Prediction of Blood Levels after Multiple Doses from Single-Dose Blood Level Data: Data Generated with Two-Compartment Open Model Analyzed According to the One-Compartment Open Model

Wagner, John G.; Metzler, Carl M.

doi:10.1002/jps.2600580118

Cited by 45 publications

(12 citation statements)

References 25 publications

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“…(3a) Despite the one compartment origin the Bateman function can be applied for predicting plasma concentrations even though the disposition course of the drug does not strictly obey a one compartment model [5,[32][33][34][35]. For example, early distribution processes that would become visible in the beginning of the plasma concentration-time course after fast intravenous administration of a drug (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…It has to be recognised that the Bateman function assumes linear pharmacokinetics for the absorption and elimination processes and no further kinetically relevant distribution phases. However, despite its one compartment model origin, it should be noted that the Bateman function can be applied for predicting drug concentrations in plasma even though the disposition course of the drug does not strictly obey a one compartment model [5,[32][33][34][35]. Hence, for the application of the Bateman function it is more important that the plasma concentration-time course after oral administration approximately corresponds to a monophasic profile post the peak of the curve, regardless of the assumed underlying disposition characteristics.…”

Section: Two Times T Max Methodsmentioning

confidence: 99%

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Proposal for a standardised identification of the mono‐exponential terminal phase for orally administered drugs

Scheerans

Derendorf

Kloft

2008

Biopharm & Drug Disp

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The area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) is generally considered to be the most appropriate measure of total drug exposure for bioavailability/bioequivalence studies of orally administered drugs. However, the lack of a standardised method for identifying the mono-exponential terminal phase of the concentration-time curve causes variability for the estimated AUC(0-inf). The present investigation introduces a simple method, called the two times t(max) method (TTT method) to reliably identify the mono-exponential terminal phase in the case of oral administration. The new method was tested by Monte Carlo simulation in Excel and compared with the adjusted r squared algorithm (ARS algorithm) frequently used in pharmacokinetic software programs. Statistical diagnostics of three different scenarios, each with 10,000 hypothetical patients showed that the new method provided unbiased average AUC(0-inf) estimates for orally administered drugs with a monophasic concentration-time curve post maximum concentration. In addition, the TTT method generally provided more precise estimates for AUC(0-inf) compared with the ARS algorithm. It was concluded that the TTT method is a most reasonable tool to be used as a standardised method in pharmacokinetic analysis especially bioequivalence studies to reliably identify the mono-exponential terminal phase for orally administered drugs showing a monophasic concentration-time profile.

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Section: Discussionmentioning

confidence: 99%

Section: Two Times T Max Methodsmentioning

confidence: 99%

Proposal for a standardised identification of the mono‐exponential terminal phase for orally administered drugs

Scheerans

Derendorf

Kloft

2008

Biopharm & Drug Disp

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“…If a theoretically irrational guideline accurately predicts the concentrations of drug achieved 210 in a patient, it can still be used (Wagner and Metzler, 1969). No matter what the theoretical liabilities or advantages of a particular nomogram, the bottom line is how well it performs in patient populations.…”

Section: Evaluation Of the Predictability And Accuracy Of A Nomogrammentioning

confidence: 99%

Nomograms for Drug Use in Renal Disease

Chennavasin

Brater

1981

Clinical Pharmacokinetics

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The medical literature is replete with dosing guidelines for patients with renal dysfunction. Altering dosing regimens in such patients is particularly important with drugs with a narrow therapeutic index, such as digoxin and the aminoglycoside antibiotics. A variety of methods have been used to devise dosing nomograms. This article reviews the salient features of different methods, and addresses the issues of predictability or unpredictability in attaining desired plasma concentrations of drug. It is suggested that therapy must be individualised, and that the clinician can best plan his therapy by understanding the principles on which dose adjustment is based, rather than using the same nomogram or guideline for each and every patient.

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“…There has been considerable argument over the relative merits of one-and two-compartment systems (Riegelman, Loo & Rowland, 1968;Wagner & Metzler, 1969). Here it is assumed that the 'best' model is the simplest giving a good fit of the experimental results which the model is intended to describe.…”

Section: Theory Derivation Of the Modelmentioning

confidence: 99%

“…Theory Derivation of the model The complexity of models developed for pharmacokinetic purposes is largely dependent on the number of compartments conceived to represent the internal environment of the body (Rescigno & Segre, 1966). There has been considerable argument over the relative merits of one-and two-compartment systems (Riegelman, Loo & Rowland, 1968;Wagner & Metzler, 1969). Here it is assumed that the 'best' model is the simplest giving a good fit of the experimental results which the model is intended to describe.…”

Section: Experimental Metabolic Experimentsmentioning

confidence: 99%

Pharmacokinetic model for the successive demethylation and biliary secretion of methyl orange in the rat

O'Reilly

Pitt

Ryan

1971

British J Pharmacology

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Summary1. A one-compartment pharmacokinetic model was developed in which a drug underwent two successive metabolical reactions (for example, metabolism followed by conjugation) and free drug and both metabolites were excreted. 2. Techniques were described whereby graphical estimates of the first-order rate constants may be derived from cumulative excretion data on the drug and its metabolites. Computer simulation techniques were used to show that the experimental data permit reasonably accurate estimation of the rate constants of the model by graphical and computer methods. 3. Tritiated methyl orange (2 mg) was administered to five groups of six rats with biliary cannulation. The bile produced by each animal was collected at hourly intervals for 6 h and the amounts of methyl orange and its metabolites, 4'sulpho-4-methylaminoazobenzene and 4'sulpho-4-aminoazobenzene, determined by thin layer chromatography and radioactive counting techniques. 4. The data were analysed graphically and with an iterative digital computer programme to yield the first-order rate constants for the successive demethylation steps in the metabolism of methyl orange. The removal of the first methyl group had a rate constant of 0-684+0-142 h-1 (+S.D.) and the second methyl group 100+0-302 h-1. The rate constant for biliary excretion of the free methyl orange was 0-164+0-042 h-1,-for the monomethyl derivative 0-672+ 0-461 h-i, and for the demethylated metabolite 6-413 + 3.222 h-1.

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Prediction of Blood Levels after Multiple Doses from Single-Dose Blood Level Data: Data Generated with Two-Compartment Open Model Analyzed According to the One-Compartment Open Model

Cited by 45 publications

References 25 publications

Proposal for a standardised identification of the mono‐exponential terminal phase for orally administered drugs

Proposal for a standardised identification of the mono‐exponential terminal phase for orally administered drugs

Nomograms for Drug Use in Renal Disease

Pharmacokinetic model for the successive demethylation and biliary secretion of methyl orange in the rat

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