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Electronic Resource

APriori lithium dosage regimen using population characteristics of pharmacokinetic parameters (1979)

Gaillot, Jean ; Steimer, Jean-Louis J. ; Mallet, Alain J. ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 579-628

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ISSN: 1573-8744

Keywords: lithium therapy ; linear pharmacokinetics ; steady-state pattern ; therapeutic range ; interindividual variability ; optimization of dosage regimen ; personalized dosage schedule

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The important problem of initiation of long-term lithium treatments tackled by means of the selection of an a prioridosage regimen based on the presumed efficacy of lithium and absence of toxicity. The pharmacokinetics of Li + ion is represented by a four-compartment open model including the supposed first-order processes for the release of the active compound from the dosage form and its absorption. Experimental protocols for measurements of serum concentrations and of urinary amounts after single and multiple dosing to healthy volunteers were derived with several oral dosage forms. Estimation of the pharmacokinetic parameters for each subject made it possible to validate the model for the various dosage forms. The interindividual variability of these parameters is taken into account by estimating the characteristics of the statistical distribution for the whole population. A dosage regimen is considered optimum when serum concentration profiles at steady state range from the threshold of efficacy (0.8 mmol/liter) to the threshold of toxicity (2.0 mmol/liter). When the number of daily intakes is fixed, the search for the optimum dose for the whole population is effected by minimizing the expected value of the random variable which characterizes the risks of excursion out of the therapeutic range. By this means universal dosages are shown to be unsatisfactory. However, certain dosage regimens individualized with respect to the renal clearance value of lithium and based on two or three daily intakes can give excellent results even when conventional dosage forms are used.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01061210

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2

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On the dose dependency of Cyclosporin a absorption and disposition in healthy volunteers (1988)

Reymond, Jean-Philippe ; Steimer, Jean-Louis ; Niederberger, Werner

Springer

Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 331-353

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ISSN: 1573-8744

Keywords: Cyclosporin A ; pharmacokinetics ; dose dependency ; oral absorption ; disposition ; healthy subjects

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The pharmacokinetics of Cyclosporin A (CyA, SandimmuneR) was studied in 12 healthy male volunteers after oral dosing of 350 mg, 700 mg, and 1400 mg as a drinking solution. Blood samples were collected over 96 hr and analyzed by high pressure liquid chromatography. Concentration data were evaluated with model-independent and model-based linear pharmacokinetic concepts. Individual CyA concentration-time profiles in whole blood were well described by a two-compartment open model with zero-order absorption for all three doses. Comparison of pharmacokinetic parameters across doses indicates that both absorption and disposition are dose-dependent. Nonlinear disposition is suggested by the significant increase of the terminal half-life from 8.9±4.9hr to 11.9±4.9hr (mean±SD) after a 350 mg and a 1400 mg dose, respectively. Changes in the metabolic activity of the liver with concentration might be responsible for this phenomenon. In addition, the modeling approach indicated that bioavailability decreases with increasing dose. Moreover, the dependence of the rate of CyA absorption (zero-order rate constant) versus dose was well described by a hyperbola. The limited solubility of the drug in the gastrointestinal tract might be responsible for this behavior. The lag time (0.2–0.8 hr) was independent of dose. This value is similar to the time of gastric emptying in fasting volunteers. The duration of absorption for 11 of 12 subjects was in the range 2.5–3.5 hr over all doses and agrees well with the small intestine transit time. Some subjects showed a marked secondary peak at one or two doses, which could be adequately fitted by a model with two successive zero-order inputs. This double-peak behavior was ascribed to the influence of the food on gastric emptying. Dose dependency of disposition and absorption counterbalance each other in the usual dose range. This leads to an almost proportional increase of area under the blood CyA concentration-time profile with increasing dose.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01062550

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3

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Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125 (1994)

Kawai, Ryosei ; Lemaire, Michel ; Steimer, Jean-Louis ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 327-365

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ISSN: 1573-8744

Keywords: SDZ IMM 125 ; cyclosporins ; physiologically based pharmacokinetics ; interspecies scaling ; allometry ; blood cells ; membrane-transport limitation

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The immunosuppressant, SDZ IMM 125 (IMM), is a derivative of cyclosporin A (CyA). The disposition kinetics of IMM in plasma, blood cells, and various tissues of the rat was characterized by a physiologically based pharmacokinetic (PBPK) model; the model was then applied to predict the disposition kinetics in dog and human. Accumulation of IMM in blood cell is high (equilibrium blood cell/plasma ratio=8), although the kinetics of drug transference between plasma and blood cell is moderately slow, taking approximately 10 min to reach equilibrium, implying a membranelimited distribution into blood cells. A local PBPK model, assuming blood-flow limited distribution and tissue/blood partition coefficient (K P) data, failed to adequately describe the observed kinetics of distribution, which were slower than predicted. A membrane transport limitation is therefore needed to model dynamic tissue distribution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, and glomerular filtration) of IMM were assessed at steady statein vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, which described closely the IMM concentration-time profiles in arterial blood as well as 14 organs/tissues of the rat after intravenous administration. The model was then scaled up to larger mammals by modifying physiological parameters, tissue distribution and elimination clearances;in vivo enzymatic activity was considered in the scale-up of metabolic clearance. The simulations agreed well with the experimental measurements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric relationship. In addition, the nonlinear increase in maximum blood concentration andAUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitatively link preclinical and clinical data.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02353860

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4

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Nonparametric maximum likelihood estimation for population pharmacokinetics, with application to cyclosporine (1988)

Mallet, Alain ; Mentré, France ; Steimer, Jean -Louis ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 311-327

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ISSN: 1573-8744

Keywords: population pharmacokinetics ; random regression ; distribution estimation ; nonparametric estimation ; maximum likelihood ; cyclosporine

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A new method, nonparametric maximum likelihood (NPML), for statistical analysis of population kinetic data is proposed. NPML provides a discrete estimate of the whole probability density function of the pharmacokinetic parameters. This permits a straightforward derivation of usual population characteristics. To illustrate the application of the NPML method, a population analysis of cyclosporine RIA measured plasma levels in 188 bone marrow transplant patients after intravenous infusion, is presented. The capability of NPML to extract population information from sparse individual data is also outlined.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01062140

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A mathematical model for dynamics of cardiovascular drug action: Application to intravenous dihydropyridines in healthy volunteers (1993)

Francheteau, Patrice ; Steimer, Jean -Louis ; Merdjan, Henri ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 489-514

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ISSN: 1573-8744

Keywords: antihypertensive agent ; baroreceptor ; mathematical model ; pharmacokineti-pharmacodynamic modeling ; vasodilator agent

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A physiologically based mathematical model was built to describe the pharmacodynamic effects in response to the administration of intravenous (iv)dihydropyridine drugs in healthy volunteers. This model incorporates a limited number of hemodynamic variables, namely, mean arterial blood pressure (MAP),cardiac output (CO)or heart rate (HR),stroke volume (SV),and total peripheral resistance (TPR),into a closed-loop system supposed to represent essential features of the cardiovascular regulation. We also defined an additional auxiliary control variable (U)which is thought to represent primarily the role of the baroreceptor reflex. It was assumed that the variable Uwas related to MAPchanges through both deviation- and ratesensitive mechanisms. Other model parameters are the baseline levels for MAP, CO(or HR),and TPR,as well as time constants to account for further temporal aspects of the regulation. Finally, TPRwas assumed to be linked to the plasma concentrations of dihydropyridine drugs via a conventional pharmaco-kinetic/pharmacodynamic (PK/PD) model, relying upon an effect compartment and a linear, hyperbolic, or sigmoidal relationship between the reduction in TPRand the drug concentrations at the effect site. The model characteristics were explored by studying the influence of various parameters, including baseline levels and deviation- and rate-sensitive control parameters, on the hemodynamic responses to a fictive constant rate ivinfusion of a vasodilator drug. Attempts were also made to mimic literature data with nifedipine, following ivadministration under both constant and exponentially decreasing infusion rates. The applicability of the model was demonstrated by fitting hemodynamic data following ivinfusion of nicardipine to healthy volunteers, under experimental conditions similar to those described above for nifedipine. The effect model for the action of nicardipine on TPR,combined with the physiological model including a feedback control loop, allowed an adequate quantitative description of time profiles for both cardiac output and mean arterial pressure. The suggested model is a useful tool for integrated data analysis of hemodynamic responses to vasodilator drugs in healthy volunteers. Computer simulations suggest that a graded variation of a few model parameters-including baseline levels of TPRand MAPand the deviaion-sensitive parameter of the arterial pressure control-would also be able to account for the pattern of hemodynamic response observed in hypertensive patients, which is qualitatively different to that seen in normotensive subjects. Extrapolation of drug response from the healthy volunteer to the hypertensive patient is allowed by our model. Its usefulness for an early evaluation of drug efficacy during drug development is under current investigation.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF01059111

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