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Central Volume (central + volume)
Selected AbstractsThe pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trialsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2009C. VEYRAT-FOLLET Summary.,Background: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. Objectives: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. Patients and methods: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance <30 mL min,1). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. Results: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h,1, 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux , rapid onset of action and long-acting anticoagulant effect , offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux. [source] Clonidine disposition in children: a population analysisPEDIATRIC ANESTHESIA, Issue 6 2007AL Potts Background:, There are few data describing clonidine population pharmacokinetics in children (0,15 years) despite common use. Current paediatric data, described in terms of elimination half-life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically. Methods:, Published data from four studies investigating clonidine PK after intravenous, rectal and epidural administration (n = 42) were combined with an open-label study undertaken to examine the pharmacokinetics of IV clonidine 1,2 ,g·kg,1 bolus in children after cardiac surgery (n = 30, EC approval granted). A population pharmacokinetic analysis of clonidine time-concentration profiles (380 observations) was undertaken using nonlinear mixed effects modelling. Estimates were standardised to a 70 kg adult using allometric size models. Results:, Children had a mean age of four (SD 3.6 years, range 1 week,14 years) year and weight 17.8 (SD 12.6, range 2.8,60 kg). A two compartment disposition model with first order elimination was superior to a one compartment model. Population parameter estimates (between subject variability) were clearance (CL) 14 (CV 28.3%) 1 h,1·70 kg,1, central volume of distribution (V1) 56.7 (67.5%) l·70 kg,1, inter-compartment clearance (Q) 143 (19.1%) l h,1 70 kg,1 and peripheral volume of distribution (V2) 123 (72.8%) l.70kg,1. Clearance at birth was 4.7 l·h,1·70kg,1 and matured with a half-time of 25.5 weeks to reach 85% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 180%, V2 117%). There was a lag time of 2.6 (CV 64%) min before absorption began in the rectum. The absorption half-life from the epidural space was slower than that from the rectum 1.04 (CV31%) h vs 0.28 (CV24%) h. The relative bioavailability of epidural and rectal clonidine was unity (F = 1). Conclusions:, Clearance in neonates is approximately one third that described in adults, consistent with immature clearance pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach. [source] Interindividual variability in the concentration,effect relationship of antilymphocyte globulins,a possible influence of Fc,RIIIa genetic polymorphismBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008David Ternant WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ,,There is interindividual variability in the antilymphocyte globulin (ALG) effect, but there is no pharmacokinetic,pharmacodynamic study of this subject. ,,In addition, a time dependence of the pharmacokinetics of some therapeutic antibodies has been described. ,,ALGs may partly act by antibody-dependent cellular cytotoxicity (ADCC), but their mechanism of action in humans is not known. WHAT THIS STUDY ADDS ,,Horse ALG pharmacokinetics can be described using a two-compartment model with time-dependent central volume of distribution. ,,After an initial concentration-independent lymphocyte depletion, the concentration,effect relationship can be described using a physiological indirect response model. ,,The genetic polymorphism of Fc,RIIIa at position 158 may influence the ALG concentration,effect relationship and these polyclonal antibodies may therefore act by ADCC. AIMS Polyclonal antilymphocyte globulins (ALGs) are currently used in transplantation, but the sources of interindividual variability of their effect are poorly understood. No pharmacokinetic,pharmacodynamic (PK,PD) study of ALG is available. Moreover, the genetic polymorphism of Fc,RIIIa, a receptor for the Fc portion of immunoglobulins involved in antibody-dependent cellular cytotoxicity (ADCC), may influence their concentration,effect relationship. METHODS Fourteen kidney transplant patients treated by horse ALG were included in a prospective, noncomparative study. A population two-compartment PK model including a time dependence of the central volume of distribution was developed. Total lymphocyte count was used as biomarker of effect. Concentration,effect data were described using a physiological indirect response model, combining concentration-dependent and -independent inhibitions of lymphocyte input into the circulation. In addition, six kidney transplant patients in whom ALG concentrations were not available were included retrospectively. All patients were genotyped for FCGR3A. RESULTS Both the PK and the PK,PD model described the data satisfactorily and showed high interindividual variability. Asymptotic T1/2 -, and T1/2 -,-values were 1.3 and 25 days, respectively. The concentration of ALG leading to a 50% inhibition of lymphocyte input (IC50) was lower in FCGR3A- V carriers than in FCGR3A- F/F patients (383 ± 199 vs. 593 ± 209 mg l,1, P = 0.008). CONCLUSIONS This is the first description of the ALG effect on lymphocyte count using PK,PD modelling. Our results show that part of the variability in their concentration,effect relationship may be explained by Fc,RIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC. [source] Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemateBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2001Jörn Lötsch Aims, To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects. Methods, Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg (,test') or two tablets of 200 mg (,reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account. Results, Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 µg ml,1 (test), and 18.2 and 20 µg ml,1 (reference). Areas under the plasma concentration vs time curves were 39.7 and 67.5 µg ml,1 h (test), and 41.1 and 68.2 µg ml,1 h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h,1 (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h,1, central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h,1, peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h,1, and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation. Conclusions, Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen. [source] | ||||||||||