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Background and Objective: Drugs undergoing enterohepatic circulation (EHC) are associated with typical pharmacokinetic characteristics such as multiple-peak phenomenon in the plasma concentration-time profile and prolongation of the apparent elimination half-life (t((1/2))). Currently, versatile pharmacokinetic models are lacking that could test the hypothesis of an EHC for observed multiple-peak phenomenon in pharmacokinetic profiles and its quantitative contribution. The aim of this analysis was to accomplish a model that is able to describe typical plasma concentration-time profiles of compounds undergoing EHC using data from intravenous studies of tesofensine and meloxicam. In addition, the developed model should be able to quantify the contribution of an EHC to the pharmacokinetics by determining the influence of interrupting the EHC of tesofensine and meloxicam to various extents.Methods: Two studies were investigated retrospectively for model development and model evaluation. Twenty-one healthy subjects received a single 6-hour infusion of tesofensine (0.3, 0.6, 0.9, 1.2 mg) in a double-blind, randomized, placebo-controlled, single rising-dose study. Twelve healthy subjects were treated in a randomized, crossover study with meloxicam 30 mg as a single dose given intravenously (bolus) either alone or concomitantly with cholestyramine. The EHC model was developed based on data from the tesofensine study, where EHC is suspected. Model evaluation was performed with data from the meloxicam trial. Modelling and simulation analyses were performed using the software programs NONMEM, SAS and Berkeley Madonna.Results: Plasma concentration-time profiles of tesofensine were best described by a three-compartment model (absorption, central and gallbladder) with first-order elimination. The release of the bile compartment was controlled by a sine function model, switching the bile compartment periodically on and off using the actual clock time as the control element. A four-compartment model (absorption, central, peripheral and gallbladder) with first-order elimination and the sine function for gallbladder control described the meloxicam data best. Coadministration of cholestyramine resulted in a predicted 56% withdrawal of meloxicam from the EHC process causing a reduction in the t((1/2)) from approximately 19 hours to approximately 12 hours.Conclusion: A quantitative EHC model was successfully developed that was capable of describing the multiple peaks in plasma concentration-time profiles of tesofensine and meloxicam very well. Additionally, the model successfully quantified the observed results for an interruption of the meloxicam EHC. The model offers an in silico method to support an EHC hypothesis using standard pharmacokinetic data and might help to guide dosing recommendations of compounds undergoing EHC. [ABSTRACT FROM AUTHOR]

Objectives: A developed population pharmacokinetic model of the humanized monoclonal antibody (mAb) matuzumab was evaluated by external evaluation. Based on the estimates of the final model, simulations of different dosing regimens and the covariate effect were performed.Methods: The development dataset included 90 patients, and the evaluation dataset included 81 patients; the two sets of patients were from three different studies. In all studies, the patients had different types of advanced carcinoma - mainly colon, rectal and pancreatic cancer. They received matuzumab as multiple 1-hour intravenous infusions in a wide range of dosing regimens (development dataset: from 400 mg every 3 weeks to 2000 mg in the first week followed by 1600 mg weekly; evaluation dataset: from 100 mg weekly to 800 mg weekly). In addition to 1256 serum mAb concentrations for model development, there were 1124 concentrations available for model evaluation. Serum concentration-time data were simultaneously fitted using NONMEM software. The developed two-compartment model - with the parameters central volume of distribution (V(1)) and peripheral volume of distribution (V(2)), intercompartmental clearance and linear clearance (CLL), an additional nonlinear elimination pathway (Michaelis-Menten constant: the concentration with the half-maximal elimination rate and V(max): the maximum elimination rate) and covariate relations - was evaluated by an external dataset. Different simulation scenarios were performed to demonstrate the impact of the incorporated covariate effect and the influence of different dosing regimens and dosing strategies on the concentration-time profiles.Results: The developed model included the covariate fat-free mass (FFM) on V(1) and on CLL. The evaluation did not support the covariate FFM on V(1) and, after deletion of this covariate, the model parameters of the refined model were estimated. The model showed good precision for all parameters: the relative standard errors (RSEs) were <42% for the development dataset and < or = 51% for the evaluation dataset (excluding the higher RSEs for the correlation between V(2) and V(max) and the interindividual variability on V(2) for the evaluation dataset). The model showed good robustness for the ability to estimate highly precise parameters for the combined dataset of 171 patients (RSE <29%). Simulations revealed that variability in concentration-time profiles for minimum and maximum steady-state concentrations was reduced to a marginal extent by a proposed dose adaptation.Conclusion: The population pharmacokinetic model for matuzumab was improved by evaluation with an external dataset. The new model obtained precise parameter estimates and demonstrated robustness. After correlation with efficacy data simulation results in particular could serve as a tool to guide dose selection for this 'targeted' cancer therapy. [ABSTRACT FROM AUTHOR]

A population pharmacokinetic model based on data from three phase I studies was to be developed including a covariate analysis to describe the concentration-time profiles of matuzumab, a novel humanised monoclonal antibody. Matuzumab was administered as multiple 1 h i.v. infusions with 11 different dosing regimens ranging from 400 to 2000 mg, q1w-q3w. For analysis, 90 patients with 1256 serum concentration-time data were simultaneously fitted using the software NONMEM. Data were best described using a two-compartment model with the parameters central (V1) and peripheral distribution volume (V2), intercompartmental (Q) and linear (CLL) clearance and an additional nonlinear elimination pathway (Km, Vmax). Structural parameters were in agreement with immunoglobulin characteristics. In total, interindividual variability on Vmax, CLL, V1 and V2 and interoccasion variability on CLL was 22-62% CV. A covariate analysis identified weight having an influence on V1 (+0.44% per kg) and CLL (+0.87% per kg). All parameters were estimated with good precision (RSE<39%). A robust population pharmacokinetic model for matuzumab was developed, including a nonlinear pharmacokinetic process. In addition, relevant and plausible covariates were identified and incorporated into the model. When correlated to efficacy, this model could serve as a tool to guide dose selection for this 'targeted' cancer therapy. [ABSTRACT FROM AUTHOR]

In contrast to conventional chemotherapy, carboplatin is still dosed per unit of body surface area (BSA) in high-dose chemotherapy protocols in clinical practice. To individualise dosing, a population pharmacokinetic model for poor-risk germ cell tumour patients receiving 1500?mg?m-2 carboplatin was developed. The typical central volume of distribution (19.9?l) and typical clearance (110?ml?min-1) corresponded approximately to the extracellular fluid space or glomerular filtration rate, respectively. The covariate analysis identified several patient-specific factors. Carboplatin clearance was significantly related to creatinine clearance and body height, explaining 73% of the interindividual variability. Thus, an equation to predict individual clearance prior to treatment was developed (CL=0.41 × creatinine clearance+1.05 × body height-124.4). The relative frequency of developing toxicity increased significantly with higher AUC values for different types of toxicity. In addition, overall nonhaematological toxicity correlated significantly with exposure of carboplatin, leading to the assessment of a target AUC. Based on the prediction of individual clearance and the definition of a target AUC associated with moderate toxicity, an individualised dosing equation is proposed. Retrospectively, the individualised dosing strategy would have led to a higher dose on average and a broader range to be administered, compared to empirical dosing per unit BSA in the high-dose setting.British Journal of Cancer (2003) 89, 787-794. doi:10.1038/sj.bjc.6601215 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Purpose: To compare etoposide pharmacokinetics following administration of high-dose etoposide and etoposide phosphate, a water-soluble prodrug of etoposide. Bioequivalence was assessed using a two-treatment randomized crossover design. Methods: Ten patients with high-risk or relapsed lymphoma were treated with a sequential high-dose chemotherapy. They were randomized to receive either 3×400 mg/m2 etoposide or an equimolar amount of etoposide phosphate (as 1-h infusions on three consecutive days) in the first course and the alternative drug in the second course. Serial plasma and ultrafiltered plasma samples were collected and analysed for etoposide by a reversed-phase HPLC method with UV and electrochemical detection. Pharmacokinetic parameters were estimated using a two-compartment model. Bioequivalence was assessed calculating the 90% confidence intervals (CI) for the ratios of the geometric means of AUC0-∞ and additionally of Cmax of etoposide derived from etoposide phosphate relative to etoposide in plasma and ultrafiltered plasma as point estimates (level of significance α<0.05). Results: Pharmacokinetic parameters of etoposide were comparable in both treatment arms except that terminal half-life was significantly shorter and apparent Vss in ultrafiltered plasma was significantly larger following administration of the prodrug. The point estimates for AUC0-∞ of etoposide derived from etoposide phosphate relative to etoposide were 102.9% and 88.4% for plasma and ultrafiltered plasma, respectively. The 90% CIs were in the range from 80% to 125% where bioequivalence can be assumed. The point estimates of Cmax on day 3 of chemotherapy were 96.5% and 81.7% in plasma and ultrafiltrate with the 90% CI in ultrafiltered plasma being out of the range from 80% to 125%. Conclusion: With respect to total drug exposure, represented by AUC0-∞, high-dose etoposide phosphate is bioequivalent to high-dose etoposide. [ABSTRACT FROM AUTHOR]