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  • 1
    Electronic Resource
    Electronic Resource
    Generalizations in linear pharmacokinetics using properties of certain classes of residence time distributions. II. Log-concave concentration-time curves following oral administration (1987)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 15 (1987), S. 57-74 
    Details
    ISSN: 1573-8744
    Keywords: Pharmacokinetics ; oral administration ; noncompartmental approach ; log-concavity ; dissolution profile ; reliability theory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The present approach enables a noncompartmental assessment of log-concave plasma concentration-time profiles following oral drug administration. Observed log-concavity corresponds to a nonparametric class of residence time distributions with the following properties: (1) The fractional rate of elimination kB(t) (failure rate of the distribution) increases monolonically until reaching the terminal exponential coefficient kB,Z.(2) The relative dispersion of body residence times CV B 2 (ratio of variance to the squared mean , VBRT/MBRT2,)acts as a shape parameter of the curve. The role of the input process in determining the shape of the concentration profile is discussed. In this connection evidence is provided for the importance of log-concave percent undissolved versus time plots, introducing the general concept of a time-varying fractional rate of dissolution. The governing factor for the appearance of log-concavity is the ratio of mean absorption time to mean disposition residence time (MAT/MDRT);this factor exceeds a particular threshold value which depends on the distributional properties of the drug. Generalizing previous approaches which are valid for first-order input processes, the “flipflop” phenomenon and the problem of “vanishing of exponential terms” are explained using fewer assumptions. Upper bounds for the elimination time (more than 90% eliminated) and the cutoff error in AUCdetermination are presented. The concept of logconcavity reveals general features of the pharmacokinetic behavior of oral dosage forms exhibiting a dominating influence of the absorption/dissolution process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062939
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  • 2
    Electronic Resource
    Electronic Resource
    Generalizations in linear pharmacokinetics using properties of certain classes of residence time distributions. I. Log-convex drug disposition curves (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 635-657 
    Details
    ISSN: 1573-8744
    Keywords: drug disposition curve ; log-convexity ; residence time distribution ; noncompartmental analysis ; time-varying volume of distribution ; terminal exponential phase ; reliability theory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Introducing the phenomenoiogical concept of a time-varying fractional rate of elimination kD(t)and applying the theory of lifetime distributions, implications of the log-convexity of drug disposition curves are examined and some important applications are described. Linear pharmacokinetic systems exhibiting a log-convex impulse response and satisfying the basic conditions underlying the noncompartmental approach have the following properties: (1) The time-varying volume of distribution V(t)increases, and consequently the fractional rate of elimination kD(t)=CL/V(t)decreases monotonically. (2) The concentration-time curve and the time course of total amount of drug in the body, respectively, have an exponential tail [where V(t)approaches the equilibrium value VZ].The relative dispersion of residence times (CV D 2 =VDRT/MDRT2)and the ratio Vss/VZ (V ss is the volume of distribution at steady state) act as measures of departure from pure monoexponential decay (one-compartment behaviour). The role of the latter parameters as shape parameters of the curve that characterize the distributional properties of drugs is discussed. Upper and lower bounds of the time course of drug amount in the body are derived using the parameters MDRTand CV D 2 or λz (terminal exponential coefficient), respectively. This approach is also employed to construct upper bounds on the fractional error in AUCdetermination by numerical integration that is due to curve truncation. The significance of the fractional elimination rate concept as a unifying approach in interspecies pharmacokinetic scaling is pointed out. Some applications of the results are demonstrated, using digoxin data from the literature.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01067968
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  • 3
    Electronic Resource
    Electronic Resource
    Dynamics of drug distribution. I. Role of the second and third curve moments (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 253-278 
    Details
    ISSN: 1573-8744
    Keywords: dynamics of drug distribution ; curve moments ; residence time distribution ; circulation time distribution ; variance ; skewness ; drug disposition curve ; mixing curve ; non-compartmental analysis ; recirculation model ; noneliminating and eliminating system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Conventionally, the dynamics of distribution in the body is evaluated by the so-called distribution half-life (e.g., t 1/2,α but then the mean time of the distribution process is underestimated due tothe influence of elimination. By contrast, information about the dynamics of distribution contained in drug disposition curves can be extracted by the second and third curve moments, parameters that are related to the variance (VDRT)and skewness (SDRT)of residence time distributions; whereas the equilibrium state characterized by the volume of distribution (Vss), isdetermined by the mean residence time (MDRT)or the first curve moment. The approach represents a general noncompartmental analysis that is independent of a detailed structural model or a particular disposition function. Two parameters are introduced to characterize the dynamics of drug distribution: (i)the degree of departure of the system from “well-mixed” behavior of instantaneous distribution equilibrium (related to VDRT)and (ii)the mean time until equilibration is achieved (mean equilibration time, MEQT),which additionally depends on SDRT.Both parameters are quantitative measures of the dynamics of distribution and display explicit physical significance in terms of distribution within the corresponding noneliminating system. It is further shown that the so-called “distribution phase” in biexponential disposition curves is related to a monoexponential mixing curve of its corresponding noneliminating system with an equilibration or mixing half-time, t 1/2,M =t 1/2,α (Vβ/V ss * ), where V ss * denotes the distribution volume of the noneliminating system. The results are applied to mixing and disposition curves measured for acetaminophen in liver-ligated and intact rats, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062527
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