PEGylation of somatropin (recombinant human growth hormone): Impact on its clearance in humans. Export

@article{citeulike:3378428, abstract = {1. PHA-794428 is a PEGylated version of somatropin (human growth hormone). The pharmacokinetics of PHA-794428 have been studied in humans following single subcutaneous administration (dose range 10-500 microg kg(-1)). In the same study the pharmacokinetics of somatropin were also determined following a 3.6 mg (51 microg kg(-1)) subcutaneous dose. Comparison of the pharmacokinetics of both molecules indicates that PEGylation of somatropin with a 40 kD PEG results in a ten- to 20-fold increase in area under the curve and a similar increase in half-life when compared with somatropin in human (at equivalent subcutaneous doses). 2. Literature data indicate that somotropin is cleared by two mechanisms. The first processes is clearance by glomerular filtration. This is a passive, non-capacity-limited process. A second, capacity-limited, process is mediated by interaction with growth hormone receptors present in a number of tissues including the liver. It is hypothesized that PHA-794428 shares the same clearance mechanisms. However, the addition of the PEG moiety has modulated the clearance by both of these processes. Pharmacokinetic modelling of human serum concentration data obtained for these molecules strongly supports this hypothesis. The renal clearance is reduced due to the increased size of the molecule (Cl/F reduced from 9.6 to 0.1 l h(-1) for somatropin and PHA-794428, respectively). In addition, the reduction in growth hormone receptor affinity has reduced the clearance mediated by interaction with this receptor (somatropin K(m) = 3.6 microg l(-1) and V(max) = 104 microg h(-1)/PHA-794428 K(m) = 53 microg l(-1) and V(max) = 84 microg h(-1)).}, author = {Webster, R and Xie, R and Didier, E and Finn, R and Finnessy, J and Edgington, A and Walker, D}, citeulike-article-id = {3378428}, citeulike-linkout-0 = {http://dx.doi.org/10.1080/00498250802413856}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18802875}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18802875}, day = {22}, doi = {10.1080/00498250802413856}, issn = {1366-5928}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, keywords = {biologics, pegylation, pharmacokinetics}, month = {September}, pages = {1--12}, posted-at = {2008-10-06 04:59:27}, priority = {2}, title = {PEGylation of somatropin (recombinant human growth hormone): Impact on its clearance in humans.}, url = {http://dx.doi.org/10.1080/00498250802413856}, year = {2008} }

TY - JOUR ID - citeulike:3378428 L3 - citeulike-article-id:3378428 N2 - 1. PHA-794428 is a PEGylated version of somatropin (human growth hormone). The pharmacokinetics of PHA-794428 have been studied in humans following single subcutaneous administration (dose range 10-500 microg kg(-1)). In the same study the pharmacokinetics of somatropin were also determined following a 3.6 mg (51 microg kg(-1)) subcutaneous dose. Comparison of the pharmacokinetics of both molecules indicates that PEGylation of somatropin with a 40 kD PEG results in a ten- to 20-fold increase in area under the curve and a similar increase in half-life when compared with somatropin in human (at equivalent subcutaneous doses). 2. Literature data indicate that somotropin is cleared by two mechanisms. The first processes is clearance by glomerular filtration. This is a passive, non-capacity-limited process. A second, capacity-limited, process is mediated by interaction with growth hormone receptors present in a number of tissues including the liver. It is hypothesized that PHA-794428 shares the same clearance mechanisms. However, the addition of the PEG moiety has modulated the clearance by both of these processes. Pharmacokinetic modelling of human serum concentration data obtained for these molecules strongly supports this hypothesis. The renal clearance is reduced due to the increased size of the molecule (Cl/F reduced from 9.6 to 0.1 l h(-1) for somatropin and PHA-794428, respectively). In addition, the reduction in growth hormone receptor affinity has reduced the clearance mediated by interaction with this receptor (somatropin K(m) = 3.6 microg l(-1) and V(max) = 104 microg h(-1)/PHA-794428 K(m) = 53 microg l(-1) and V(max) = 84 microg h(-1)). JF - Xenobiotica; the fate of foreign compounds in biological systems SN - 1366-5928 EP - 12 TI - PEGylation of somatropin (recombinant human growth hormone): Impact on its clearance in humans. SP - 1 KW - biologics KW - pegylation KW - pharmacokinetics AU - Webster, R AU - Xie, R AU - Didier, E AU - Finn, R AU - Finnessy, J AU - Edgington, A AU - Walker, D PY - 2008/09/22/ UR - http://dx.doi.org/10.1080/00498250802413856 ER -