Pharmacokinetics of Midazolam in preterm neonates with an insight in brain Tissue: A PBPK approach.

Physiological maturity is a gradual process taking place throughout infancy and childhood. Though for years anatomical growth has been the basis for dose calculation in pediatric population, physiological immaturity can-not be overlooked especially in neonates. The potential difference in physiology can significantly affect the outcomes of treatment and may result in under dosing or over-dosage.

Sex-Related Differences in Drugs with Anti-Inflammatory Properties.

There is increasing evidence of sex differences in the action of anti-inflammatory drugs, with women being at significantly higher risk of adverse effects. Nevertheless, clinicians' awareness of the implications of these sex differences on dosing and adverse event monitoring in routine practice is still in need of improvement. We reviewed the literature evaluating sex differences in terms of pharmacokinetics and pharmacodynamics of anti-inflammatory drugs.

Sex-Related Differences in Pharmacokinetics and Pharmacodynamics of Frequently Prescribed Drugs: A Review of the Literature.

While there is considerable evidence about sex-related differences between men and women in drug metabolism, efficacy and safety of frequently prescribed drugs such as analgesics, tranquillizers, statins and beta-blockers, clinicians' awareness of the implications on dosing and adverse event monitoring in routine practice is inadequate. Some drugs are more effective in men than women (e.g.

WB-PBPK approach in predicting zidovudine pharmacokinetics in preterm neonates.

Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically.

Enzyme and Transporter Kinetics for CPT-11 (Irinotecan) and SN-38: An Insight on Tumor Tissue Compartment Pharmacokinetics Using PBPK.

Background: Computational tools are becoming more and more powerful and comprehensive as compared to past decades in facilitating pharmaceutical, pharmacological and clinical practice. Anticancer agents are used either as monotherapy or in combination therapy to treat malignant conditions of the body. A single antineoplastic agent may be used in different types of malignancies at different doses according to the stage of the disease.

Hepatic arterial infusion of irinotecan and EmboCept S results in high tumor concentration of SN-38 in a rat model of colorectal liver metastases.

Intraarterial chemotherapy for colorectal liver metastases (CRLM) can be applied alone or together with embolization particles. It remains unclear whether different types of embolization particles lead to higher intratumoral drug concentration. Herein, we quantified the concentrations of CPT-11 and its active metabolite SN-38 in plasma, liver and tumor tissue after hepatic arterial infusion (HAI) of irinotecan, with or without further application of embolization particles, in a rat model of CRLM.

Phase Ib trial combining capecitabine, erlotinib and bevacizumab in pancreatic adenocarcinoma - REBECA trial.

Background Purpose of this phase Ib trial was to establish the maximum tolerable dose (MTD) of capecitabine and to escalate the dosages of erlotinib and bevacizumab to determine the recommended phase II dose (RP2D) in patients with advanced/metastatic pancreatic adenocarcinoma not pretreated for metastatic disease. Methods Starting doses were capecitabine 500 mg/m bid orally continuously, erlotinib 100 mg orally daily, and bevacizumab 5 mg/kg intravenously q 2 weeks. Dose escalation was performed according to a 3 + 3 design for capecitabine until MTD, for erlotinib and bevacizumab until the maximum doses registered by applying a substance-related, toxicity-based scheme accompanied by pharmacokinetic analysis.

Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model.

Purpose: In this study, a therapeutic drug monitoring (TDM) of erlotinib in pancreatic cancer patients was performed over 50 weeks to reveal possible alterations in erlotinib plasma concentrations. Additionally, a physiologically based pharmacokinetic (PBPK) model was created to assess such variations in silico.

Methods: Patients with advanced pancreatic cancer received a chemotherapeutic combination of 100 mg erlotinib q.

Zytoprotektion mit Amifostin (Ethyol) in der Chemotherapie: Meta-Analyse zum pharmakokinetischen Interaktionspotential mit Zytostatika.

The cytoprotective agent amifostine (AMI) is capable to protect healthy cells (contrary to tumor cells) due to higher activity of alkaline phosphatase at the membrane site of normal cells. In seven clinical trials the influence of AMI on the pharmacokinetics of different cytostatics was investigated. Preadministration of AMI increased Cmax of doxorubicin (+ 44 %, p < 0.

Physiologically based pharmacokinetic modeling for predicting irinotecan exposure in human body.

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents.

Systemic side effects of eye drops: a pharmacokinetic perspective.

When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amounts can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye. Furthermore, the concentration of active ingredients in such medicinal preparations is usually very high, so that despite the correct application of the recommended dose, considerable amounts may be absorbed in an unwanted manner through various routes. Children are subject to a much higher risk of systemic side effects because ocular dosing is not weight adjusted and physiological development (eg, liver status) differs from that of adults.

Assessment of Pharmacokinetic Interaction Between Capecitabine and Cetuximab in Metastatic Colorectal Cancer Patients.

Aim: This study focuses on the plasma disposition and metabolic activation of capecitabine (CCB) when administered alone or when combined with cetuximab (CTX).

Patients And Methods: Twenty-four chemo-naïve patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone (1,000 mg/m(2) bid p.o.

A simple method for comparing enzymatic capecitabine activation in various mono- and combination chemotherapies.

Before being able to develop a pharmacodynamic effect, a number of drugs have to be activated by enzymes, which are known to be potentially influenced by manifold factors, leading to a possible alteration of their activity behaviour. Based on capecitabine, we report a simple and rapid method for the estimation and comparison of the so-called 'apparent enzyme activity' (R), not only intra- (different dose levels) but also inter-schedule, to contribute to therapeutic success. Dividing the area under the curve (AUC) of the product by the AUC of the precursor generates a factor which indicates the apparent activity of the enzyme involved in the biotransformation of a compound.

Clinical pharmacokinetics of capecitabine and its metabolites in combination with the monoclonal antibody bevacizumab.

Aim: Capecitabine, designed as a pro-drug to the cytotoxic agent 5-fluorouracil, is widely used in the management of colorectal cancer. This study was designed to investigate whether co-administration of the monoclonal antibody bevacizumab (BVZ) shows potential to modulate the plasma disposition of capecitabine (CCB) and its metabolites.

Patients And Methods: Nine patients treated with CCB and BVZ for advanced colorectal cancer entered this pharmacokinetic study.

Impact of co-administered drugs on drug monitoring of capecitabine in patients with advanced colorectal cancer.

Background: Drug monitoring is a useful tool for obtaining detailed information about the disposition of a drug in an individual patient during chemotherapy. According to the international guidelines, the analytical assay for quantification of a compound in biological samples must be validated. Among a number of parameters, peak purity is an important requirement.

Validation of a simple assay for the quantification of the capecitabine metabolites 5'-DFCR and 5'-DFUR for drug monitoring in patients receiving outpatient chemotherapy.

A simple and precise analytical method for the determination of 5'deoxy-5-fluorocytidine (DFCR) and 5'deoxy-5-fluorouridine (DFUR), the enzymatically formed metabolites of capecitabine in plasma, was developed using a reversed-phase high performance liquid chromatography gradient method with external standard method. Blood samples were analyzed after separation of DFCR/DFUR by solid-phase extraction from matrix compounds using a C16 amide reversed-phase column operated at a flow rate of 0.8 ml/min in gradient elution mode with a mobile phase composed of water-methanol (10 mM ammonium acetate in water; m/v).

A rapid and simple HPLC assay for quantification of capecitabine for drug monitoring purposes.

Aim: Capecitabine, a 5-fluorouracil prodrug, has been integrated into the management of multiple cancer types. In order to obtain information about plasma levels of capecitabine in patients who had drug intake at home during chemotherapy, a simple HPLC method for capecitabine monitoring has been developed and validated.

Patients And Methods: Capecitabine levels were quantified by a simple reversed-phase HPLC system with an external standard method.

Pharmacokinetics of irinotecan in combination with biweekly cetuximab in patients with advanced colorectal cancer.

Background: The effect of biweekly cetuximab (CTX) on the pharmacokinetics of CPT-11 and its metabolites was evaluated in this prospective, paired, crossover study.

Patients And Methods: Patients with epidermal growth factor receptor-positive advanced colorectal cancer received infusions of CPT-11 (180 mg/m(2); FOLFIRI schedule) every second week. CTX (500 mg/m(2) for 120 min) was infused on day 2, followed by biweekly infusions (500 mg/m(2) for 120 min).

Plasma disposition of capecitabine and its metabolites 5'DFCR and 5'DFUR in a standard and dose-intensified monotherapy regimen.

Purpose: In view of a potential gain in anticancer activity in advanced colorectal cancer (ACRC), there has been considerable interest in using a higher than the approved standard dose of capecitabine (CCB) combined with oxaliplatin. This pharmacokinetic study was designed to evaluate whether CCB is metabolized at the same extent when administered as a monotherapy in two different dose regimens, comparing standard dose (CCB 1) and intensified dose (CCB 2).

Patients And Methods: Seven patients suffering from ACRC received subsequently two CCB schedules: In the standard schedule, 1,250 mg/m² CCB p.

[Pharmaceutical aspects of clinical trials: concepts of pharmacokinetic investigations].

Pharmacokinetic investigations of a drug - and of its pharmacologically active metabolite, if necessary - represent an essential part of clinical trials. The European Union (EMEA, European Medicines Agency) strictly regulates the separation and quantification of a drug from biological matrix, e.g.

Pharmacokinetics and metabolism of irinotecan combined with capecitabine in patients with advanced colorectal cancer.

Background: Irinotecan (CPT-11) in combination with 5-fluorouracil/folinic acid is used successfully for first-line treatment of metastatic colorectal cancer. Capecitabine (CCB) represents a very convenient alternative to 5-fluorouracil, either as single agent or in a combination of regimens acting synergistically and with the potential to further improve efficacy. Both CPT-11 and CCB need to be activated by human carboxyl esterases, therefore a probable pharmacokinetic drug interaction was checked.

Pharmacokinetics of gemcitabine combined with trastuzumab in patients with advanced breast cancer.

Background: Combining the monoclonal antibody trastuzumab (TMAB) with chemotherapy is a new strategy in treatment of advanced breast cancer in HER+++ overexpressing patients.

Patients And Methods: The disposition of gemcitabine has been investigated in 8 breast cancer patients (prospective cross-over design). Gemcitabine was administered as a 30-min i.