Pharmacokinetic parameters clearance

Figure 1 Correlation of pharmacokinetic parameters (clearance, panel A volume of distribution, panel B and half-life, panel Q of 170C-la antagonists obtained by cassette (y-axis) or singlet (x-axis) intravenous dosing to rats. (Reproduced with permission from Ref. 4.)...

Covariate screening methods are used when there are a large number of covariates, such that evaluating every possible combination in a model is prohibitive. With this methodology, EBEs of the random effects are treated as data and then exploratory methods are used to assess the relationship between the random effects and the covariate of interest. In other words, each individual s pharmacokinetic parameter, clearance for example, is estimated and treated as a being without measurement error. These Bayes estimates are then compared against subject-specific covariates for a relationship using either manual or automated methods. 

Fig. 4 Allometric plots of the pharmacokinetic parameters clearance, volume of the central compartment ( /c), volume of distribution at steady state Vss), and elimination half-life of rPSGL-lg. Each data point within the plot represents an averaged value ofthe pharmacokinetic parameter with increasing weight from mouse, rat, monkey (3.74 kg), monkey (6.3 kg), and pig, respectively. The solid line is the best fit with a power function to relate pharmacokinetic parameters to body weight (from [54]).

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

From the AUC and knowing the dose, one can immediately derive from eq. (39.12) an important pharmacokinetic parameter which is the clearance Cl of the drug from the plasma ... 

Although most CF patients have shorter half-lives and larger volumes of distribution than non-CF patients, some patients exhibit decreased clearance. Possible causes include concomitant use of nephrotoxic medications, presence of diabetic nephropathy, history of transplantation (with immunosuppressant use and/or procedural hypoxic injury), and age-related decline in renal function in older adult patients. Additionally, CF patients are repeatedly exposed to multiple courses of IV aminoglycosides, which can result in decreased renal function. Evaluation of previous pharmacokinetic parameters and trends, along with incorporation of new health information, is key to providing appropriate dosage recommendations. 

Drugs can be cleared from the body by metabolism as well as renal excretion, and when this occurs it is not possible to measure directly the amount cleared by metabolism. However, the total clearance rate (TCR), or total body clearance, of the drug can be calculated from its pharmacokinetic parameters using the following equation ... 

Studies interested in the determination of macro pharmacokinetic parameters, such as total body clearance or the apparent volume of distribution, can be readily calculated from polyexponential equations such as Eq. (9) without assignment of a specific model structure. Parameters (i.e., Ah Xt) associated with such an equation are initially estimated by the method of residuals followed by nonlinear least squares regression analyses [30],... 

The term clearance is used here in the sense of total body clearance and is analogous to the term renal clearance. The body as a whole is regarded as acting as a xenobiotic-eliminating system, where the rate of elimination divided by the average plasma concentration of the compound is the total body clearance. Here clearance is calculated (25) by dividing the administered dose of the substance by the area under the plasma concentrationtime curve produced by that dose. This pharmacokinetic parameter, as well as others presented in this publication, was calculated by the use of the MLAB on-line computer system established at the National Institutes of Health by Knott and Reece (26). Similar to t the total clearance is a composite of the individual clearances of the material by the various tissues of the body. 

The pharmacokinetic parameters of octane are more like those of dieldrin than DDT while the clearance of all three of these compounds is somewhat greater than that of PAH. While the initial half life of DEHP is longer (36 min.) than any other compound in Table VI, its second phase t is rapid (3 hrs.) while the is equal to that of the plasma volume. The clearance of DEHP isu about one-half that of PAH. 

Numerous studies have been published on the in vivo metabolism of peptides. However, these studies are concerned mainly with assessment of pharmacokinetic parameters such as half-life and clearance. Only seldom is the in vivo biotransformation of peptides that contain only common amino acids investigated in any detail, due to the difficulty of monitoring products of proteolysis that are identical to endogenous peptides and amino acids. More importantly, such studies fail to yield mechanistic and biochemical insights. For this reason, we begin here with a discussion of the metabolism of just a few peptides in some selected tissues, namely portals of entry (mouth, gastro-intestinal tract, nose, and skin), plasma, organs of elimination (liver, kidney), and pharmacodynamic sites (brain and cerebrospinal fluid). These examples serve as introduction for the presentation in Sect. 6.4.2 of the involvement of individual peptidases in peptide metabolism. 

The three main parameters of clinical pharmacokinetics are clearance, distribution volume, and bioavailability. Clearance is the rate at which the body eliminates a drug. In order to achieve a steady-state concentration, the drug must be given so that the rate of clearance equals the rate of administration. If the drug is given as quickly as it is eliminated, a consistent level in the body will be maintained. 

Bioavailability is the other important conceptual pharmacokinetic parameter, in addition to clearance. The key concepts are summarised in Box 5.3. Bioavailability is defined as the proportion of an administered dose that reaches the systemic circulation. It has no units and is... 

Physicians may be surprised to see that mention of half-life has been dealt with so late in this chapter, as it is likely to be the pharmacokinetic term most familiar to them. The key concepts are summarised in Box 5.5. As mentioned earlier, half-life is not only a primary pharmacokinetic parameter but is also one of the descriptive terms. Although many physicians will readily accept that changes in clearance wiU alter half-life, what is not quite so obvious is that half-life is equally determined by volume of distribution and in fact there is an equation relating these three terms ... 

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

For drugs that follow first-order kinetics, in addition to clearance, the half-life is a useful pharmacokinetic parameter to describe elimination. The elimination half-life (tj/j) is the time required for the concentration of drug to decrease by 50%. In clinical practice, this parameter is referred to as the plasma (or serum) half-life and is usually assessed by measuring the fall of... 

Valproic acid is eliminated by first-order kinetics and has an elimination half-life of 5-20 hours (average, 10.6 hours). Pediatric patients (3 months to 10 years) have a 50% higher clearance of the drug expressed by weight (i.e., mL/min/kg) over the age of 10 years, pharmacokinetic parameters of valproic acid approximate those in adults (Cloyd et al., 1993). Valproic acid is metabolized principally in the liver by (3 (over 40%) and CO oxidation (up to 15%-20%). Thirty through 50% of an administered dose is excreted as glucuron-ide conjugates (Cloyd et al., 1993). 

Cohen et al. (1999) reported an absence of a clinically significant pharmacokinetic interaction between DMI and stimulants in children. In their study, 403 serum concentrations from 142 subjects were examined. Pharmacokinetic parameters were similar for both the DMI and DMI + stimulant groups, including the mean weight-corrected dose (mg/kg), weight and dose-normalized DMI serum concentrations [( ig/L)/ mg/kg], and DMI clearance (L/kg)/hr. 

Pharmacokinetics A mean elimination half-life of approximately 5 hours has been reported after intravenous doses of Roferon-A. Pharmacokinetic parameters are similar in healthy subjects and cancer patients after intramuscular doses. Dose-proportionate increases in serum levels occur with doses up to 198 MIU. The bioavailability of interferon alfa-2a after intramuscular administration is 80% to 83%, and its volume of distribution is 0.223 to 0.748 liter/kg. The total body clearance of interferon alfa-2a has been reported to range from 2.14 to 3.62ml/min per kg. 

Pharmacokinetics After administration of Enbrel 25 mg by a single subcutaneous injection to patients with RA, a median half-life of 115 hours (range 98-300 hours) was observed with a clearance of 89ml/h. Based on available data, individual patients may undergo a two-to five-fold increase in serum levels of etanercept with repeated dosing. Pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. No formal phar-... 

The basic principles outlined above can be applied to the interpretation of clinical drug concentration measurements on the basis of three major pharmacokinetic variables absorption, clearance, and volume of distribution (and the derived variable, half-life) and two pharmacodynamic variables maximum effect attainable in the target tissue and the sensitivity of the tissue to the drug. Diseases may modify all of these parameters, and the ability to predict the effect of disease states on pharmacokinetic parameters is important in properly adjusting dosage in such cases. (See The Target Concentration Strategy.)... 

For women, the result should be multiplied by 0.85 (because of reduced muscle mass). It must be emphasized that this estimate is, at best, a population estimate and may not apply to a particular patient. If the patient has normal renal function (up to one third of elderly patients), a dose corrected on the basis of this estimate will be too low—but a low dose is initially desirable if one is uncertain of the renal function in any patient. If a precise measure is needed, a standard 12- or 24-hour creatinine clearance determination should be obtained. As indicated above, nutritional changes alter pharmacokinetic parameters. A patient who is severely dehydrated (not uncommon in patients with stroke or other motor impairment) may have an additional marked reduction in renal drug clearance that is completely reversible by rehydration. 

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