Serum half-life

The 5-HT3 antagonist palonosetron is the first 5-HT3 antagonist to be approved for prevention of both acute and delayed CINV.40 Compared to the other 5-HT3 antagonists, palonosetron has a longer serum half-life (40 hours compared to 4 to 9 hours) and a higher receptor binding affinity, which may contribute to its efficacy in preventing delayed CINV.41... 

Although the affinity was decreased fivefold upon PEGylation, PEGylated antibody fragments showed an 8.5-fold higher accumulation in tumors than unmodified antibody fragments, because of a longer serum half-life [46]. 

Roffler, S.R., and Tseng, T.-L. (1994) Enhanced serum half-life and tumor localization of PEG-modified antibody-enzyme conjugates for targeted prodrug activation. Antibody Engineering Conference. San Diego, California. 

Increases product serum half-life, thereby reducing the frequency of dosage... 

Immunogenicity. Many, if not most, therapeutic proteins are potentially immunogenic when administered to humans. The likelihood that non-human proteins (e.g. murine monoclonal antibodies Chapter 13) are immunogenic in humans is an obvious one. However, human proteins can also be potentially immunogenic, as discussed in Box 4.1. Antibodies raised in this way can bind the therapeutic protein, neutralizing its activity and/or affecting its serum half-life. 

A number of different approaches may be used in order to alter a protein s pharmacokinetic profile. This can be desirable in order to achieve a predefined therapeutic goal, such as generating a faster-or slower-acting product, lengthening a product s serum half-life or altering a product s tissue... 

Chimaeric and humanized antibodies Rendering murine antibodies more human in sequence, thereby decreasing their immunogenicity and increasing their serum half-life 13... 

Engineered tPA Increasing serum half-life, allowing administration by a single i.v. injection as opposed to infusion over 90 min 12... 

Mammalian cell culture is more technically complex and more expensive than microbial cell fermentation. Therefore, it is usually only used in the manufacture of therapeutic proteins that show extensive and essential post-translational modifications. In practice, this usually refers to glycosylation, and the use of animal cell culture would be appropriate where the carbohydrate content and pattern are essential to the protein s biological activity, its stability or serum half-life. Therapeutic proteins falling into this category include EPO (Chapter 10), the gonadotrophins (Chapter 11), some cytokines (Chapters 8-10) and intact monoclonal antibodies (Chapter 13). 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

The oligosaccharide components play a direct and central role in the biosynthesis, secretion, serum half-life and potency of the gonadotrophins. The sugar components attached to the a-subu-nits play an important role in dimer assembly and stability, as well as hormone secretion and possibly signal transduction. The sugars associated with the P-subunit, while contributing to dimer assembly and secretion, appear to play a more prominent role in clearance of the hormone from circulation. 

The product displays a mean serum half-life of 18.8 h in humans. It has been evaluated in four clinical trials involving a total of 128 subjects and in the context of both spontaneous bleeding and surgery. Some 88 per cent of the total infusions administered for bleeding were rated as providing a good or excellent response. Reported side effects, although uncommon, included hypersensitivity, as well as headache, fever and nausea. BeneFix is marketed by Wyeth. 

Alteplase has proven effective in the early treatment of patients with acute myocardial infarction (i.e. those treated within 12 h after the first symptoms occur). Significantly increased rates of patient survival (as measured 1 day and 30 days after the initial event) are noted when tPA is administered in favour of streptokinase, a standard therapy (see later). tPA has thus established itself as a first-line option in the management of acute myocardial infarction. A therapeutic dose of 90-100 mg (often administered by infusion over 90 min) results in a steady-state alteplase concentration of 3-4 mg l 1 during that period. However, the product is cleared rapidly by the liver, displaying a serum half-life of approximately 3 min. As is the case for most thrombolytic agents, the most significant risk associated with tPA administration is the possible induction of severe haemorrhage. 

Table 13.4 The serum half-life values of some IgG antibody preparations when administered to humans...

When compared with human monoclonals (half-life 14-21 days), murine monoclonals administered to humans display a relatively short half-life (30-40 h). Chimaerization increased serum half-life by fivefold, with typical values of 230 h being recorded (Table 13.4). A prolonged half-life is desirable if the antibody is to be used therapeutically, as it decreases the required frequency of product administration. Chimaeric antibodies also allow activation of Fc-mediated functions (e.g. activation of complement, etc.), as this domain displays human sequence. 

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

Serum Half-Life in Increased Factors Resulting in... 

In a study with human subjects, whose urine pH was controlled with sodium bicarbonate and ammonium chloride, it was found that 10-25% of the administered pseudoephedrine hydrochloride was metabolized to norpseudoephedrine and the elimination of pseudoephedrine and norpseudoephedrine was related to urine pH. As the urine pH increased, the serum half-life of pseudoephedrine and norpseudoephedrine increased.15 In another similar study it was found that a decrease... 

Adir J, Caplan YH, Thompson BC. 1978. Kepone serum half-life in humans. Life Sci 22(8) 699-702. 

Pharmacokinetic measurements, for example, plasma (serum) half-life, concentration-time curves of parent drug or active metabolite. 

Conversion from epoetin alfa to darbepoetin Estimate the starting weekly dose of darbepoetin based on the weekly epoetin alfa dose at the time of substitution. Titrate doses to maintain the target hemoglobin. Due to the longer serum half-life, administer darbepoetin less frequently than epoetin alfa. Administer once a week if... 

Excretion - Naloxone is excreted in the urine. The serum half-life in adults ranged from 30 to 81 minutes in neonates, 3.1 0.5 hours. 

Pharmacokinetics After oral administration approximately 2.4% of a single 1 g oral dose is absorbed. Maximum serum concentrations appear after approximately 1 hour, and are low even after a single 1 g dose. Olsalazine has a very short serum half-life of approximately 0.9 hours and is greater than 99% bound to plasma proteins. Urinary recovery is less than 1%. Total oral olsalazine recovery ranges from 90% to 97%. 

Renal function impairment Cephalosporins may be nephrotoxic use with caution in the presence of markedly impaired renal function (Ccr less than 50 mL/min/1.73 m ). Hepatic function impairment Cefoperazone is extensively excreted in bile. Serum half-life increases 2-fold to 4-fold in patients with hepatic disease or biliary obstruction. 

The serum half-life averaged 1.7 hours in subjects with normal renal function. In healthy subjects, the serum clearance was 91 mL/min and renal clearance was 56 mL/min the apparent mean volume of distribution at steady state averaged 12.6 L. 

---