Clearance concepts

Acta Poloniae Pharmaceutica, 2012

This study presents an application of the piecewise rational quadratic interpolant to the AUC calculation in the bioavailability study. The objective of this work is to find an area under the plasma concentration-time curve (AUC) for multiple doses of salbutamol sulfate sustained release tablets (Ventolin oral tablets SR 8 mg, GSK, Pakistan) in the group of 24 healthy adults by using computational mathematics techniques. Following the administration of 4 doses of Ventolin tablets 12 hourly to 24 healthy human subjects and bioanalysis of obtained plasma samples, plasma drug concentration-time profile was constructed. The approximated AUC was computed by using computational mathematics techniques such as extended rectangular, extended trapezium and extended Simpson's rule and compared with exact value of AUC calculated by using software - Kinetica to find best computational mathematics method that gives AUC values closest to exact. The exact values of AUC for four consecutive doses of Ventolin oral tablets were 150.58, 157.81, 164.41 and 162.78 ngxh/mL while the closest approximated AUC values were 149.24, 157.33, 164.25 and 162.28 ngxh/mL, respectively, as found by extended rectangular rule. The errors in the approximated values of AUC were negligible. It is concluded that all computational tools approximated values of AUC accurately but the extended rectangular rule gives slightly better approximated values of AUC as compared to extended trapezium and extended Simpson's rules.

Drug Metabolism and Disposition, 2023

AUC inf , area under the curve from time 0 to infinity; B max , maximum binding capacity; CL b , total blood clearance; CL h: , hepatic clearance; CL int , hepatic intrinsic clearance; C max , maximum concentration; CQ, chloroquine; CyA, cyclosporine A; DLZ, diltiazem; D N , dispersion number; DM, dispersion model; DPH, phenytoin; DZP, diazepam; EB, ethoxybenzamide; ER, extraction ratio; F, oral bioavailability; F g , pre-hepatic bioavailability; FTY720, fingolimod; f ub , unbound fraction in blood; f up , unbound fraction in plasma; GI, gastrointestinal; HB, hexobarbital; IP, intraperitoneal; IV, intravenous; IVIVE, in vitro-in vivo extrapolation; K d , equilibrium dissociation constant; K m , Michaelis-Menten constant; K ph , liver-to-plasma partition coefficient;

Journal of Pharmacokinetics and Pharmacodynamics, 2007

To compare the performance of the standard lag time model (LAG model) with the performance of an analytical solution of the transit compartment model (TRANSIT model) in the evaluation of four pharmacokinetic studies with four different compounds. Methods: The population pharmacokinetic analyses were performed using NONMEM on concentration-time data of glibenclamide, furosemide, amiloride, and moxonidine. In the TRANSIT model, the optimal number of transit compartments was estimated from the data. This was based on an analytical solution for the change in drug concentration arising from a series of transit compartments with the same first-order transfer rate between each compartment. Goodness-of-fit was assessed by the decrease in objective function value (OFV) and by inspection of diagnostic graphs. Results: With the TRANSIT model, the OFV was significantly lower and the goodness-of-fit was markedly improved in the absorption phase compared with the LAG model for all drugs. The parameter estimates related to the absorption differed between the two models while the estimates of the pharmacokinetic disposition parameters were similar. Conclusion: Based on these results, the TRANSIT model is

European Journal of Clinical Pharmacology, 1993

Published data on the renal clearance of creatinine, p-aminohippuric acid (PAH) and kanamycin in relation to glomerular filtration rate (GFR) in patients with various renal diseases were analysed by a physiological model of renal clearance. Fitting of the data by the general linear equation representing the model proposed by Levy [10] resulted in insignificant intercepts with the ordinate, indicating the unsuitability of the model for the detection of tubular secretory activity. Use of this model also did not lead to significant improvement in goodness of fit compared to simple proportionality of renal clearance and GFR. On the other hand, parameter estimates of the physiological model obtained from the data by nonlinear regression analysis revealed statistically significant tubular secretion both of PAH and creatinine. The much lower tubular secretory activity estimated from the kanamycin data did not reach statistical significance. For compounds exhibiting statistically significant tubular secretion, use of the physiologically based relationship between renal clearance and GFR significantly improved the goodness of fit to the data as compared to simple proportionality of both variables. It is concluded that analysis of the relationship between renal clearance of drugs and GFR using the physiological model of renal clearance can contribute to our knowledge of drug handling by the kidney, and may facilitate drug classification according to total extraction by this organ.

The Open Nursing Journal

Bulletin of Mathematical Biology, 1989

Amiodarone concentrations y(t) have been measured from 1 min to more than 50 days following 10 min of infusion, with about 40 observations on each of six normal subjects (Tucker et al., 1984, Eur. J. clin. Pharmacol. 26, 655-656). The form of the log-log plots-In(y) vs In(t)-is investigated. These appear to show three phases. First there is a rapid decrease of y(t). then a straight line corresponding to a small negative power of t, ca-0.3, and this line changes continuously but quickly at about 0.5 day into a steeper line that is almost straight. For the curve fitting a simple "spline-type" device was successful. Two continuity conditions were imposed at the time of changeover, which was one of the unknown parameters. The results are compared in detail with those from a set of 15 radiocalcium curves obtained during 2 weeks or more from a single injection of 47Ca (Neer et al., 1967, J. clin. Invest. 46, 1364-1379). Again two power functions of time can be seen. The changeover is much more gradual than with amiodarone, and the fits are still better. Both sets of curves are fitted with fewer adjustable parameters than with the usual multiexponentials that are interpreted in terms of homogeneous compartments. Theoretical and practical implications are mentioned. There is much indirect evidence that hundreds of other clearance curves may consist largely of one or two of such power functions of time.

Therapeutic Advances in Drug Safety, 2013

European Journal of Drug Metabolism and Pharmacokinetics, 2004

The purpose of the study was to investigate the factors upon which the first order rate constant depends in order to assess the impact on the body-drug concentration when it changes throughout a treatment. A reasoning for linking the first order rate constants with several factors in a multiplicative way was proposed out taking into account kinetic and thermodynamic aspects. A multi-compartment model for drug disposition was analyzed and compartment mean drug concentrations at steady state were obtained as a function of the model kinetic constants. At the moment, only four factors were identified as responsible for the actual rate constant value. Apart from an intrinsic kinetic constant, they are the inverse of compartment volume, the transfer surface area, the fraction of mass able to be transferred, and the fraction of mass that effectively can be transferred. In clinical practice some of these factors might change throughout time (because of chronophysiological rhythms or drug availability at the action sites) and consequently, an inconstant extra-plasmal plasma drug concentration ratio could be obtained. In conclusion, therapeutic response prediction for a treatment does not upon plasma drug concentration monitoring. Equivalence in plasma drug exposure should not mean therapeutic equivalence, because differences in the rate and in the extent between test and reference products may induce a change in the action site / plasma drug concentration ratio.

International Journal of Pharmaceutics, 2011

The attention of this review is focussed on the mathematical modeling of the simultaneous processes of drug release and absorption/distribution/metabolism/elimination (ADME processes) following different administration routes. Among all of them, for their clinical importance, the oral, transdermal and local delivery are considered. The bases of the presented mathematical models are shown after the discussion of the most relevant phenomena characterising the particular administration route considered. Then, model performances are compared to experimental evidences in order to evaluate their reliability and soundness.