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Mordenti, Joyce; Chen, Sharon A.; Moore, Jerome A.; Ferraiolo, Bobbe L.; Green, James D.

doi:10.1023/a:1015836720294

Cited by 172 publications

(33 citation statements)

References 36 publications

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“…Positive results from human clearance prediction of macro-molecule drugs using allometric scaling have already been reported by several groups (Mordenti et al, 1991, Mahmood, 2004, Mahmood, 2009b, Ling et al, 2009, Wang and Prueksaritanont, 2010). Mordenti et al demonstrated reasonable accuracy in predicting human clearance and volume of distribution using interspecies scaling for five protein drugs with molecular weights ranging from 6 to 98 kDa (Mordenti et al, 1991).…”

Section: Introductionmentioning

confidence: 74%

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

2011

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Human clearance prediction for small- and macro-molecule drugs was evaluated and compared using various scaling methods and statistical analysis.Human clearance is generally well predicted using single or multiple species simple allometry for macro- and small-molecule drugs excreted renally.The prediction error is higher for hepatically eliminated small-molecules using single or multiple species simple allometry scaling, and it appears that the prediction error is mainly associated with drugs with low hepatic extraction ratio (Eh). The error in human clearance prediction for hepatically eliminated small-molecules was reduced using scaling methods with a correction of maximum life span (MLP) or brain weight (BRW).Human clearance of both small- and macro-molecule drugs is well predicted using the monkey liver blood flow method. Predictions using liver blood flow from other species did not work as well, especially for the small-molecule drugs.

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Section: Introductionmentioning

confidence: 74%

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

2011

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“…For example, preparations of PEG-adenosine deaminase are efficacious when given weekly, compared with the daily injections of unmodified adenosine deaminase for the treatment of severe combined immune deficiency disease in children (22). Because proteins are cleared faster in rodents than in humans (23), it is possible that PEG-5-hGH given at bi-weekly or even monthly intervals could have efficacy comparable with daily injections of hGH in humans.…”

Section: Figmentioning

confidence: 99%

Long-acting Growth Hormones Produced by Conjugation with Polyethylene Glycol

Clark¹,

Olson²,

Fuh

et al. 1996

Journal of Biological Chemistry

235

150

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Derivatives of human growth hormone (hGH) of increasing size were produced by reaction with the Nhydroxysuccinimide ester of polyethylene glycol-5000 (PEG 5000 ), a 5-kDa reagent that selectively conjugates to primary amines. By adjusting the reaction conditions and purification procedure, it was possible to isolate hGH derivatives containing up to seven PEG moieties that altered the Stokes radius and thereby the effective molecular masses of the unmodified hormone from 22 to 300 kDa. Fortunately, the most reactive amines were ones that did not lie in either of the two sites important for receptor binding. Nonetheless, increasing the level of PEG modification linearly reduced the affinity of hGH for its receptor and increased the EC 50 in a cellbased assay up to 1500-fold. Most of the reduction in affinity was the result of slowing the association rate for the receptor. The clearance rate of hGH in rats was inversely proportional to effective molecular weight and closely fit a filtration model. We have tested the potency of these analogs by injecting them daily or every 6 days into hypophysectomized rats and determining the effects on body and organ growth. The efficacy of these analogs was optimal for hGH conjugated with 5 eq of PEG 5000 , and the potency was increased by about 10-fold compared with unmodified hGH. Such PEG-hGH derivatives show promise as long-acting alternatives to daily injections of hGH. More generally these studies show that improving hormone clearance properties, even at the expense of reducing receptor binding affinity, can lead to dramatic increases in hormone efficacy.The ability of a hormone to elicit a biological effect in vivo depends on many factors including the affinity for its receptor and the rate at which it is cleared from the circulation. Some hormones, like atrial natriuretic peptide, have a very high affinity for their receptor (10 pM) and are cleared very rapidly (t1 ⁄2 ϳ0.5 min) by receptor and protease-mediated events (1). Other hormones, like human growth hormone (hGH), 1 have lower affinity for their receptor (300 pM) but are cleared more slowly (t1 ⁄2 ϳ30 min in rats), primarily via the kidney (2, 3).Understanding the relationships between hormone affinity, clearance, and efficacy is important in optimizing hormone therapy. To study this systematically one would like to vary these parameters and evaluate their relative importance in regulating biopotency. hGH is a good model system in this regard as much is known about its structure and function (for review see Ref. 4). Simple receptor binding (5, 6), cell-based assays (7,8), and growth parameters in rodents (9) can be used to determine biopotency in vitro and in vivo. The properties of proteins such as hGH that are cleared by kidney filtration can be modulated by attachment of polyethylene glycol (PEG) polymers, which increases the hydrodynamic volume of the hormone and thereby slows its clearance (10, for recent review see Ref. 11).Here, we describe a set of hGH derivatives conjugated with increasing numbers of PEG ...

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“…t 1/2β may be predicted by indirect methods which involve a reasonable prediction of the volume of distribution and clearance (t 1/2β = 0.693 × V dss /CL) or MRT (t 1/2β = MRT/1.44). However, Mordenti et al [121] who analyzed the clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immunoglobulin G, growth hormone, tissueplasminogen activator, and relaxin) in laboratory animals as a function of body weight using allometric scaling technique.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Recombinant Human Endostatin in Rats

Yang

Chan

et al. 2006

CDM

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The pharmacokinetics of recombinant human endostatin (rh-Endo) has not been established in the rat, although this species of animal is commonly used in the pharmacological studies of rh-Endo. This study aimed to investigate the pharmacokinetics, tissue distribution, and excretion of rh-Endo in rats. 125I-radiolabeled rh-Endo was administered to healthy rats by intravenous (i.v) bolus injection at 1.5, 4.5 and 13.5 mg/kg. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of rh-Endo increased proportionally with the increase of the dosage. There were no significant differences in total body clearance (CL) and elimination half-life (t1/2beta) of rh-Endo among the three dosages used. A 93.5% and 2.2% of the radioactivity was recovered in the urine and feces, respectively, in bile-duct intact rats; whereas only 0.1% of the total radioactivity was excreted into the bile in bile-duct cannulated rats. rh-Endo was rapidly and widely distributed in the liver, kidneys, spleen and lungs. Furthermore, a significant allometric relationship between CL, but not volume of distribution (Vd) and t1/2beta of rh-Endo, and the body weight was observed across mouse, rat and monkey, with the predicted values in humans significantly lower than those observed in cancer patients. rh-Endo exhibited a linear pharmacokinetics in rats and it is mainly excreted through the urine.

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Cited by 172 publications

References 36 publications

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

Long-acting Growth Hormones Produced by Conjugation with Polyethylene Glycol

Pharmacokinetics of Recombinant Human Endostatin in Rats

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