Pharmacokinetic parameters bioavailability

To overcome the pharmacokinetic problems of CSA, a microemulsion formulation was developed. Both forms are available commercially in the United States, referred to as cyclosporine, USP and cyclosporine, USP [MODIFIED]. The two formulations are not bioequivalent and should not be used interchangeably. The microemulsion formulation is self-emulsifying and forms a microemulsion spontaneously with aqueous fluids in the gastrointestinal tract, making it less dependent on bile for absorption. The result is a sig-niflcantly greater rate and extent of absorption and decreased intraindividual variability in pharmacokinetic parameters. Bioavailability is enhanced owing to better dispersion and absorption and does not require bile excretion. The relative bioavailability of the microemulsion formulation is 60%. Peak concentrations generally are reached within 1.5 to 2 hours after oral administration. The terminal half-life is 8.4 hours. 

In vitro antifungal activities evaluation for sampangine metabolites demonstrated comparable activities to sampangine. However, an in vivo efficacy study revealed that SAh 2 is inactive. The antifungal activity profile of sampangine metabolites led us to conclude that metabolism per se is not the cause for the in vivo inactivity of sampangine, hence, further studies on the other pharmacokinetic parameters (bioavailability, distribution, clearance, etc.) will be necessary. 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

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] ... 

The pharmacokinetics of minaprine (orally administered) in humans have been studied [ 146,147]. The bioavailability has been found to be excellent, and the pharmacokinetic parameters did not show a dose-dependency [147]. The binding of (41) to human serum proteins and erythrocytes has been investigated [148]. Minaprine has been found to undergo extensive biotransformation in different species, with major groups of metabolites derived from degradation of the morpholine subunit and from hydroxylation of the phenyl substituent [149-152],... 

Pharmacokinetic parameters (e.g., bioavailability, peak plasma concentration, half-life) cannot be predicted based solely on in vitro studies. 

This exposure relationship is frequently more important in establishing human safety margins, as dose alone may be subject to a variety of differences between species such as absolute bioavailability, distribution, and excretion. This aspect, now commonly referred to as "toxicokinetics," has been outlined in an ICH guideline.6 This guideline specifies minimum requirements in terms of number of time points examined, number of animals per time point, and the requirements for calculation of various pharmacokinetic parameters such as Cmax, AUC. These will become important for comparison with human data as it becomes available later. 

Bioavailability is the other important conceptual pharmacokinetic parameter, in addition to clearance. The key concepts are summarised in Box 5.3. Bioavailability is defined as the proportion of an administered dose that reaches the systemic circulation. It has no units and is... 

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

The standard pharmacokinetic parameters of the compound such as a half-life or bioavailability cannot be reliably calculated, because the concentrations in plasma are below lOpg/mL. As analogously expected from the results on the shift in keto-alcohol equilibrium of 16,16-difluoro-PGE2, it is rapidly metabolized by C-15 reduction mediated by the ubiquitously expressed carbonyl reductase. The metabolism followed by jS-oxidation and co-oxidation forms a mixture of a and fi epimers at the 15-hydroxy moiety as a sole measurable metabolite [46], In 2006, the US Food and Drug Administration approved the drug application for an oral treatment of chronic idiopathic constipation in adults, estimating that 4-5 million Americans are affected. Lubiprostone has also completed a phase II trial in constipation-predominant irritable bowel syndrome, and has been further evaluated for other bowel dysfunctions. 

Pharmacokinetics A mean elimination half-life of approximately 5 hours has been reported after intravenous doses of Roferon-A. Pharmacokinetic parameters are similar in healthy subjects and cancer patients after intramuscular doses. Dose-proportionate increases in serum levels occur with doses up to 198 MIU. The bioavailability of interferon alfa-2a after intramuscular administration is 80% to 83%, and its volume of distribution is 0.223 to 0.748 liter/kg. The total body clearance of interferon alfa-2a has been reported to range from 2.14 to 3.62ml/min per kg. 

Pharmacokinetics attd Pharmacology. Older macrolides such as erythromycin exhibit relatively low serum concentrations, short in vivo half-hves, highly variable oral absorption, and low oral bioavailability. Improvements in these pharmacokinetic parameters have been accomplished for newer derivatives. The principal side effects of macrolides aie gastrointestinal problems, such as pain, indigestion, diarrhea, nausea, and vomiting. 

Hellriegel et al. (1996) observed a signiLcant inverse linear relationship between the bioavailability of a drug and its coefLcient of variation. An insoluble drug with very low oral bioavailability usually has a very large intersubject variability in its absorption pharmacokinetic parameters, which may result in a worrisome safety proLle or unfavorable efLcacy. 

Pharmacokinetic studies of 63a and 65a in mice demonstrated that the compounds had modest bioavailability (21% and 13%, respectively) but short plasma half-lives (tm <10 min).80 While pharmacokinetic parameters in other species have not been reported, it seems likely that issues relating to the absorption, distribution, metabolism, and excretion of this first generation of tricyclic inhibitors needs to be... 

Table 3.4 Approved dosing regimens and pharmacokinetic parameters related to absorption/bioavailability for therapeutic monoclonal antibodies.

Robust and rugged LC-MS/MS methods are essential in support of drug discovery, toxicology studies, and clinical trials, for the data generated from these bioanalytical methods is used to evaluate the bioavailability, bioequivalence, toxicokinetic, and pharmacokinetic parameters of drug candidates. Thus, it is critical to invest significant thought and effort in the method development process [25-27], Fast sample... 

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