A phase Ib/II study of regorafenib and paclitaxel in patients with beyond first-line advanced esophagogastric carcinoma (REPEAT).

Purpose: Regorafenib monotherapy, a multikinase inhibitor of angiogenesis, tumor microenvironment, and tumorigenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in patients with advanced esophagogastric cancer (EGC) refractory to first-line treatment, and explore potential biomarkers.

Methods: Patients received paclitaxel (80 mg/m) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on days 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort.

A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with -Mutated Solid Tumors.

Background: Mutations in isocitrate dehydrogenase 1 () occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid -mutated tumors produce the oncometabolite -2-hydroxyglutarate (-2HG) and are more vulnerable to disruption of their metabolism.

Methods: Patients with -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine.

Efficacy of dashboard driven dosing of infliximab in inflammatory bowel disease patients; a randomized controlled trial.

Objectives: Loss of response (LOR) to infliximab (IFX) remains a challenge in the management of inflammatory bowel diseases (IBD). Proactive dosing strategies to achieve and maintain predefined IFX trough levels (TL) may prevent LOR. We aimed to investigate the efficacy of dashboard driven IFX dosing compared to standard dosing in a prospective trial in IBD patients.

Pharmacokinetics of golimumab in moderate to severe ulcerative colitis: the GO-KINETIC study.

Golimumab (GLM) is approved for the treatment of moderate to severe ulcerative colitis (UC). Higher serum concentrations of anti-tumor necrosis factor (TNF) agents are associated with improved clinical and endoscopic outcomes. Correlations between GLM serum concentrations and clinical and endoscopic outcomes were investigated during induction and maintenance treatment.

Pharmacokinetic-guided dosing of factor VIII concentrate in a morbidly obese severe haemophilia A patient undergoing orthopaedic surgery.

A 58-year-old morbidly obese male (body mass index: 38 kg/m) with severe haemophilia A underwent total knee replacement surgery. Perioperatively, factor VIII (FVIII) levels were measured daily and maximum (MAP) Bayesian estimation was used to calculate the individual pharmacokinetic (PK) parameters and doses required to obtain prescribed FVIII target levels. In the MAP Bayesian procedure, a population PK model was used in which PK parameters were normalised using body weight.

An effective modestly intensive re-induction regimen with bortezomib in relapsed or refractory paediatric acute lymphoblastic leukaemia.

This trial explored the efficacy of re-induction chemotherapy including bortezomib in paediatric relapsed/refractory acute lymphoblastic leukaemia. Patients were randomized 1:1 to bortezomib (1.3 mg/m /dose) administered early or late to a dexamethasone and vincristine backbone.

Explaining Interpatient Variability in Adalimumab Pharmacokinetics in Patients With Crohn's Disease.

Background: A significant proportion of patients with Crohn's disease (CD) require dose escalation or fail adalimumab (ADL) therapy over time. ADL, a monoclonal antibody directed against tumor necrosis factor, is approved for treatment of CD. Understanding pharmacokinetics (PK) of ADL is essential to optimize individual dosing in daily practice.

Therapeutic Drug Monitoring of Gentamicin Peak Concentrations in Critically Ill Patients.

Background: Adequate gentamicin peak concentrations (Cmax) are important for optimal clinical efficacy. Within a critically ill patient, substantial variability in Cmax can occur over time, hampering the usefulness of therapeutic drug monitoring (TDM). The aim of this study was to evaluate the effect of gentamicin dosing based on Cmax after the first dose on gentamicin target attainment in critically ill patients.

A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme.

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with -mutated or -mutated solid tumours.

Introduction: High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes and (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma.

Golimumab for moderate to severe ulcerative colitis.

Golimumab (GLM) is a subcutaneously administered human anti-tumor necrosis factor (TNF) agent that has been approved by the regulatory authorities for the treatment of moderate to severe ulcerative colitis (UC) in 2013. Areas covered: Maintained clinical remission rates up to 50% have been shown in UC patients receiving GLM, and higher GLM serum concentrations have been associated with improved clinical outcomes. Approximately 50% of UC patients do not respond to induction therapy with GLM, and up to 40% of GLM responders will lose response over time.

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L).

Quantitative Method for Simultaneous Analysis of Acetaminophen and 6 Metabolites.

Background: Hepatotoxicity after ingestion of high-dose acetaminophen [N-acetyl-para-aminophenol (APAP)] is caused by the metabolites of the drug. To gain more insight into factors influencing susceptibility to APAP hepatotoxicity, quantification of APAP and metabolites is important. A few methods have been developed to simultaneously quantify APAP and its most important metabolites.

Determinants of gentamicin concentrations in critically ill patients: a population pharmacokinetic analysis.

When treating critically ill patients with gentamicin for severe infection, peak concentrations (C) determine clinical efficacy and trough concentrations (C) determine toxicity. Despite administration of body weight-standardised starting doses, a wide range of C is generally observed. Furthermore, in therapeutic drug monitoring, several measures of renal function are used to predict appropriate C and gentamicin dosing intervals, but the most accurate predictor is not known.

Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria.

The aim of this study was to describe the population pharmacokinetics (PK) of gentamicin in neonates with suspected or proven Gram-negative sepsis and determine the optimal dosage regimen in relation to the bacterial MICs found in this population. Data were prospectively collected between October 2012 and January 2013 in the Neonatal Intensive Care Unit (NICU) at the Academic Medical Center (AMC), Amsterdam, The Netherlands. A single nonlinear mixed-effects regression analysis (NONMEM) was performed to describe the population PK of gentamicin.

Quantitative Method for Simultaneous Analysis of a 5-Probe Cocktail for Cytochrome P450 Enzymes.

Background: The metabolic activity of P450 enzymes in vivo can be determined using selective probe drugs. The simultaneous administration of multiple CYP-specific probe drugs is commonly known as the "cocktail approach." Disadvantages of a cocktail are large volumes of samples required for analysis and time-consuming analyses.

Pharmacokinetic-guided dosing of factor VIII concentrate in a patient with haemophilia during renal transplantation.

A 29-year-old man with severe haemophilia A and end-stage renal disease underwent a renal transplantation. To prevent bleeding, patient was treated with replacement therapy using factor VIII (FVIII) concentrate, according to National guidelines. Bayesian analysis was performed by combining observed FVIII concentrations with a population pharmacokinetic (PK) model for patients with severe haemophilia A in a perioperative setting.

Pharmacodynamics and Pharmacokinetics of Morphine After Cardiac Surgery in Children With and Without Down Syndrome.

Objective: To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome.

Design: Prospective, single-center observational trial.

Setting: PICU in a university-affiliated pediatric teaching hospital.

Prevalence and Implications of Abnormal Laboratory Results in Patients in the Terminal Phase of Life.

Background: Pathophysiological changes at the end of life may affect pharmacokinetics of drugs. However, caregivers typically do not extensively monitor patients' laboratory parameters at the end of life.

Objective: Our aim was to describe laboratory parameters of hospice patients in the week before death.

A short-term high fat diet increases exposure to midazolam and omeprazole in healthy subjects.

Objectives: Knowledge of factors contributing to variation in drug metabolism is of vital importance to optimize drug treatment. This study assesses the effects of a short-term hypercaloric high fat diet on metabolism of five oral drugs, which are each specific for a single P450 isoform: midazolam (CYP3A4), omeprazole (CYP2C19), metoprolol (CYP2D6), S-warfarin (CYP2C9) and caffeine (CYP1A2).

Methods: In 9 healthy volunteers, pharmacokinetics of the five drugs were assessed after an overnight fast at two separate occasions: after a regular diet and after 3 days of a hypercaloric high fat diet (i.

The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients.

Background: The aim of this study was to develop a population pharmacokinetic model of tacrolimus in paediatric patients at least 1 year after renal transplantation and simulate individualised dosage regimens.

Patients And Methods: We included 54 children with median age of 11.1 years (range 3.

Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia.

Aim(s): Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients

Methods: Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin.

Pharmacokinetics of Morphine, Morphine-3-Glucuronide and Morphine-6-Glucuronide in Terminally Ill Adult Patients.

Background And Objective: Morphine dosing can be challenging in terminally ill adult patients due to the heterogeneous nature of the population and the difficulty of accurately assessing pain during sedation. To determine the pharmacokinetics of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in this population, and to find clinically relevant parameters for dose individualisation, we performed a population pharmacokinetic analysis.

Methods: Blood samples were randomly collected from 47 terminally ill patients in both the pre-terminal and terminal phases.

Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis.

Background & Aims: The pharmacokinetics of infliximab during induction treatment for ulcerative colitis (UC) have not been studied. We investigated serum concentrations of infliximab and the early appearance of antibodies to infliximab (ATI) during induction treatment in patients with moderate-to-severe UC.

Methods: We performed a prospective analysis of 19 consecutive patients with moderate-severe UC (endoscopic Mayo ≥ 2) receiving induction therapy with infliximab (5 mg/kg at weeks 0, 2, and 6) at 2 centers in Amsterdam, The Netherlands, from July 2012 through March 2014.