Pharmacological differences between pharmacokinetics

We are indebted to the authors from the first edition who have worked to update their chapters, but are sad to report that Mary Berg, author of the chapter on Pharmacological Differences between Men and Women, died on October 1, 2004. She was an esteemed colleague and effective advocate for studying sex differences in pharmacokinetics and... 

The drive to produce stereoisomerically pure drugs is based on the recognition that there are pharmacological differences between drug stereoisomers. These differences are addressed in the third section of this book, which discusses the pharmacokinetic, plasma protein binding, efficacy, toxicity, and biotransformation of stereoisomeric drugs. 

Dtug interactions can cause serious problems in clinical practice especially when the affected dmg has the potential to be highly toxic. Furthermore, pharmacokinetic interactions are clinically important if the affected dmg has a narrow therapeutic range (i.e. small difference between the minimum effective concentration and the toxic concentration Fig. 1) and a steep concentration-response curve (i.e. significant alterations in pharmacological and/or adverse effects caused by small changes in blood concentration). 

Bioequivalence and -avalibility can be assessed in vitro, for example in dissolution tests for controlled release forms, or in vivo in experimental animals in pharmacokinetic and/or pharmacodynamic studies. The results should be correlated with the pharmacological effects in the target organism. If the modified product is not bioequivalent or shows different therapeutic effects, clinical studies will be necessary. Products which have a narrow therapeutic ratio (e.g. a less than twofold difference between the minimum toxic and minimum effective concentration in the body 21 CFR 320) require clinical studies under all circumstances. 

Lizarraga, I. Sumano, H. Brumbaugh, G.W. Pharmacological and pharmacokinetic differences between donkeys and horses. Equine Vet. Educ. 2004, 62, 130-144. 

Drayer, D.E. (1986) Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans an overview. Clinical Pharmacology and Therapeutics, 40, 125-133. 

Overall, there are some profound differences between the pharmacokinetic (PK) behavior of biologies and small molecules. Table 41.1 summarizes the major differences between these two broad classes of molecules. When evaluating the PK behavior of any protein, it is important to understand the biology and the pharmacology of the system that the therapeutic biologic is acting on in order to anticipate the expected covariates and behavior of the drug. 

Given the complexities of the pharmacology and pharmacokinetics of therapeutic proteins, the effect of race would not be expected to be important. There is no known difference between racial characteristics that would cause additional PK variability. Attempts have been made to examine the effect of race as a covariate, but it has only rarely been identified once patient weight or sex and other covariates (particularly those related to disease) were taken into account. Such was the case for cetuximab (70). 

As the compound reaches the late discovery and candidate selection stage, the focus is to determine its major metabolic pathways, metabolic difference between species, and to identify potential pharmacologically active or toxic metabolites. Because of the complexity, comprehensive metabolite characterization studies have been typically conducted at this stage with radiolabeled standard. Identification of circulating metabolites is also important at this stage to explain the pharmacokinetic or the pharmacodynamic profile. An NCE may show efficacy that is inconsistent with what is predicted based upon the known concentration of the parent drug. These inconsistencies could be due to the presence of active metabolites. The knowledge of these metabolites will also dictate how the analysis of samples will be conducted in the development and clinical studies. 

The newer selective alphaj-adrenoreceptor-blocking agents, such as trimazosin, doxasozin, and terazosin, display a pharmacologic profile virtually identical to that of prazosin, but pharmacokinetic differences between the various alpha,-blockers exist. 

Comparison of metabolic pathways across species which can in turn be used to explain pharmacologic or toxicologic differences between species Justification of species for preclinical safety and pharmacokinetics studies Help identify enzyme systems involved in metabolic clearance Support clinical development... 

Many pharmaceutical excipients consist of chiral molecules. The common chiral excipients are listed in Table 3 [54]. When a chiral excipient is used in a formulation, the dissolution rate of the opposite enantiomers may differ, because the interactions between the excipient and each enantiomer are diastereomeric and may therefore differ. In the field of chromatography, the different strengths of the diastereomeric interactions form the basis of enantiomeric separation on a chiral column. Because the opposite enantiomer may exhibit different pharmacological, toxicological, or pharmacokinetic properties, it is of practical value to compare the release rate of the opposite enantiomers from a formulation containing a chiral excipient. 

The most important differences between enantiomers occur in drug receptor interactions. Indeed, Lehmann [34] has stated, the stereoselectivity displayed by pharmacological systems constitutes the best evidence that receptors exist and that they incorporate concrete molecular entities as integral components of their active-sites. In contrast to the pharmacokinetic properties of a pair of enantiomers (Sec. 4), differences in pharmacodynamic activity tend to be more marked, and eudismic ratios of 100 to 1000 are not uncommon. 

---