Pharmacokinetic Data

Pharmacokinetics describes the time dependence of transport and distribution of a drug in the different compartments of a biological system, e.g. by rate constants of absorption, blood and tissue levels, and metabolism and elimination rate constants. Quantitative structure-pharmacokinetics relationships [433, 442, 451, 452, 472, 761 — 766] investigate the structural dependence of such parameters within groups of chemically related compounds. 

Much more complex models correlate the buccal absorption rate constants of these acids at different pH values, e.g. eq. 165 [479]. Even the rate constants for acidic and basic drugs can be combined to obtain one equation by using log Papp instead of log P (eq. Ill, chapter 4.5). 

The colonic absorption of different acidic compounds is described by eq. 110 (chapter 4.5) [442]. 

The blood-brain barrier penetration of Hj receptor antihistaminics has been correlated with A log P, the difference between n-octanol/water and cyclohexane/ water partition coefficients (eqs. 23 and 24, chapter 3.1) [199, 200]. An even better correlation could be obtained by using Aaik, a hydrogen-bonding capability parameter, and V, the van der Waals volume (eq. 169) [773]. 

Hansch emphasized the importance of lipophilicity for central nervous system-mediated and other nonspecific (e.g. toxic) side effects of drugs [771] hydrophobic 

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Table 9. Cephalosporin In I%ro Antibacterial Activity, pg/mL, and Pharmacokinetic Data ...

Many authors reported poor elimination of antiepileptic drug carbamazepine [6,13,17,49, 54]. Pharmacokinetic data indicate that only 1-2% of carbamazepine is excreted unmetabolized. However, glucuronide conjugates of carbamazepine can presumably be cleaved in the sewage, and thus increase its environmental concentrations [51]. This is confirmed by its high ubiquity in the enviromnent at concentration levels of several hundred nanograms per liter in different surface waters. Due to its recalcitrant nature, it can be used as anthropogeiuc marker for the contamination of aquatic environment. 

The terminase inhibitors so far tested in the clinic have shown excellent safety, tolerability and pharmacokinetic data after single oral doses in healthy male subjects (Nagelschmitz et al. 1999 Reefschlaeger et al. 1999). 

Sculier, J. P., Coune, A., Brassine, C., Laduron, C., Atassi, G., Ruysschaert, J. M., and Fruhling, H. (1986). Intravenous infusion of high doses of liposomes containing NSC 251635, a water-insoluble cytostatic agent. A pilot study with pharmacokinetic data, J. Clin. Oncol., 4, 789-797. 

Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters. II. Biexponential model and experimental pharmacokinetic data. / Pharmacokinet Biopharm 1981 9 635-51. 

Analysis of most (perhaps 65%) pharmacokinetic data from clinical trials starts and stops with noncompartmental analysis (NCA). NCA usually includes calculating the area under the curve (AUC) of concentration versus time, or under the first-moment curve (AUMC, from a graph of concentration multiplied by time versus time). Calculation of AUC and AUMC facilitates simple calculations for some standard pharmacokinetic parameters and collapses measurements made at several sampling times into a single number representing exposure. The approach makes few assumptions, has few parameters, and allows fairly rigorous statistical description of exposure and how it is affected by dose. An exposure response model may be created. With respect to descriptive dimensions these dose-exposure and exposure-response models... 

Air Force. 1990. Development and validation of methods for applying pharmacokinetic data in risk assessment Volume n. Trichloroethylene. Wright-Patterson Air Force Base, OH U.S. Air Force, Air Force Systems Command, Harry G. Armstrong Medical Research Laboratory, Human Systems Division. NTIS No. AD-A237 366. 

G. S. Klonicki, Using SAS/ETS Software for Analysis of Pharmacokinetic Data. SAS Institute Inc., Cary, NC, 1993. 

J. Powers, Statistical analysis of pharmacokinetic data. J. Vet. Pharmacol. Therap., 13 (1990) 113-120. 

Our pharmacokinetic data indicate that detectable PCP levels may remain in the urine for 4 to 5 weeks after the last use, similar to previous reports (Khajawall and Simpson 1983). The observed elimination kinetics were equally consistent with a one- or two-compartment model, but methodological problems with our data make... 

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). 

DWA Bourne. Mathematical Modeling of Pharmacokinetic Data. Lancaster, PA Technomic Publishing Company, 1995. 

All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

No intermediate-duration dermal studies of hydrogen sulfide were identified. As significant human dermal exposure to hydrogen sulfide is unlikely, dermal exposure studies should not be a high priority. However, no pharmacokinetic data are available that might support the identification of target organs across routes of exposures in the absence of route-specific toxicity data. 

Major questions that arise whenever a pesticide exposure evaluation is completed are how good are the data and how close to the real answer have we gotten For most commercially sold insecticides, there are no appreciable pharmacokinetic data in human systems, although some data normally exist for animal models. Because such pharmacokinetic data do not exist for most active insecticides, passive dosimetry measurements must be used to estimate the exposure and eventually dose. Once such passive dosimetry data exist, certain assumptions must be made to arrive at an estimate of dose. 

R Brown, H Seifried. Extrapolation of in vivo metabolic rate constants from in vitro pharmacokinetic data. Washington, DC US Environmental Protection Agency, 1988. 

LZ Benet, S 0ie, JB Schwartz. Design and optimization of dosage regiments pharmacokinetic data. In JG Hardman, LE Limbird, AG Gilman, eds. The Pharmacological Basis of Therapeutics. 9th ed. New York McGraw-Hill 1996, pp 1707-1793. 

In assessing animal data, careful attention must be paid to the quality of the data, the incidence of spontaneous tumors in the control population, consistency if more than one study is available, and statistical validity. If the exposure route and experimental regimen employed do not agree with the most likely mode(s) of human exposure (e.g., intramuscular injection), the data must be interpreted cautiously. Consideration should be given to data on metabolism of the compound by the animal species tested, as compared with metabolism in humans if this information is known. If only in vitro data are available, only qualitative estimates may be possible because of uncertainties regarding the association between in vitro results and human or animal effects. The availability of associated pharmacokinetic data, however, may allow development of a rough quantitative estimate. 

Jack, D. B., Handbook of Clinical Pharmacokinetic Data, Macmillan Publishers Ltd, Basingstoke, 1992. 

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