuterated internal standard were extracted from 250 microL of plasma or urine using hexane/ether (1:1, v/v). Subsequently, 10-microL aliquots of reconstituted extracts were injected onto an Inertsil ODS analytical column (50 x 2.

Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulated dosage form of cisplatin.

Purpose: To investigate the safety and pharmacokinetics of a new liposomal formulation of cisplatin, SPI-77, in patients with advanced malignancies.

Patients And Methods: Patients with histologically proven malignancies not amenable to other treatment were eligible for this study. The starting dose of SPI-77 (cisplatin in Stealth liposomes) was 40 mg/m(2) administered every 4 weeks in a 2-h infusion, and doses were escalated up to 420 mg/m(2).