Pharmacokinetics mean residence time

The truncated part of the integral can be obtained by numerical integration (e.g. by means of the trapezium rule) of the function rCp(r) between times 0 and T. The mean residence time MRT is an important pharmacokinetic parameter, especially when a substantial fraction of the drug is excreted or metabolized during its first pass through an organ, such as the liver. 

Chanter DO. The determination of mean residence time using statistical moments is it correct J Pharmacokinet Biopharm 1985 13 93-100. 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

The pharmacokinetics of meropenem in pediatric patients 2 years of age and oider are essentiaiiy simiiar to those in aduits. In infants and chiidren 2 months to 12 years of age, no age- or dose-dependent effects on pharmacokinetic parameters were observed. Mean haif-iife was 1.13 hours, mean voiume of distribution at steady state was 0.43 L/kg, mean residence time was 1.57 hours, ciearance was 5.63 mL/min/kg and renai ciearance was 2.53 mL/min/kg. The eiimination haif-iife is siightiy proionged (1.5 hours) in pediatric patients 3 months to 2 years of age. 

H. Cheng, W. R. Gillespie, and W. J. Jusko. Review article mean residence time concepts for non-linear pharmacokinetic systems. Biopharm. Drug Dispos. 15 627-641, 1994. 

Pharmacokinetic Measures of Systemic Exposure Both direct (e.g., rate constant, rate profile) and indirect (e.g., Cmax, Tmax, mean absorption time, mean residence time, Cmax normalized to AUC) pharmacokinetic measures are limited in their ability to assess rate of absorption. This guidance, therefore, recommends a change in focus from these direct or indirect measures of absorption rate to measures of systemic exposure. Cmax and AUC can continue to be used as measures for product quality BA and BE, but more in terms of their capacity to assess exposure than their capacity to reflect rate and extent of absorption. Reliance on systemic exposure measures should reflect comparable rate and extent of absorption, which in turn should achieve the underlying statutory and regulatory objective of ensuring comparable therapeutic effects. Exposure measures are defined relative to early, peak, and total portions of the plasma, serum, or blood concentration-time profile, as follows ... 

The data pertinent to the assessment of the impact of obesity on the disposition of the developmental drug from study described above, was evaluated as follows Descriptive pharmacokinetic parameters (total clearance (CL or CL/F), mean residence time (MRT),... 

The focus before IND is on Tmax, Cmax and AUCs, while the complexity of pharmacokinetic characterization (like oral bioavailability, plasma half life, volume of distribution, mean residence time, absorption, solubility and concentration) is built up during clinical trials and on the basis of comparable human data. 

The use of the mean residence time matrix can be a powerful tool in pharmacokinetic analysis with a compartmental model, especially if one is dealing with a model of the system in which physiological and/or anatomical correlates are being assigned to specific compartments (2). Modeling software tools such as SAAM II (21) automatically calculate the mean residence time matrix from the compartmental matrix, making the information easily available. 

Ward KW, Smith BR. A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. II. Volume of distribution and mean residence time. Drug Me tab Dispos 2004 32 612-19. 

Cheng, H. Gillespie, W.R. Jusko, W.J. Mean residence time concepts for non-linear pharmacokinetic systems. Biopharm Drug Dispos. 1994, 15 (8), 627-641. 

The mean in vitro dissolution time is compared to either the mean residence time or the mean in vivo dissolution time. Level B correlation, like Level A correlation, uses all of the in vitro and in vivo data but is not considered to be a point-to-point correlation and does not uniquely reflect the actual in vivo plasma level curve, since several different in vivo plasma level-time curves will produce similar residence times. A Level C correlation is the weakest IVIVC and establishes a single point relationship between a dissolution parameter (e.g., time for 50% of drug to dissolve, or percent drug dissolved in two hours, etc.) and a pharmacokinetic parameter (e.g., AUC, Cmax, Tmax). Level C correlation does not reflect the complete shape of the plasma drug concentration-time curve of dissolution profile. 

The mutual pharmacokinetic interaction of nevirapine with ethinylestradiol + norethindrone has been studied in 10 women (26). After a single dose of ethinylestradiol -I- norethindrone, they took oral nevirapine 200 mg/day (days 2-15), followed by 200 mg bd (days 16-29) on day 30 they took another dose of ethinylestradiol + norethindrone. Steady-state nevirapine reduced the AUC of ethinylestradiol by 29% and significantly reduced its mean residence time and half-life. The AUC of norethindrone was significantly reduced by 18%, but there was no change in C ax, mean residence time, or half-life. The kinetics of nevirapine were not affected by the oral contraceptive. The authors attributed this interaction to increased clearance of ethinylestradiol and concluded that oral contraceptives should not be the primary method of birth control in women of child-bearing potential who are taking nevirapine. 

The mean residence time is the equivalent of half-life and is the parameter calculated when non-compartmental methods are used to determine pharmacokinetic values. Some pharmacokinetic studies report mean residence time instead of half-life. The mean residence time is actually the time taken for the plasma drug concentration to decrease by 63.2% and should thus be somewhat greater than half-life. 

The advantages of using non-compartmental methods for calculating pharmacokinetic parameters, such as systemic clearance (CZg), volume of distribution (Vd(area))/ systemic availability (F) and mean residence time (MRT), are that they can be applied to any route of administration and do not entail the selection of a compartmental pharmacokinetic model. The important assumption made, however, is that the absorption and disposition processes for the drug being studied obey first-order (linear) pharmacokinetic behaviour. The first-order elimination rate constant (and half-life) of the drug can be calculated by regression analysis of the terminal four to six measured plasma... 

Pharmacokinetics After Oral and Intravenous Administration. For proper characterization of an inhalation drug, information on the systemic pharmacokinetic properties needs to be provided. One of the major challenges for such studies is to provide a suitable formulation for injection, especially because new drug candidates are often very lipophilic. The resulting parameters of such studies (systemic clearance, volume of distribution, half-life, mean residence time) can then easily be extracted from concentration-time profiles after IV administration and subsequent standard pharmacokinetic analysis by noncompartmental approaches. In addition, a detailed compartmental analysis based on concentration-time profiles will be useful in evaluating the systemic distribution processes in sufficient detail. This will be especially important if deconvolution procedures (see later) are included for the assessment of the pulmonary absorption profiles. 

This approach is robust because it does not rely on any pharmacokinetic assumptions and allows the characterization of absorption processes among different drugs if IV data are available. For example, differences in the absorption profiles between fluticasone propionate and budesonide can easily be identified with this method, while differences in fmax were not able to readily provide this information. The mean residence time without availability of intravenous data should not be used to compare absorption profiles of different drug entities, because it is also determined by the systemic elimination of the drug. This approach is, however, suitable for evaluating the differences of different formulations of the same drug. 

Pharmacodynamics. Since ranibizumab is delivered via an intravitreal injection, studies were undertaken to determine if the drug could cross the neural retina and access the subretinal space where the CNV lesions are located. A study in rhesus monkeys demonstrated that 25 pg in 50 pL of Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer after one hour and persisted in this location for up to seven days (10). The half-life in the vitreous was 3.2 days. These data are consistent with the results of a pharmacokinetic study done by a noninvasive fluorophotometric method that showed that fluorescein-labeled ranibizumab disappeared from the vitreous with a mean terminal half-life of 2.9 days and a mean residence time of 4.2 days (11). 

The same extract was given to healthy volunteers as film-coated tablets in single doses of 300, 600 and 1200 mg. Mean Cmax concentrations of 153, 302 and 437 ng/ml were observed after 3 h (Table 4). The lag time of absorption was about 1.5 h. Terminal half-life (t p) and mean residence time (MRT) were 9 and 12 h, respectively. Pharmacokinetics were linear up to 600 mg, at 1200 mg lower Cmax and AUC values were observed as were expected from a linear function. The plasma concentration time course could be described by an open two-compartment model, with a distribution half-life (imo) of about 2.7 h. 

Salmonson et al. [54] also described the pharmacokinetics of rHuEPO after intravenous and subcutaneous administration of 50U/kg to six healthy male volunteers. The calculated mean values for volume of distribution at steady state and clearance after an i.v. dose were 76 33 mL/kg and 12.0 + 3.0mL/h/kg, respectively. Serum concentrations of rHuEPO peaked at 13.0 6.0h after the s.c. dose and the bioavailability over 72 h was 36 23%. The mean residence time and half-life of rHuEPO were 6.2 1.0 and 4.5 0.9 h after i.v. and 46 18 and 25 + 12h after s.c. administration. They found that the serum concentration time profiles after i.v. adminisitaration followed a mono- or bi-exponential decline, and the elimination after s.c. dose was described by a mono-exponential decline. 

Pharmacokinetic Analysis. Standard noncompartmental analyses were conducted to assess ATI and ATF pharmacokinetics using WinNonlin software (v. 2.1) (Pharsight, Mountain View, CA). The areas under the plasma concentration versus time curve from time zero to inhnity (AUCint) were determined via the log-linear trapezoidal method. The terminal half-life was determined from the relationship of ti/2 = In 2/, where k is the negative slope of the terminal phase of the InC versus time plot. Systemic clearance (CL) was estimated by dividing the administered dose by AUCint. The volume of distribution at steady state (Vss) was determined by the product of clearance and the mean residence time. 

Some pharmacokinetic software packages perform noncompartmental analysis without fitting the entire response curve. These programs compute the elimination rate constant (k) for the terminal elimination phase of the data, and then use a trapezoidal rule with this elimination rate constant to compute AUC and AUMC. With these terms, the total body clearance, the steady-state volume of distribution, and the mean residence time in the body can be calculated. Without C , it is not possible to calculate the volume of distribution of the central compartment or the mean residence time of the sampling compartment. The latter term is therefore critical in accurately determining these parameter values and depends on an unbiased and close fit of the data to Equations 13.2 and 13.6. 

Veng-Pedersen, P, Mean time parameters in pharmacokinetics. Definition, computation and clinical implications (Part II), Clin. Pharmacokinet., 17 424 40, 1989. Veng-Pedersen, R, Mean time parameters in pharmacokinetics. Definition, computation and clinical implications (Part I), Clin. Pharmacokinet., 17 345-366, 1989. Aarons, L., Mean residence time for drugs subject to reversible metabolism, J. Pharm. Pharmacol., 39 565-567, 1987. 

Veng-Pedersen, P. and Gillespie, W., Mean residence time in peripheral tissue a linear disposition parameter useful for evaluating a drug s tissue distribution, J. Pharmacokinet. Biopharm., 12 535-543, 1984. 

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