Pharmacokinetics data availability

The Mann et al. (1985) study is limited in that too few animals were used, organs other than the liver were not adequately evaluated, and only males were studied. Although an adequate acute-duration oral study would be useful to corroborate or refute the thyroid effects seen in the Mann et al. (1985) study, this does not represent a data need, since an acute oral MRL has been derived. Ingestion of contaminated drinking water is expected to be the predominant route of exposure for individuals living in the vicinity of hazardous waste sites. However, acute-duration inhalation and dermal studies in animals are needed to assess the potential toxicity of di- -octylphthalate following exposure via these routes because there are insufficient pharmacokinetic data available to support the extrapolation of data obtained after oral administration to other routes of exposure. 

Are the available data from the same route of exposure as the expected human exposures If not, are pharmacokinetic data available to extrapolate across route of exposure ... 

As discussed above, the main therapeutic value of DNase I is in the treatment of respiratory diseases. As a consequence, most of the pharmacokinetic data available are on the pharmacokinetics of DNase I after inhalation. Pharmacokinetic studies on animals have been reviewed by Green [87]. Inhalation experiments with ihDNase I revealed a low bioavailability of <15% in rats and <2% in monkeys. Studies in rats have indicated that the half-life of rhDNase from the lung is about 11 hours. Based upon the results from a phase I clinical trial, Aitken et al. reported the DNase I concentration in serum only increased slightly after 5 days inhalation of 6-30 mg rhDNase per day [64], The serum DNase levels did not differ significantly from the endogenous serum DNase levels as measured by Sinicropi et al. [88]. This suggested a low systemic exposure of DNase I in... 

The in vitro experiments, combined with the pharmacokinetic data available from the literature the absorption characteristics of the drugs and the optical properties of the tissues, resulted in an estimate of the capability of each compound to act as an in vivo photosensitizer. A thorough discussion of the photoreactivity of the... 

An important drug in the symptomatic treatment of spasticity associated with multiple sclerosis, baclofen, is chiral and used as the racemate. Although there is no stereo specific pharmacokinetic data available, it is known that the (—) enantiomer is more potent than antipode in alleviating spasticity and in eliciting antinociceptive reaction [218]. 

Approximately one hundred studies have been published to date on the bioavailability and pharmacokinetics of individual polyphenols following a single dose of pure compound, plant extract or whole food/beverage to healthy volunteers. We recently reviewed the pharmacokinetic data available for each class to estimate average pharmacokinetic parameters including the maximum concentration in plasma (Qnax)> Tmax> the area under the plasma concentration versus time curve (Al/Q, ehmination half-life (Ti/2) and percent of dose excreted in urine (Manach and Donovan 2004). Here, we present a summary of that data... 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

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. 

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. 

For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires experienced scientific judgment. The toxicity data from animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, the data from the most sensitive animal species are used to set AEGLs. Uncertainty factors are commonly used when animal data are used to estimate minimal risk levels for humans. The magnitude of uncertainty factors depends on the quality of the animal data used to determine the no-observed-adverseeffect level (NOAEL) and the mode of action of the substance in question. When available, pharmacokinetic data on tissue doses are considered for interspecies extrapolation. 

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... 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

Early IPL studies focused mostly on the metabolism of the bronchodilators and corticosteroids or the pharmacological activity of bronchodilators on the ex vivo preparation. Recently, the absorptive transfer of beclomethasone dipro-prionate (BDP) has been measured following administration to the human lung reperfusion model by two different commercially available inhalers for which human pharmacokinetic data are available for comparison [43],... 

The type of outcome data that are available from the patient samples will influence the choice of genes to be assessed. If only pharmacokinetic data are available, then there is no need to include pharmacodynamic genes in the study. However, pharmacokinetic genes could have an influence on outcome/toxicity and should be included with pharmacodynamic genes if outcome/toxicity data are available. 

Individual subjects skip a dose level when they receive placebo so that no pharmacokinetic data are available for this subject/occasion and the subject is exposed to a large dose increment on the next occasion. This disadvantage can be avoided by administering every dose of A to each subject and in addition each subject receives placebo on one randomised occasion. 

Rats and rabbits are the preferred species for prenatal toxicity studies because of the accumulated experience in developmental toxicity studies over many years. However, other species should be considered if the available metabolism or pharmacokinetic data show that they are more relevant to the human (see Note 1). 

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