High Pharmacokinetic Variability Research Articles

Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs.

Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin. carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration-time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued.

Efficacy of C 2 monitoring of cyclosporine neoral in adult liver transplantation: a comparative study

THE INRODUCTION of CsA has been a major advance in transplantation. Subsequently, the development of the new formulation, Neoral microemulsion, has helped to overcome the problems associated with Sandimmune, including poor bioavailability, dependence on bile for absorption, and need for intravenous administration in the early postoperative period. The use of Neoral has resulted in better absorption and bioavailability, leading to less toxicity and a marked reduction in the incidence of acute cellular rejection. A second major advance has been the introduction of a new tool for monitoring levels of Neoral. Classical monitoring with C0 trough levels (predose) has been demonstrated to be inadequate due to high intrapatient and interpatient pharmacokinetic variability and poor correlation with the true drug exposure (AUC and Cmax). In addition, recent reviews of studies correlating pharmacokinetics with clinical outcome confirmed that C0 levels did not always correlate with the incidence of acute rejection and toxicity. By contrast, a single blood level measurement, made 2 hours after dosing (C2 or Cmax), has been shown to be a significantly more accurate predictor of drug exposure in liver transplantation recipients. Therefore, C2 level is the best marker of Neoral absorption (the best surrogate of AUC and Cmax), and is currently considered the best way to monitor Neoral cyclosporine levels. However, because sampling of C2 must be performed 2 hours ( 15 minutes) after intake, the most important problem associated with this method of drug monitoring is implementation in daily clinical practice. The purpose of this study was to evaluate the feasibility, efficacy, and safety of C2 monitoring of Neoral as compared with standard C0 levels. Feasibility was assessed in relation to problems with timing of sampling, and implementation in the ICU, ward, and laboratory. Efficacy was evaluated in terms of rate of rejection. The safety profile was compiled based on incidence of renal dysfunction.

Stereoselective Pharmacokinetics of Chlorpheniramine and the Effect of Ranitidine

This single-dose, randomized, crossover study was carried out to investigate the potential effect of ranitidine on the pharmacokinetics of chlorpheniramine. The study also afforded an, opportunity to add to the limited data currently available on the stereoselective pharmacokinetics of chlorpheniramine. Healthy subjects received a single oral 4mg dose of racemic chlorpheniramine on two separate occasions: alone, and on day 6 of dosing with ranitidine 75mg b.i.d. for 8days. Serum concentrations and urinary recovery of (S)-(+)- and (R)-( −)-chlorpheniramine were unaffected by administration of ranitidine, indicating no pharmacokinetic drug–drug interaction. The observed chlorpheniramine pharmacokinetic data were consistent with previous data and indicated approximately 2.5-fold higher serum concentrations of the (S)-(+) enantiomer. Previously reported high variability in chlorpheniramine pharmacokinetics was greatly reduced by well-controlled food and fluid intake.

125 The high pharmacokinetic variability of adriamycin, etoposide and ifosfamide among small cell lung cancer patients

125 The high pharmacokinetic variability of adriamycin, etoposide and ifosfamide among small cell lung cancer patients

Diminution du risque de rejet chronique et de variabilité de lʼabsorption avec Néoral® par rapport à Sandimmun®

The inter- and intrapatient variability in cyclosporin pharmacokinetics obfuscates the relationship between therapeutic outcome and administered dose. We defined patients with high pharmacokinetic variability and an increased risk of chronic rejection by means of serial pharmacokinetic profiling of 204 renal transplant patients treated for up to 5 years with cyclosporin doses selected to achieve a target average cyclosporin concentration (Cav). Patients were stratified into cohorts according to high versus low pharmacokinetic variability, which was based on the cut-off values of percentage coefficient of variation (%CV) of the dose-corrected Cav (Cav/mg; 35%) or 0-hour concentration (C0/mg; 53%). These values are the inflection points of curves that express the relationships between true positives (patients with high %CV and chronic rejection) versus false positives (patients with high %CV but no evidence of chronic rejection).

Cyclosporine monitoring in allogeneic bone marrow transplantation

Objective. To review the benefits and limitations of cyclosporine concentration monitoring to maximize efficacy of graft-versus-host disease prophylaxis and minimize risk of cyclosporine toxicity. Data Sources. A CANCERLIT search of articles published from 1980 to 1995, using the MESH head ings "cyclosporine," and "bone marrow transplant." References listed in the identified publications were reviewed for additional pertinent literature. Study Selection. Human clinical trials and re view articles evaluating cyclosporine pharmacokinet ics and pharmacodynamics in patients status follow ing bone marrow transplantation. Data synthesis. Cyclosporine concentration monitoring has been proposed due to the critical need for drug efficacy, substanial drug-induced toxic ity, and high pharmacokinetic variability. Selection of biological fluid (blood, serum, or plasma) for moni toring as well as the selectivity of the assay employed for cyclosporine versus its metabolites, is a critical factor in evaluating this literature. Both the relation ship between cyclosporine trough concentration and clinical outcome has been evaluated in this patient population. Conclusions. Cyclosporine trough concentra tion monitoring, especially in the blood using an assay specific for the parent compound, has a role in the care of the allogeneic bone marrow transplantation patient. Cyclosporine levels have been correlated with risk for nephrotoxicity and to a lesser extent hepatotoxicity. Low cyclosporine levels are one fac tor contributing to the risk for acute graft-versus-host disease in these patients. Proper evaluation of cyclo sporine levels with due consideration to patient spe cific factors can assist the clinician in maximizing the chances for graft-versus-host disease prevention while reducing the risk of cyclosporine side effects.

Cyclosporine monitoring in allogeneic bone marrow transplantation

Objective. To review the benefits and limitations of cyclosporine concentration monitoring to maximize efficacy of graft-versus-host disease prophylaxis and minimize risk of cyclosporine toxicity.Data Sources. A CANCERLIT search of articles published from 1980 to 1995, using the MESH head ings cyclosporine, and marrow transplant. References listed in the identified publications were reviewed for additional pertinent literature.Study Selection. Human clinical trials and re view articles evaluating cyclosporine pharmacokinet ics and pharmacodynamics in patients status follow ing bone marrow transplantation.Data synthesis. Cyclosporine concentration monitoring has been proposed due to the critical need for drug efficacy, substanial drug-induced toxic ity, and high pharmacokinetic variability. Selection of biological fluid (blood, serum, or plasma) for moni toring as well as the selectivity of the assay employed for cyclosporine versus its metabolites, is a critical factor in evaluating this literatu...

Algorithms for dosage and therapeutic monitoring of theophylline.

Theophylline is widely prescribed in Spain. Because this drug has a narrow therapeutic range and high interindividual pharmacokinetic variability, it is essential to adapt the dosage to each patient. In order to simplify the drug individualization we are proposing three algorithms to apply to intravenous loading and maintenance doses and to oral doses. The initial recommended dosages have been established using the pharmacokinetic parameters obtained from patients treated with theophylline in our hospital. Because the pharmacokinetic behavior of theophylline may be different in other populations, dosage requirements may not be the same. A minimum number of blood sample collections is proposed in an attempt to improve the cost-benefit relationship in theophylline therapy.