Total systemic exposure measurement

Pharmacokinetic Measures of Systemic Exposure Both direct (e.g., rate constant, rate profile) and indirect (e.g., Cmax, Tmax, mean absorption time, mean residence time, Cmax normalized to AUC) pharmacokinetic measures are limited in their ability to assess rate of absorption. This guidance, therefore, recommends a change in focus from these direct or indirect measures of absorption rate to measures of systemic exposure. Cmax and AUC can continue to be used as measures for product quality BA and BE, but more in terms of their capacity to assess exposure than their capacity to reflect rate and extent of absorption. Reliance on systemic exposure measures should reflect comparable rate and extent of absorption, which in turn should achieve the underlying statutory and regulatory objective of ensuring comparable therapeutic effects. Exposure measures are defined relative to early, peak, and total portions of the plasma, serum, or blood concentration-time profile, as follows ... 

AUC, Area under the plasma concentration curve over all time A measure of total systemic exposure. AUC((M) denotes the area under the curve from zero to any time point t. 

Total systemic exposure to an administered drug is usually measured by the area under the drug concentration curve. For each participant the drug concentration (in nanograms/milliliter) can be plotted as a function of time, as displayed in Figure 7.1. The maximal drug concentration (Cni ) and the time at which it is observed... 

The area nnder the plasma drng concentration and time cnrve (AUC AUC., or AUC Xnnits = ag.h/ml, ng.h/ml, etc.) AUC is the measure of the extent of drug bioavailability. This gives a measure of the total systemic exposure. The AUC can be calculated from Equation 5.1, which can be rearranged as Equation 5.2 to determine the fraction of the dose absorbed. 

The oral bioavailability (F) of a drug is dependent on (a) the absorption of the drug from the gastrointestinal (GI) tract and (b) the capability of the liver to clear the drug during its first pass through the portal venous system. Oral bioavailability may be described as the fraction of the total oral dose for which systemic exposure is achieved. It is a measurement of the extent of exposure and contrasts with the rates of absorption or elimination discussed above. 

AUC can be obtained by a numerical integration method such as the trapezoidal rule. A recent recommendation by the EDA has been the use of early exposure as a measure of rate of systemic exposure. This can be calculated as a partial AUC, where the area can be truncated at the population median of the values. Measurement of early exposure may be useful when rapid onset of action is desirable (e.g., an analgesic effect) or if a slow input is required to achieve efficacy or safety. The FDA has recently proposed a shift away from the focus on rate and extent of absorption to the measurement of systemic exposure, which can be determined as total, peak, or early exposure (if needed). This is based on the understanding that these measures better reflect the rate and extent of absorption. - ... 

Studies showing the portion of dermal exposure that has been attributed to the hands are summarized In Table III. Regardless of the isethod used to measure hand exposure these studies show that the hands contribute from 272 to 99% of the total dermal exposure. In mlxer/loader situations where the worker Is more likely to contact the concentrate, the majority of dermal exposure is to the hands regardless of whether extra protective gloves were worn over the cotton gloves or a closed mixing system was used. 

Nickel carbonyl should be used in totally enclosed systems or under good local exhaust. Plants and laboratories where nickel carbonyl is used should make use of air-monitoring devices, alarms should be present in case of accidental leakage, and appropriate personal respiratory protective devices should be readily available for emergency uses. Monitoring of urinary nickel levels is useful to help determine the severity of exposure and identify appropriate treatment measures. Some large-scale users of nickel carbonyl maintain a supply of sodium diethyldithiocarbamate, or Antabuse, a therapeutic agent, on hand for use in case of overexposure. 

The impacts of contaminants on the structure of the immune system can be assessed by examining white blood cell (WBC) numbers and the mass and cellularity of immune organs, although these indicators are usually not as sensitive as measures of immune function. Avian immunotoxicity studies frequently assess total and (or) differential WBC counts [79], and immunosuppression can be indicated by reduced numbers of WBCs or elevated WBC numbers caused by recurrent infections. An elevated heterophil to lymphocyte ratio can indicate altered immune status in response to corticosteroid stress hormones or other factors [78,7 9], Exposure to lead shot or lead acetate has been shown to alter total and (or) differential WBC numbers in Japanese quail (Coturnix coturnix) and mallards [81-83], In western grebes (Aechmophorus occidentalis) from California, concentrations of mercury in the kidney were positively correlated with heterophil... 

A dermal absorption rate of 329 mnol/minute/cm ( 60 nmol/minute/cm ) was calculated for the shaved abdominal skin of mice (Tsumta 1975). This is equivalent to a human absorption rate of 29.7 mg/minute, assuming that a pair of hands are immersed in liquid chloroform (Tsumta 1975). However, this calculation was based on the assumptions that the rate of chloroform penetration is uniform for all kinds of skin and that the total surface area of a pair of human hands is 800 cm the former assumption is especially dubious. Islam et al. (1995) investigated the fate of topically applied chloroform in male hairless rats. For exposures under 4 minutes, chloroform-laden water was applied to shaved back skin for exposures of 4-30 minutes, rats were submerged in baths containing chloroform-laden water. Selected skin areas were tape-stripped a various number of times after various delay periods. It appeared that there was an incremental build-up of chloroform in the skin over the first four minutes. When compared to uptake measured by bath concentration differences, approximately 88% of lost chloroform was not accounted for in the stratum comeum and was assumed to be systemically absorbed. 

Hematological Effects. Intermediate and chronic inhalation exposure of humans to mixtures of heptachlor, chlordane, and other chemicals has been associated with leukemia and aplastic and hemolytic anemias. These exposures were either occupational or followed the use of termiticides in homes. These exposures were probably primarily inhalation combined with dermal. There are oral animal studies that confirm that the hematopoietic system, specifically the white cells, can be affected by heptachlor exposure. Rats fed 0.5 mg/kg/day heptachlor in the diet showed a statistically significant increase in total white blood count (Enan et al. 1982). It appears that although the hematopoietic system is not a primary target for heptachlor or heptachlor epoxide, it can be measurably affected. 

The basic principle of the method is simple. A cohort of patients with the disease in question is identified, and then a cohort of patients without the disease (usually two to three times as many) is matched with respect to a number of critical characteristics and used as the control group. Differences between the two groups with respect to exposure to the suspected causative agent are then measured. A major advantage is that uncommon or rare conditions are accessible to study, which is not the case for cohort studies or for computerised systems, where the total number of patients available is less than the several millions that might be needed. 

Under normal conditions of exposure borates are primarily irritants of the skin and respiratory system. Workers exposed to anhydrous sodium tetraborate complained of nasal irritation, nose bleeds, cough, shortness of breath, and dermatitis. Exposure levels were not measured, but total dust levels were described as high enough to obscure visibility in production areas. In another study of borax workers, symptoms of acute respiratory irritation including dryness of the mouth, nose, or throat, cough, nosebleeds, and shortness of breath were related to exposures of 4mg/m or more. ... 

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