Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure.

The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal and plasma compartments using NONMEM software.

Pharmacokinetically based estimation of patient compliance with oral anticancer chemotherapies: in silico evaluation.

Background And Objectives: More and more anticancer chemotherapies are now available as oral formulations. This relatively new route of administration in oncology leads to problems with patient education and non-compliance. The aim of this study was to explore the performances of the 'inverse problem', namely, estimation of compliance from pharmacokinetics.

[Pharmacology of anticancer drugs in the elderly: tools for dose-adjustment].

Life expectancy increasing and cancer incidence rising with age, geriatric and cancer care will become a significant medical, public health, challenge. It is possible that the lack of efficacy of cancer therapies in the elderly may simply be due to the fact that physicians reduce anticancer drug doses empirically, in order to avoid "putative" toxicities that might arise as a result of alterations of physiological functions or as a result of co-morbidities generally present within this population. However, many authors have demonstrated that some patients over 70 years old could tolerate and obtain same benefit from therapies as younger adults, when some who are frail need less aggressive therapies.

Etoposide pharmacokinetics and survival in patients with small cell lung cancer: a multicentre study.

Purpose: To investigate the prognostic value of systemic exposure to etoposide (Area Under the concentration Curve (AUC(VP16))) on overall survival (OS) in patients with small cell lung cancer (SCLC).

Patients And Methods: Data from 52 patients with limited stage (n=17) or metastatic (n=35) SCLC were analysed. They received at least two courses of etoposide (120mg/(m(2)day) on 3 days) combined with either doxorubicin-ifosfamide (AVI, n=29) or platinum compounds (carboplatin: n=16; cisplatin: n=7).

Advantages of prostate-specific antigen (PSA) clearance model over simple PSA half-life computation to describe PSA decrease after prostate adenomectomy.

Objectives: A population kinetic approach based on PSA clearance (CL(PSA)) may be a more rational strategy to characterize prostate-specific antigen (PSA) decrease profile after prostate surgery than the commonly used method (half-life from mono/bi-exponential models).

Methods: We used 182 post-adenomectomy PSA concentrations from 56 benign prostatic hyperplasia patients to build, with NONMEM software, a multi-exponential and a CL(PSA) model for comparison.

Results: The best multi-exponential model was PSA(t)=4.

Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG.

Aims: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients.

Patients And Methods: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling.

Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group.

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.

[Issues of the study of patient compliance to treatment with oral anticancer chemotherapy: advantages of pharmacokinetics-pharmacodynamics modelisation].

Nowadays, more and more oral anticancer chemotherapies are developed either for cytotoxic or new targeted drugs. But this relatively new route of administration in oncology drives to new problems in treatment management and particularly to non-compliance, i.e.

International Society of Geriatric Oncology Chemotherapy Taskforce: evaluation of chemotherapy in older patients--an analysis of the medical literature.

The elderly comprise the majority of patients with cancer and are the recipients of the greatest amount of chemotherapy. Unfortunately, there is a lack of data to make evidence-based decisions with regard to chemotherapy. This is due to the minimal participation of older patients in clinical trials and that trials have not systematically evaluated chemotherapy.

Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease.

Background And Objective: Inolimomab, a monoclonal antibody against interleukin (IL)-2Ralpha (CD25) has shown promising results in the treatment of corticosteroid-resistant acute graft-versus-host disease (GvHD). The objective of the present study was to characterise the pharmacokinetic and pharmacodynamic properties of inolimomab as first-line treatment in this condition.

Methods: The data came from 21 patients with acute GvHD (8 with an International Bone Marrow Transplant Registry [IBMTR] score of B, 11 with a score of C and 2 with a score of D) following haematopoietic stem cell transplantation after a median delay of 26 days (range 10-127 days).

Contribution of modelling chemotherapy-induced hematological toxicity for clinical practice.

Anticancer chemotherapies are responsible for numerous adverse events. Among these, hematological toxicity is one of the main causes for ending treatment. These toxicities decrease production of red blood cells (anemia), production of white blood cells (neutropenia or granulocytopenia), and production of platelets (thrombocytopenia), which may be life-threatening to the patient.

Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004.

Model evaluation is an important issue in population analyses. We aimed to perform a systematic review of all population pharmacokinetic and/or pharmacodynamic analyses published between 2002 and 2004 to survey the current methods used to evaluate models and to assess whether those models were adequately evaluated. We selected 324 articles in MEDLINE using defined key words and built a data abstraction form composed of a checklist of items to extract the relevant information from these articles with respect to model evaluation.

Evaluation of uncertainty parameters estimated by different population PK software and methods.

The uncertainty associated with parameter estimations is essential for population model building, evaluation, and simulation. Summarized by the standard error (SE), its estimation is sometimes questionable. Herein, we evaluate SEs provided by different non linear mixed-effect estimation methods associated with their estimation performances.

Therapeutic drug monitoring for dose individualization of Cisplatin in testicular cancer patients based upon total platinum measurement in plasma.

Cisplatin (CDDP) is an anticancer agent widely used in testicular cancer, for which pharmacokinetic (PK)/pharmacodynamic relationships have usually been based upon measurement of its unbound fraction in plasma. Because it has been shown that free CDDP clearance can be related to patient's body surface area (BSA), dosage is mostly adjusted a priori using only this single parameter, with mixed results for accurately predicting CDDP exposure and reducing toxicities. In contrast, the authors present here an original, 5-day continuous infusion schedule, coupled to a daily Bayesian adaptive dosing with feedback strategy, based upon the rapid assay of total, rather than free, CDDP in plasma.

Dose individualization of carboplatin after a 120-hour infusion schedule: higher dose intensity but fewer toxicities.

Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance: Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy.

Pharmacology of cytotoxic agents: a helpful tool for building dose adjustment guidelines in the elderly.

Aging is associated with multidimensional changes, including alterations in physiological functions, co-morbidities and poly-medications. These changes may lead to modifications in the absorption, distribution, metabolism and excretion of drugs. The lack of a scientific basis for optimal drug dosing in the elderly is a major problem.

Intermediate-dose (25mg/m2) IV melphalan for multiple myeloma with renal failure.

Background: Multiple myeloma is a malignant plasma cell disorder which still bears a dramatic prognosis. Renal insufficiency is a frequent and severe complication directly related to prognosis. The aim of our study was to establish whether an intermediate dose of intravenous melphalan, 25 mg/m2, could be safely and efficiently administered to patients with multiple myeloma and renal impairment.

A simultaneous oral/intravenous population pharmacokinetic model for vinorelbine.

Objectives: To develop a population pharmacokinetic (PK) model for simultaneous analysis of oral and intravenous data, to compare the variability between the two routes of administration of vinorelbine, to search for the main patient characteristics that explain this variability, and to estimate the mean population bioavailability of oral vinorelbine.

Patients And Methods: A PK model was developed from 175 phase I/II patients (419 courses) treated by intravenous (20-45 mg/m2) and/or oral (60-100 mg/m2) vinorelbine given as monotherapy. Oral and intravenous PK data were simultaneously fitted using the NONMEM program, allowing the estimation of oral PK parameters such as the bioavailability factor in patients who received only the oral formulation.

Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials.

Aims: a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters.

Methods: All data were collected from 64 patients (99 courses) entered in three different phase I trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20-45 mg m-2.