Pharmacokinetic exposure

Shelton M J, Wynn HE, Hewitt RG, DiFrancesco R. Effects of grapefruit juice on pharmacokinetic exposure to indinavir in HIV-positive subjects. J Clin Pharmacol 2001 41 (4) 435-442. 

PB-PK modelling allows further refinement of the dose-response evaluation by partitioning the relationship into pharmacokinetic (exposure vs. tissues dose) and pharmacodynamic (tissue dose vs. toxic response) components. This allows the uncertainties associated with each component to be assessed separately and adds accuracy to the overall animal to man extrapolation. Future developments of PB-PK modelling may allow specific sub-populations such as the newborn or individuals with metabolic variations to be taken into account. However, before this can be done there will need to be considerable growth in the amounts of physiological, pharmacokinetic and pharmacodynamic information available. 

Kovarik JM, Kahan BD, Kaplan B, Lorber M, Winkler M, Rouilly M, Gerbeau C, Cambon N, Boger R, Rordorf C Everolimus Phase 2 Study Group. Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 2001 69(l) 48-56. 

Since other analyses using a pharmacokinetic exposure metric [metabolized dose, as described by OEHHA 1992)] will be reported below, the analysis of these data using metabolized dose as the exposure metric was performed for comparison. Using the MSTAGE program (Crouch 1985), a linear model fitted the data with q (MLE) =1.5 and qf = 0.19 (mg/kg-day). ... 

Of relevance to the discussions just mentioned is a study recently reported by Yu and colleagues (Yu et al. 2016). The overall study included both a Phase I dose escalation, placebo-controlled study and a TQT study for mipomerseu. The Phase I study revealed no positive correlation between QTc and pharmacokinetic exposure across a wide dose range tested. The TQT yielded a negative finding, with upper bounds of two-sided 90% confidence intervals well below 10 msec at both therapeutic and supratherapeutic doses. The authors concluded that the overall study results supported the proposal that QT assessment can be made in a Phase I dose escalation study and that a TQT study may not be necessary if the Phase I dose escalation study showed a negative QT effect. ... 

The debate about the relation between autism and mercury (as thimerosal) in vaccines continues, without useful conclusions [37 ]. In a population-based study of the pharmacokinetics of mercury after immunization of 72 premature infants weighing 2000-3000 g at birth, the mean maximal blood mercury concentration was 3.6 fig/l, and it occurred at 1 day after immunization the maximal mean stool mercury concentration was 35 ng/g, and it occurred on day 5 urine mercury was almost undetectable [38 ]. The blood mercury half-life was 6.3 (95% Cl = 3.9S.8) days, and mercury concentrations returned to prevaccination values by day 30. The blood half-life of intramuscular ethyl mercury from thimerosal in vaccines given to premature infants is substantially shorter than that of oral methyl mercury in adults. Because of the differing pharmacokinetics, exposure guidelines based on oral methyl mercury in adults may not be accurate for children who receive thimerosal-containing vaccines. 

Exposure should be by the practical route. Other conditions, such as number and magnitude of exposures, should kiclude at least one level representative of the practical situation monitoring should be appropriate to the needs for conducting the study and when practically and economically possible, pharmacokinetic observations should be undertaken ki order to better define the relationship of dose to metaboHc thresholds. 

Pharmacokinetic studies should allow an assessment of the relationship between the environmental-exposure conditions and the absorbed dose, and how these influence the doses of test material and metaboHtes received by various body tissues and fluids, and the potential for storage. Numerous texts are available on the design and conduct of metaboHsm and pharmacokinetic studies (117—119). 

Vinyhdene chloride is hepatotoxic, but does not appear to be a carcinogen (13—18). Pharmacokinetic studies indicate that the behavior of vinyl chloride and vinyhdene chloride in rats and mice is substantially different (19). No unusual health problems have been observed in workers exposed to vinyhdene chloride monomer over varying periods (20). Because vinyhdene chloride degrades rapidly in the atmosphere, air pollution is not likely to be a problem (21). Worker exposure is the main concern. Sampling techniques for monitoring worker exposure to vinyhdene chloride vapor are being developed (22). 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-4 shows a conceptualized representation of a PBPK model. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987 Andersen and Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of... 

Andersen ME, MacNaughton MG, Clewell HJ, et al. 1987. Adjusting exposure limits for long and short exposure periods using a physiological pharmacokinetic model. Am Ind Hyg Assoc J 48(4) 335-343. 

BEIs apply to 8 hr exposures, five days a week. However, BEIs for altered working schedules can be extrapolated on pharmacokinetic and pharmacodynamic bases. BEIs should not be applied, either directly or through a conversion factor, to the determination of safe levels for non-occupational exposure to air and water pollutants, or food contaminants. The BEIs are not intended for use as a measure of adverse effects or for diagnosis of occupational illness. 

Figure 21.2 The exposure-response road map passes through pharmacokinetics and pharmacodynamics. This sequence of events is essentially the same as that which informs compnter simulation of clinical trials, with the addition of complicating, bnt important, factors snch as protocol adherence and dropouts.

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... 

Alcohol can affect the metabolism of trichloroethylene. This is noted in both toxicity and pharmacokinetic studies. In toxicity studies, simultaneous exposure to ethanol and trichloroethylene increased the concentration of trichloroethylene in the blood and breath of male volunteers (Stewart et al. 1974c). These people also showed "degreaser s flush"—a transient vasodilation of superficial skin vessels. In rats, depressant effects in the central nervous system are exacerbated by coadministration of ethanol and trichloroethylene (Utesch et al. 1981). 

Fisher JW, Whittaker TA, Taylor DH, et al. 1989. Physiologically based pharmacokinetic modeling of the pregnant rat A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. Toxicol Appl Pharmacol 99 395-414. 

Monster AC, Boersma G, Duba WC. 1976. Pharmacokinetics of trichloroethylene in volunteers Influence of workload and exposure concentration. Int Arch Occup Environ Health 38 87-102. 

Sato A, Nakajima T, Fujiwara Y, et al. 1977. A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure. Br J Ind Med 34 55-63. 

A knowledge of physiology and pharmacokinetics is needed (Fanis et al. 1993 Monteiro and Furness 2001). Levels of mercuiy normally vary among internal tissues, and the time to equilibrate within each tissue varies. For example, blood mercury levels normally reflect veiy recent exposure, while brain and liver levels reflect longer-term exposure. Tissue-specific mechanisms of detoxification and seqnestration, among other processes, must be understood to define the bioactive moiety in observed tissue bmdens before a clear expression of toxicity can be derived (Woodetal. 1997). 

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