Correction: A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics (PLoS ONE (2016) 11:9 (e0162866) DOI: 10.1371/journal.pone.0162866)

The thirty-Third author's name is spelled incorrectly. The correct name is: Jadranka Sertić

Bioanalytical methods for the quantification of hydromorphone, fentanyl, norfentanyl, morphine, morphine-3ss-glucuronide and morphine-6ss-glucuronide in human plasma

The aim of this study was to develop an assay for the quantification of hydromorphone, morphine, fentanyl and the metabolites norfentanyl, morphine-3ss-glucuronide and morphine-6ss-glucuronide in human plasma to support pharmacokinetic studies investigating the large interpatient variability in response to opioid treatment. For the quantitation of hydromorphone, morphine, fentanyl and its metabolite norfentanyl aliquots of 200muL human potassium EDTA plasma were deproteinized with deuterated internal standards in a mixture of acetonitrile and acetone, followed by a liquid-liquid extraction with 4% ammonium hydroxide and ethyl acetate. Morphine-3ss-glucuronide and morphine-6ss-glucuronide were extracted by a solid phase extraction using 10mM ammonium carbonate pH 8.8 and a deuterated internal standards solution. Morphine, hydromorphone, fentanyl and norfentanyl were separated on an Aquity UPLC((R)) BEH C18 column 1.7mum, 100mmx2.1mm at 50 degrees C. Separation, was achieved on a gradient of methanol with an overall run time of 6min. The compounds were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. Morphine-3ss-glucuronide and morphine-6ss-glucuronide were separated on a VisionHT C18-P; 3mum 2.1x50mm, column at 40 degrees C on a gradient of acetonitrile, with an overall run time of 10min. Both methods were precise and accurate, with within-run and between-run precisions within acceptable limits and accuracy ranging from 84.0 to 105.5%. The methods were successfully applied to support clinical pharmacological studies in patients treated with opioids for the treatment of moderate to severe cancer-related pain

A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients

Fentanyl is a strong opioid that is available for various administration routes, and which is widely used to treat cancer-related pain. Many factors influence the fentanyl pharmacokinetics leading to a wide inter- and intrapatient variability. This systematic review summarizes multiple studied factors that potentially influence fentanyl pharmacokinetics with a focus on implications for cancer patients. The use of CYP3A4 inhibitors and inducers, impaired liver function, and heating of the patch potentially influence fentanyl pharmacokinetics in a clinically relevant way. In elderly patients, current data suggest that we should carefully dose fentanyl due to alterations in absorption and metabolism. The influence of BMI and gender on fentanyl pharmacokinetics is questionable, most probably due to a large heterogeneity in the published studies. Pharmacogenetics, e.g. the CYP3A5*3 gene polymorphism, may influence fentanyl pharmacokinetics as well, although further study is warranted. Several other factors have been studied but did not show significant and clinically relevant effects on fentanyl pharmacokinetics. Unfortunately, most of the published papers that studied factors influencing fentanyl pharmacokinetics describe healthy volunteers instead of cancer patients. Results from the studies in volunteers may not be simply extrapolated to cancer patients because of multiple confounding factors. To handle fentanyl treatment in a population of cancer patients, it is essential that physicians recognize factors that influence fentanyl pharmacokinetics, thereby preventing potential side-effects and increasing its efficacy

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Contains fulltext : 203020.pdf (publisher's version ) (Open Access

Response to letter entitled re: UGT1A1 genotype-guided dosing of irinotecan: A prospective safety and cost analysis in poor metaboliser patients Is it time for everyone treated with irinotecan to be tested for UGT1A1 gene polymorphism?

Personalised Therapeutic

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

Contains fulltext : 232078.pdf (Publisher’s version ) (Open Access)Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day- 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours

Contains fulltext : 136010.pdf (publisher's version ) (Open Access)Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade 3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg.Results:Twenty-nine out of 43 patients were evaluable for PK assessments. Grade 3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.Conclusions:In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice

Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database

Contains fulltext : 196658.pdf (publisher's version ) (Open Access)INTRODUCTION: As both anti-tumour effects and toxicity are thought to be dose-dependent, patients with the greatest toxicity may also have the best outcome. We assessed whether severity of doxorubicin-induced hematological toxicity is associated with outcome in advanced soft tissue sarcoma (STS) patients. In addition, risk factors for hematological toxicity were explored. METHODS: Worst haematological toxicities (anaemia, leukopenia, neutropenia and thrombocytopenia) seen during treatment were scored according to CTCAE toxicity score. Differences in overall survival (OS), progression free survival (PFS) and response rate (RR) between patients with or without high haematological toxicity (grades 0-2 vs. 3-4) were assessed using conventional statistical tests. Associations between baseline characteristics and hematological toxicity were established using logistic multivariate regression. RESULTS: In 557 patients eligible for this analysis, 47.2% of the patients received at least six cycles of treatment; 45% stopped treatment early due to progression, 3% because of toxicity. Relative dose intensity (RDI) was constant over the cycles. OS, PFS, and RR did not differ between patients with grade 3/4 toxicity during treatment versus those with grade 1/2. Risk factors for grade 3/4 haematological toxicity, in particular neutropenia, were age above 60 years, low BMI, and female gender. CONCLUSION: In this large series, risk factors for haematological toxicity in STS patients receiving doxorubicin monotherapy were revealed. The finding that there was no association between outcome and haematological toxicity during doxorubicin treatment may be useful to reassure advanced STS patients that failure to experience haematological toxicity during treatment does not equate to under-treatment