The relevance of pharmacokinetics in the development of biotechnology products

Abstract

Biotechnology derived medicines will have an increasing impact not only upon medical practice but also upon the working lives of many pharmaceutical scientists. Whilst such medicines may be viewed as highly sophisticated to the clinician and scientist, the computer will still rightly demand that they are both efficacious and safe. Impacting as it does upon all phases of drug development and facilitating quantitative relationship between administered dose and systemic drug concentration, pharmacokinetics has an important role to play in the development of all medicines. Bioanalysis is an essential prelude to any pharmacokinetic investigation. For many biotechnology products the immunoassay and bioassay methodologies employed are often relatively non-specific and imprecise and yield assay dependent pharmacokinetic parameters. Other factors may also confound the pharmacokinetic evaluation of biotechnological products. In vivo binding proteins (including antibodies) may not only interfere with bioanalytical methodology but also have a significant effect on the pharmacokinetics and biological activity of certain macromolecules. Antibody formation is a particular problem in the preclinical evaluation of human proteins. Unlike most conventional pharmaceuticals, the rate and time of delivery into the systemic circulation is a fundamental component of the biological activity of many biological molecules.

Pediatric Dosing and Body Size in Biotherapeutics

“…Protein binding has been reported to affect the transport and regulation of some proteins and peptides such as growth hormone, recombinant human growth factor, cytokines and fusion proteins (e.g. enfuvirtide) [18,19,20,21]. …”

Lymphatic Transport of Proteins After Subcutaneous Administration

“…Even though S.C. delivery has been utilized extensively for a number of years, very little is known about the processes that govern the absorption of macromolecules from the interstitial space and the resulting impact of these processes on bioavailability and pharmacokinetic profiles. Proteins larger than about 16-20 kDa are generally thought to be taken up primarily by the lymphatic system, [1][2][3][4][5][6][7] but very few studies have experimentally investigated this process. Furthermore, the effects of various external factors, including the site and method of administration and even "simple" formulation variables (e.g., pH and ionic strength) on the lymphatic transport of subcutaneouslyinjected proteins are still largely undefined.…”

Early Development of Therapeutic Biologics - Pharmacokinetics

“…Finally, the supply of adequate amounts of new biologics in pre-clinical and clinical development is a major issue with manufacturing costs easily reaching 100 fold those of small molecules [16]. The fact that the pre-clinical development program has to be planned and performed with the final material is a huge and costly effort.…”

“…These binding proteins may have an inhibitory or stimulatory effect on the biological activity of the biologic and may also significantly influence pharmacokinetics [16]. Surface plasmon resonance technology has been successfully used in our group to measure the interaction of biologics with serum components like human serum albumin [23].…”