Protein pharmacokinetics

A prerequisite to pharmacokinetic/pharmacodynamic studies is the availability of a sufficiently selective and sensitive assay. The assay must be capable of detecting and accurately quantifying the therapeutic protein in the presence of a complex soup of contaminant molecules characteristic of tissue extracts/body fluids. As described in Chapter 7, specific proteins are usually detected and quantified either via immunoassay or bioassay. Additional analytical approaches occasionally used include liquid chromatography (e.g. HPLC) or the use of radioactively labelled protein. 

The macromolecular structure of drugs and the fact that relatively minor structural alterations can potentially have a major influence upon bioactivity are often complicating factors. For example, an immunoassay may be blind to the oxidation of an amino acid residue, or very limited proteolytic processing, although such events can activate or decrease bioactivity. 

After initial filtration many proteins are actively reabsorbed (endocytosed) by the proximal tubules and subjected to lysosomal degradation, with subsequent amino acid reabsorption. Thus, very little intact protein actually enters the urine. 

Pharmacokinetic and indeed pharmacodynamic characteristics of therapeutic proteins can be rendered (even more) complicated by a number of factors, including  

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Ferraiolo, B. 1992. Protein Pharmacokinetics and Metabolism. Plenum Publishers. 

Colburn, W. 1991. Peptide, peptoid, and protein pharmacokinetics/pharmacodynamics. In P. Garzone.W. Colburn, and M. Mokotoff (Eds.), Peptides, peptoids, and proteins. Harvey Whitney Books, Cincinnati, OH, pp. 94-115. 

As discussed in Chapter 30 and elsewhere (13), interspecies scaling is based upon allometry (an empirical approach) or physiology. Protein pharmacokinetic parameters such as volume of distribution (Pd), elimination half-life (b/2)/ and elimination clearance (CL) have been scaled across species using the standard allometric equation (14) ... 

Fibroblast growth factor protein has been infused into the coronary arteries, or injected directly into the heart muscle. Because of poor FGF protein pharmacokinetics (i.e., low retention by the heart) [18], stimulation of myocardial angiogenesis requires high doses of FGF protein intracoronary infusion over a long period of time. 

Trang, J.M. Pharmacokinetics and metabolism of therapeutic antibodies. In Protein Pharmacokinetics and Metabolism, Ferraiolo, B.L., Mohler, M.A., Gloff C.A. (eds). Plenum, New York, 1992. 

Working PK. Potential effects of antibody induction by protein drugs. In Protein Pharmacokinetics and Metabolism, edited by Ferraiolo BE, Mohler MA, Gloff CA, pp. 73-92. New York, NY Plenum Press, 1992. 

Ferraiolo B L, Mohler M A, Gloff C A (1992). Protein pharmacokinetics and metabolism, in Pharmaceutical Biotechnology, vol. 1. Plenum Press, New York, p. 136. 

Colburn VJA. Peptide, peptoid, and protein pharmacokinetics/pharmacodynamics. In Garzone PD, Colburn WA, Mokotoff M, eds. Peptides, Peptoids, and Proteins. Pharmacokinetics and Pharmacodynamics, vol 3. Cincinnati Harvey Whitney, 1991. 

Uludag, H., D Augusta, D., Golden, J., Li, J., Timony, G., Riedel, R., and Wozney, J.M. Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers a correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model. /. Biomed. Mater. Res. 50 227-238, 2000. 

Urea Pharmacokinetics. Pharmacokinetics summarizes the relationships between solute generation, solute removal, and concentration in a patient s blood stream. In the context of hemodialysis, this analysis is most readily appHed to urea, which has, as a consequence, become a surrogate for other uremic toxins in the quantitation of therapy and in attempts to describe its adequacy. In the simplest case, a patient is assumed to have no residual renal function. Urea is generated from the breakdown of dietary protein, accumulates in a single pool equivalent to the patient s fluid volume, and is removed uniformly from that pool during hemodialysis. A mass balance around the patient yields the following differential equation ... 

Taken together ABC-transporters represent a large family of proteins affecting the pharmacokinetic parameters of various drugs. Here, P-gp is currently the best characterized member and it may also be one of the most important ABC-transporters with regard to drug transport. However, it becomes more and more apparent that ABC-transporter act in a coordinated... 

Urographic contrast agents are contrast agents which possess the characteristics of very little enteral absotp-tion, almost no protein binding or uptake into cells, an extracellular (interstitial) distribution and glomerular filtration. These pharmacokinetics are due to very little interaction with the organism, resulting in very low toxicity, preferably nonionic (neutral) molecules. 

Bain VG, Kaita KD, Yoshida EM, Swain MG, Heathcote EJ, Neumann AU, FisceUa M, Yu R, Osborn BE, Cronin PW, Ereimuth WW, McHutchison JG, Subramanian GM (2006) A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 44 671-678... 

Osborn BL, Olsen HS, NardeUi B, Murray JH, Zhou JX, Garcia A, Moody G, Zaritskaya LS, Sung C (2002) Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 303 540-548 Ozes ON, Reiter Z, Klein S, Blatt LM, Taylor MW (1992) A comparison of interferon-Conl with natural recombinant interferons-alpha antiviral, antiproliferative, and natural kiUer-inducing activities. J Interferon Res 12 55-59... 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

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