Bioavailability variability

In these studies, standard bioavailability variables such as the extent of bioavailability determined from area under the curve (AUC), rate of bioavailability related to peak plasma drug levels (Cmax) and time to peak (fmax) are determined. A more detailed presentation of the assumptions and interpretations of bioavailability data is given in Chapter 7. The bioavailability after administration in more distal parts of the intestine, such as the terminal ileum and different parts of the colon, is compared with a reference administration either as an oral solution or as a regional delivery to the upper small intestine. This is exemplified in Figure 4.18, which shows the plasma drug concentrations of metoprolol after administration to jejunum, terminal ileum and colon ascendens or transversum. 

The plasma sampling schedule has to be designed so that the desired accuracy of the primary bioavailability variables can be obtained. In cases of evaluation of formulation performance, it is crucial to have frequent sampling during the absorption phase. In addition, at least three samples should be obtained during the major terminal elimination phase in order to obtain a relevant measure of the rate constant for this phase, which is needed for a correct estimate of the extent of absorption. Numerous late plasma samples, when the drug concentration is below the limit of quantification of the bioanalythical assay, should be avoided. 

The standard bioavailability variables after a single-dose administration are the maximum plasma concentration (Cmax), the time to reach Cmax (fmax) and the area under the plasma concentration—time curve from time zero to infinity (AUC). 

The in vivo predictability of an in vitro model with or without a scaling function should be evaluated. A subjective assessment can be made by comparing the modelled in vitro dissolution data and the corresponding in vivo dissolution-time curves in a graph. However, a more stringent approach, applied in regulatory contexts, is to predict the plasma concentration-time profiles from the in vitro model and compare them to measured in vivo data. The latter step is performed by comparing the estimated and measured primary bioavailability variables, Cmax and AUC. 

This evaluation may be performed either by use of the same data, as included in the establishment of an IVIVC (internal predictability), or by use of other data sets (external predictability). The criteria for concluding a level A IVIVC in a regulatory context requires, in the case of internal predictability, an average percentage PE of < 10 percent for Cmax and AUC, respectively, and the percentage PE for each formulation regarding these two bioavailability variables should not exceed 15 percent (FDA 1997a). 

Some of the factors affecting just how much of an oral dose of a drug makes it into the bloodstream are beyond the researcher s ability to control. Variations in transit time in the GI tract, adsorption onto food, PGx effects, and a host of other things can make oral bioavailability variable and hard to predict. Even carefully controlled PK studies done with multiple animals per time point can have substantial error bars, in large part reflecting animal-to-animal variability. 

The liquid property of the API-ILs seems to be one solution to overcome the disadvantages of limited solubility, low bioavailability, variable polymorphs, and limited membrane transport, but in the same time may also present challenges related to their preparation, handling, and the need for special devices for dehvery. Recently, we showed that a supported ionic Hquid phase (SILP) strategy [17] not only can be successfully applied to API-ILs, but also provides an easier way to handle and dose these liquid APIs with additional advantages such as improved thermal stability and rapid and complete leaching from the solid support... 

Among the physical factors, current velocity has a special significance for benthic biofilms because it can modulate the diffusion of metals through the biofilm and their effects [18, 40]. pH and organic complexation are particularly significant for metal bioavailability [42]. Therefore, metal toxicity will also depend on the influence that environmental variability has on its bioavailability. 

Two orally bioavailable compounds that target HIV-1 attachment have been described. BMS-806 and BMS-043 bind to gpl20 (reviewed by Kadow et al. 2006) and demonstrate variable activity when tested in vitro against panels of virus isolates (Lin et al. 2003). BMS-043 has shown efficacy in short-term monotherapy studies... 

A number of factors described as influencing carotenoid bioavailability were regrouped under the SLAMENGFll mnemonic. Species of carotenoid. Linkages at molecular level. Amount of carotenoids consumed in a meal. Matrix in which the carotenoid is incorporated. Effectors of absorption and bioconversion. Nutrient status of the host. Genetic factors. Host-related factors, and Interactions among these variables. Only the factors that affect the micellarization of the compound in the gut are discussed and summarized in Table 3.2.1. 

Watersheds are sinks for atmospheric Hg deposition (Grigal 2002). However, they are highly variable in their ability to retain inputs of total Hg (THg), convert ionic Hg (Hg(ll)) to bioavailable methylmercury (MeHg), and snpply Hg(II) and MeHg to downstream aqnatic ecosystems, ultimately influencing exposure to sensitive biota and hnmans. 

Intravenous antibiotic administration is the most common delivery method for surgical prophylaxis. Intravenous administration ensures complete bioavailability while minimizing the impact of patient-specific variables. Oral administration is also used in some bowel operations. Non-absorbable compounds like erythromycin base and neomycin are given up to 24 hours prior to surgery to cleanse the bowel. Note that oral agents are used adjunctively and do not replace IV agents. 

The effect of particle size reduction on the bioavailability of nitrofurantoin was shown in Fig. 4. The microcrystalline form (< 10 pm) is more rapidly and completely absorbed from the tablet dosage form than is the macrocrystalline form (74-177 pm) from the capsule dosage form. This is not a completely satisfactory illustration of the effect of particle size on the rate and extent of availability, since other manufacturing variables have not been held constant. Nevertheless, it does suggest some correlation between particle size, dissolution rate, and rate of availability. 

Another new development has been the application of oral absorption promoters. These materials are designed to enhance the oral bioavailability of many compounds and improve variable absorption. However, many of these compounds are hydrophobic in nature and cause difficulty during tableting itself. The challenge for formulators is to arrive at clever solutions to the process problems while retaining material performance. 

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 ... 

ND Eddington, M Ashraf, LL Augsburger, JL Leslie, MJ Fossler, LJ Lesko, VP Shah, GS Rekhi. Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets. Pharm Dev Tech 3(4) 535-547, 1998. 

Parenteral administration of drugs by intravenous (IV), intramuscular (IM), or subcutaneous (SC) routes is now an established and essential part of medical practice. Advantages for parenterally administered drugs include the following rapid onset, predictable effect, predictable and nearly complete bioavailability, and avoidance of the gastrointestinal (GI) tract and, hence, the problems of variable absorption, drug inactivation, and GI distress. In addition, the parenteral route provides reliable drug administration in very ill or comatose patients. 

In conclusion, it should be apparent from this discussion of the absorption mechanisms that, although the major features influencing drug absorption are well known, implementation of a coherent delivery strategy is highly specific for any compound, and many variables need to be adjusted for their significant influence on absorption and more importantly, on bioavailability. In addition, from the suggestion of the role of... 

Drug absorption is highly variable in neonates and infants [21,22]. Older children appear to have absorption patterns similar to adults unless chronic illness or surgical procedures alter absorption. Differences in bile excretion, bowel length, and surface area probably contribute to the reduced bioavailability of cyclosporine seen in pediatric liver transplant patients [22a]. Impaired absorption has also been observed in severely malnourished children [22b]. A rapid GI transit time may contribute to the malabsorption of carbamazepine tablets, which has been reported in a child [23]. Selection of a more readily available bioavailable dosage form, such as chewable tablets or liquids, should be promoted for pediatric patients. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

A number of methods and models have been used at sites to estimate potential risks from exposure to lead. One method is the use of prevalence data for estimating PbB levels. In this case, PbB measurements can be made at a site and extrapolated to other sites with similar environmental and demographic data. Limitations of this method include site-to-site variability with respect to, among other things, children s behavioral patterns, age, and bioavailability issues. Estimation of past exposures can be problematic because of redistribution of Pb out of the blood compartment since PbB is only an indicator of recent exposure (<90 days). 

Banin et al. (1987) proposed a thin-horizon sampling approach to study the effects of traffic sources and atmospheric fallouts on soils in the arid zone of Israel. They pointed out that the large and systematic variability in the concentrations of the atmophile elements in the soil would be masked if a more conventional and less-detailed sampling scheme was used. The measured Pb concentration varied between 209 mg/kg in the top layer of an arid soil near the road in Israel and 66 mg/kg at a depth of 20 cm (Banin et al., 1987). If the profile had been sampled as one 0-20 cm horizon, the weighed average concentration observed would have been 76.3 mg/kg Pb. If it had been sampled in two 10-cm thick horizons, the concentrations would have been estimated to be 86.6 and 66 mg/kg in the top and bottom horizons, respectively (Banin et al., 1987). This distribution would strongly affect the bioavailability in arid soils. 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

A direct in vivo assessment of the quantitative importance of gut wall metabolism and transport of drugs and metabolites in humans is difficult and consequently has been attempted only rarely [3, 6, 11, 12, 15, 16, 23, 25-32, 34, 35, 81]. The most direct in vivo approach to investigating these processes in drugs with variable and incomplete bioavailability was intestinal perfusion by single-pass per-... 

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