Absorption pharmacokinetic characterization

The focus before IND is on Tmax, Cmax and AUCs, while the complexity of pharmacokinetic characterization (like oral bioavailability, plasma half life, volume of distribution, mean residence time, absorption, solubility and concentration) is built up during clinical trials and on the basis of comparable human data. 

In the first edition of this encyclopedia the section on absorption covered a range of topics that included discussion of the cell membrane, parenteral and enteral absorption, clinical factors, and pharmacokinetic characterization of absorption. 

Conceptual models of percutaneous absorption which are rigidly adherent to general solutions of Pick s equation are not always applicable to in vivo conditions, primarily because such models may not always be physiologically relevant. Linear kinetic models describing percutaneous absorption in terms of mathematical compartments that have approximate physical or anatomical correlates have been proposed. In these models, the various relevant events, including cutaneous metabolism, considered to be important in the overall process of skin absorption are characterized by first-order rate constants. The rate constants associated with diffusional events in the skin are assumed to be proportional to mass transfer parameters. Constants associated with the systemic distribution and elimination processes are estimated from pharmacokinetic parameters derived from plasma concentration-time profiles obtained following intravenous administration of the penetrant. 

The realization of sensitive bioanalytical methods for measuring dmg and metaboUte concentrations in plasma and other biological fluids (see Automatic INSTRUMENTATION BlosENSORs) and the development of biocompatible polymers that can be tailor made with a wide range of predictable physical properties (see Prosthetic and biomedical devices) have revolutionized the development of pharmaceuticals (qv). Such bioanalytical techniques permit the characterization of pharmacokinetics, ie, the fate of a dmg in the plasma and body as a function of time. The pharmacokinetics of a dmg encompass absorption from the physiological site, distribution to the various compartments of the body, metaboHsm (if any), and excretion from the body (ADME). Clearance is the rate of removal of a dmg from the body and is the sum of all rates of clearance including metaboHsm, elimination, and excretion. 

Absorption, distribution, biotransformation, and excretion of chemical compounds have been discussed as separate phenomena. In reality all these processes occur simultaneously, and are integrated processes, i.e., they all affect each other. In order to understand the movements of chemicals in the body, and for the delineation of the duration of action of a chemical m the organism, it is important to be able to quantify these toxicokinetic phases. For this purpose various models are used, of which the most widely utilized are the one-compartment, two-compartment, and various physiologically based pharmacokinetic models. These models resemble models used in ventilation engineering to characterize air exchange. 

It was apparent that the FDA recognized the ability of the pharmaceutical industry to develop chiral assays. With the advent of chiral stationary phases (CSPs) in the early 1980s [8, 9], the tools required to resolve enantiomers were entrenched, thus enabling the researcher the ability to quantify, characterize, and identify stereoisomers. Given these tools, the researcher can assess the pharmacology or toxicology and pharmacokinetic properties of enantiopure drugs for potential interconversion, absorption, distribution, and excretion of the individual enantiomers. 

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. 

Pharmacokinetics The pharmacokinetic profile is characterized by rapid absorption from the Gl tract and a short elimination half-life. Zolpidem is converted to inactive... 

The pharmacokinetic behavior of the aminoglycosides is characterized by poor oral absorption. 

The pharmacokinetics of stimulants are characterized by rapid absorption, low plasma protein binding, and quick extracellular metabolism (Patrick et al., 1987). Although some investigators claim that the dose-response relationship is affected by the child s weight, others have shown that individual dose-response stimulant effects are independent of the child s weight (Rapport et al., 1989). 

Pharmacokinetics Insulin glargine is characterized by slow absorption from the subcutaneous injection site and a fiat plasma insulin profile. Absorption patterns are similar after subcutaneous injection into the arm, abdomen, or thigh. A study in patients with type 1 diabetes found that the median time between injection and the end... 

Pharmacokinetics The pharmacokinetics of dornase alfa have not been characterized. Minimal systemic absorption occurs via inhalation. 

In 1937, the pioneering papttrnetics of Distribution of Substances Administered to the Body published (Teorell, 1937). Since then, pharmacokinetic theory has been well developed and matured as an independentdiscipline. Nevertheless, the characterization of drug absorption usually is assumed empirically and lacks physiological signiLcance. Even to date, some absorption processes are still not well understood and adequately deLned. 

In dmg discovery, preliminary PK studies are usually conducted in rodents to evaluate the extent of dmg exposure in vivo. This is commonly followed by PK studies in larger animals such as dog or monkey to better characterize the PK profile of the compound and to support safety studies. Pharmacokinetic scaling (also called allometry) is a discipline that is used to predict human PK profiles using preclinical data and is widely used in predicting the dmg human half-life, dose, and extent of absorption. Accurate prediction of a human PK profile is imperative to minimize dmg failure in development due to poor PK attributes. A detailed description of methods in predicting human PK is beyond the scope of this chapter but can be found in many excellent reviews (Obach et al., 1997 Miners et al., 2004 Poggesi, 2004 Raunio et al., 2004 Thomas et al., 2006 Hurst et al., 2007). A more in-depth discussion of various PK concepts and their applications can be found in various references (Gibaldi and Perrier, 1982 Rowland and Tozer, 1995 Hurst et al., 2007). 

Parenteral administration has been the preferred route because it allows complete systemic availability. Non-parenteral administration of antisense oligonucleotides is only made possible with the aid of novel formulations intended to overcome barriers to absorption (see Chapter 10). Similar to first-generation anti-sense oligonucleotides (ASOs), the pharmacokinetics of2 -MOE partially modified ASOs are characterized by ... 

During preclinical development, the structure, physical and chemical characteristics, and stereochemical identity of the IND/CTA candidate are fully characterized. This information, for example, is required for the chemical manufacture and control (CMC) section of the IND. Appropriate bioanalytical methods are developed for the evaluation of pharmacokinetics, typically a series of studies focusing on absorption, distribution, metabolism, and excretion (ADME) in toxicology species, as well as systemic exposure and metabolism in toxicological and clinical studies. 

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