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Linear Pharmacokinetics (linear + pharmacokinetic)
Selected AbstractsPrediction of the possibility of the second peak of drug plasma concentration time curve after iv bolus administration from the standpoint of the traditional multi-compartmental linear pharmacokineticsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2008Leonid M. Berezhkovskiy Abstract It is shown that the existence of the second peak on the drug plasma concentration time curve Cp(t) after iv bolus dosing can be explained by considering the traditional multi-compartmental linear pharmacokinetics. It was found that a direct solution of the general three-compartment model yields the second peak of Cp(t) for the certain values of the rate constants, and Cp(t) includes the term with oscillating preexponent, that is, K,sin(,t,+,,),exp(,,t), in this case. The considered model describes the drug entero-hepatic recirculation in the species which do not have gall bladder (rats). The model fit of the experimental data from rat pharmacokinetic studies where the second peak of Cp(t) was observed, yields the rate of bile production that is consistent with the physiological value (,0.7 mL/h). © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2385,2393, 2008 [source] The influence of drug kinetics in blood on the calculation of oral bioavailability in linear pharmacokinetics: The traditional equation may considerably overestimate the true value,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2006Leonid M. Berezhkovskiy Abstract A common calculation of oral bioavailability is based on the comparison of the areas under the concentration-time curves after intravenous and oral drug administration. It does not take into account that after the oral dosing a drug enters the systemic circulation in different states, that is, as free fraction, protein bound and partitioned into blood cells, and plasma lipids, while after intravenous input it is introduced into the systemic circulation only as a free fraction. Consideration of this difference leads to a novel equation for the oral bioavailability. In general, the traditional calculation overestimates the oral bioavailability. For a widely applied model of a linear pharmacokinetic system with central (plasma) drug elimination it is shown that the traditional calculation of the oral bioavailability could substantially overestimate the true value. If the existence of an immediate equilibrium between different drug fractions in blood is assumed, the obtained equation becomes identical to the traditional one. Thus the deviation of oral bioavailability from the value given by a common calculation appears to be a kinetic phenomenon. The difference could be significant for the drugs with the rate constant of elimination from plasma of the same order of magnitude or greater than the dissociation rate constant of drug,protein complexes, or the off-rate constant of partitioning from the blood cells, if the blood concentration profiles were used to calculate the oral bioavailability. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:834,848, 2006 [source] Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignanciesTHE PROSTATE, Issue 13 2010Mark Stein Abstract BACKGROUND A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance. METHODS Patients received 2DG orally on days 1,14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance. RESULTS The dose of 45,mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60,mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with Cmax 45,µg/ml (277,µM), 73.7,µg/ml (449,µM), and 122,µg/ml (744,µM) in dose levels 30, 45, and 60,mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24,hr. CONCLUSIONS These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy. Prostate 70: 1388,1394, 2010. © 2010 Wiley-Liss, Inc. [source] Determination of picroside II in dog plasma by HPLC and its application in a pharmacokinetics studyBIOMEDICAL CHROMATOGRAPHY, Issue 4 2005Fu-Chuan Yang Abstract A sensitive and simple high-performance liquid chromatography method with UV detection was developed and validated for determining picroside II in dog plasma. Paeoni,orin was employed as internal standard and the sample pre-treatment procedure consists of deproteinization by addition of acetonitrile. Chromatographic separations were performed on a Shimadzu VP-ODS column (250 × 4.6 mm i.d., 5 µm). The mobile phase consisted of acetonitrile,0.1% acetic acid aqueous (v/v), 23:77, v/v, at a rate of 1 mL/min. Detection was carried out at a wavelength of 266 nm. Calibration standards ranged from 0.25 to 500 µg/mL in dog plasma and the mean correlation coef,cient of 0.9981 was found for the linear calibration curves (n = 6). The limit of quanti,cation (LOQ) was 0.25 µg/mL. Intra- and inter-assay RSD ranged from 0.70 to 7.5%. Accuracy (%bias) ranged from ,6.3 to 6.0%. This method was applied to the pharmacokinetic study of picroside II in dogs. The study demonstrated the plasma picroside II concentration,time curves were ,tted to the two-compartment open model and showed linear pharmacokinetics. Copyright © 2005 John Wiley & Sons, Ltd. [source] Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin (BI 1356) , investigations in DPP-4 deficient and wildtype ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2009Silke Retlich Abstract Linagliptin (BI 1356) is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical development for the treatment of type 2 diabetes. It exhibits non-linear pharmacokinetics and shows concentration-dependent plasma protein binding to its target, DPP-4. The aim of this study was to investigate the impact of saturable binding of linagliptin to plasma and tissue DPP-4 by comparing the pharmacokinetics of linagliptin in wildtype and DPP-4 deficient Fischer rats using non-compartmental and model-based data analysis. The non-compartmental analysis revealed a significantly reduced AUC in DPP-4 deficient rats compared with wildtype rats when single intravenous doses ,1,mg/kg were administered, but the exposure was similar in both strains at higher doses. The terminal half-lives were significantly shorter in DPP-4 deficient rats compared with wildtype rats. For doses ,1,mg/kg, DPP-4 deficient rats exhibited linear pharmacokinetics, whereas the pharmacokinetics of wildtype rats was non-linear. In the model-based analysis these differences could be accounted for by assuming concentration-dependent protein binding in the central and one peripheral compartment in wildtype rats. In the model, disposition parameters for unbound linagliptin were assumed to be identical in both rat strains. Simulations with different doses of linagliptin and different concentrations of binding sites further illustrated that the interdependence of linagliptin and DPP-4 in plasma and in the periphery has a major influence on the disposition of linagliptin in wildtype rats. In conclusion, the study showed that the concentration-dependent binding of linagliptin to its target DPP-4 has a major impact on the plasma pharmacokinetics of linagliptin. Copyright © 2009 John Wiley & Sons, Ltd. [source] Population pharmacokinetics of oral diclofenac for acute pain in childrenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2008Joseph F. Standing WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range. , Diclofenac is frequently used ,off-label' in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5,2.5 mg kg,1). There is currently no licensed oral paediatric formulation of diclofenac. WHAT THIS STUDY ADDS , Using a new diclofenac oral suspension, a dose of 1 mg kg,1 in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses. AIMS To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml,1) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children. METHODS Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg,1 dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults. RESULTS A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and VD/F were 53.98 l h,1 70 kg,1 and 4.84 l 70 kg,1 respectively. Allometric size models appeared to predict adequately changes in CL and VD with age. Of the simulated doses investigated, 1 mg kg,1 gave paediatric AUC(0,12 h) to adult 50 mg AUC(0,12 h) ratios of 1.00, 1.08 and 1.18 for ages 1,3, 4,6 and 7,12 years respectively. CONCLUSIONS This study has shown 1 mg kg,1 diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses. [source] | |||||||||||||