Plasma pharmacokinetic data

Prediction of Withdholding Times from Plasma Pharmacokinetic Data... 

A typical semi-log plasma concentration versus time plot is shown in Fig. 4. This figure shows that pharmacokinetic data can also be expressed in terms of a half-life, called the biological half-life, which bears the same relationship to kei as that shown in Eqs. (14) and (15). 

AED pharmacokinetic data are summarized in Table 52-3. For populations known to have altered plasma protein binding, free rather than total serum concentrations should be measured if the AED is highly protein bound. Conditions altering AED protein binding include chronic renal failure, liver disease, hypoalbuminemia, burns, pregnancy, malnutrition, displac-... 

Metabolism and/or pharmacokinetic data, when available, should also be considered in the dose selection process. It is desirable that a drug not be administered at such a high dose that it is excreted in a different manner than at lower doses, such as the MRHD. Similarly, the high dose should not lead to the formation of metabolites other than those formed at lower (clinical) doses. If data show that a given dosage produces maximum plasma levels, administration of higher... 

Two classical methods used in the analysis of pharmacokinetic data are the fitting of sums of exponential functions (2- and 3-compartment mammillary models) to plasma and/or tissue data, and less frequently, the fitting of arbitrary polynomial functions to the data (noncompartmental analysis). 

Pharmacokinetic data reported thus far show dose-proportional exposure with a short half-life of ca. 2 h. Exposure in patients receiving 250 mg/day of CP-724714 reportedly exceeds the plasma levels required for efficacy in precHnical tiunor xenograft models (50 to 60% TGI). However, robust efficacy (stasis or minor regression) in mouse models was only achieved at doses resulting in plasma exposures 40% higher than those observed in humans. From a kinetic standpoint, it appears that within 3 h, plasma concentrations in hiunans of CP-724714 fall below the levels required for pErbB knockdown in mouse models. This analysis, of course, neglects free fraction differences that may exist between species and the differential levels of active metabohtes. Enrollment in this trial continues at the 250 mg/tid dosing level. 

Chinese hamster ovary (CHO) cells and baby hamster kidney (BHK) cell lines have been most commonly used, in addition to other cell lines, such as various mouse carcinoma cell lines. The recombinant factor VIII product generally contains only VIILC (i.e. is devoid of vWF). However, both clinical and pre-clinical studies have shown that administration of this product to patients suffering from haemophilia A is equally as effective as administering blood-derived factor VIII complex. The recombinant VIILC product appears to bind plasma vWF with equal affinity to native VIILC, upon its injection into the patient s circulatory system. Animal and human pharmacokinetic data reveal no significant difference between the properties of recombinant and native products. 

Pharmacokinetics Human pharmacokinetics data are limited. Based on preclinical data, it is slowly absorbed into systemic circulation from the eye after intravitreous administration. Metabolized by endo- and exonucleases. Excreted in urine. Half-life 10 days (plasma). 

Much has been published on the extrapolation of in vivo data from animals to humans. These include pharmacokinetic data (e.g. half-lives, plasma concentrations, clearances and rates of metabolism) and pharmacodynamic data (e.g. effective and toxic doses). Two excellent reviews present many examples and insightful discussions on isometric and allometric relationships, time scales, interspecies pharmacokinetic and pharmacodynamic scaling, and physiological models (Boxenbaum and D Souza, 1990 Chappell and Mordenti, 1991). 

Pharmacokinetic data have demonstrated very good absorption of the orally administered oxfendazole to cattle and sheep. After administration of the drug, the plasma metabolite pool is composed of oxfendazole, fenbendazole sulfone. 

Pharmacokinetic data after intravenous, intraruminal, or subcutaneous administration of 0.25-0.5 mg flumethasone/kg bw/day for 8 days in sheep showed that maximum plasma levels were reached within 48 h postdosing. The metabolic clearance was estimated at about one-quarter to three-quarters of that found for cortisol in sheep. 

As mentioned in Chapter 4, experiments have determined that the distribution of ASOs into tissues is nonlinear. This revelation invalidates the above BAV equation in that it is dependent on linear pharmacokinetics and the principle of superposition. A way to circumvent this problem is to decrease the drag input function (i.e., systemic presentation of the ASO) such that ASO plasma concentrations are maintained below the level at which saturation, and thus nonlinearity of the distribution processes, occurs. Drug administration by SC rather than IV administration has a reduced drug input rate and can produce such a scenario. The corresponding plasma-derived data are then suitable for the determination of absolute bioavailability - consistent with linear pharmacokinetic principles and the following equation ... 

Pharmacokinetic data were available for 97 patients. The tasidotin plasma concentrations declined rapidly, and were less than 1% of maximal concentrations within about 8 h after dosing (Fig. 13.2). With such a short effective half-life, accumulation with daily tasidotin administration was not likely - once-daily multiple doses resemble a series of single doses. Concentrations appeared to decline in a biphasic manner (Fig. 13.2). The presence of a third, gamma phase was observed in some patients, but was not consistently detected, and for this reason the effective half-life was calculated instead of the terminal elimination phase half-life. 

The administration of a drug by a rapid intravenous injection places the drug in the circulatory system where it is distributed (see section 2.7.1) to all the accessible body compartments and tissues. The one compartment model (Figure 8.3(a)) of drug distribution assumes that the administration and distribution of the drug in the plasma and associated tissues is instantaneous. This does not happen in practice and is one of the possible sources of error when using this model to analyse experimental pharmacokinetic data. 

The choice of the concentration of the drug to be tested should consider therapeutic levels that could be attained with clinically employed doses. In the case of a compound under pre-clinical evaluation for a potential antitumor activity, a concentration limit of 100 pg/ml is recommended. Pharmacokinetic data are available for various anti-neoplastic clinically used drugs, with information about their maximum plasma concentration, concentration versus time, and pharmaceutical half-life in plasma. When these data are not available, an approximation of plasma levels could be obtained by calculating the theoretical concentration obtained when the administered dose is uniformly distributed throughout the body fluid. 

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