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jagankm ☆ 2012-04-24 13:54 (5160 d 17:17 ago) Posting: # 8459 Views: 5,823 |
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Dear All, WE are generic pharmaceuticals developing phenytoin sodium capsules in the concentration of 25 -300mg (dose proportional)for Uk submission. The query is regarding BE study strength. as phenytoin is nonlinear pharmacokinetic drug. As per EMEA guidance we can show bioequivalence for higher strength (300 mg) and can apply Biowaiver for remaining strenghts. we are in ambiquity to decide correct BE strength. kindly advice. |
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Dr_Dan ★★ Germany, 2012-04-25 14:25 (5159 d 16:46 ago) @ jagankm Posting: # 8460 Views: 4,944 |
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Dear jagankm For drugs with non-linear pharmacokinetics characterised by a more than proportional increase in AUC with increasing dose over the therapeutic dose range, the bioequivalence study should in general be conducted at the highest strength. As for drugs with linear pharmacokinetics a lower strength may be justified if the highest strength cannot be administered to healthy volunteers for safety/tolerability reasons. Likewise a higher dose may be used in case of sensitivity problems of the analytical method in line with the recommendations given for products with linear pharmacokinetics. For drugs with a less than proportional increase in AUC with increasing dose over the therapeutic dose range, bioequivalence should in most cases be established both at the highest strength and at the lowest strength (or a strength in the linear range), i.e. in this situation two bioequivalence studies are needed. If the non-linearity is not caused by limited solubility but is due to e.g. saturation of uptake transporters and provided that conditions a) to d) above are fulfilled and the test and reference products do not contain any excipients that may affect gastrointestinal motility or transport proteins, it is sufficient to demonstrate bioequivalence at the lowest strength (or a strength in the linear range). Selection of other strengths may be justified if there are analytical sensitivity problems preventing a study at the lowest strength or if the highest strength cannot be administered to healthy volunteers for safety/tolerability reasons. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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jagankm ☆ 2012-04-26 08:17 (5158 d 22:54 ago) @ Dr_Dan Posting: # 8463 Views: 4,816 |
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Dear DR_DAN, Yes your right as per EMEA guidlines, ❝ For drugs with non-linear pharmacokinetics characterised by a more than proportional increase in AUC with increasing dose over the therapeutic dose range, the bioequivalence study should in general be conducted at the highest strength. As for drugs with linear pharmacokinetics a lower strength may be justified if the highest strength cannot be administered to healthy volunteers for safety/tolerability reasons. Likewise a higher dose may be used in case of sensitivity problems of the analytical method in line with the recommendations given for products with linear pharmacokinetics. phenytoin having nonlinear pK by a more than proportional increase in AUC with increasing dose over the therapeutic dose range. one more strategy in our formulation development is, it mat not possible to prepare dose proportional in all ranges of phenytoin (25 - 300mg). We are planning to formualate 25 - 100mg dose proportional and 150 - 300mg dose proportional. in this case as per above guidlines can we conduct Bioequvalence study for two highest strenghts (100mg & 300mg) of phenytoin and apply biowaiver for remaining strenghts? please advice. Edit: Standard quotes restored. [Helmut] |
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Dr_Dan ★★ Germany, 2012-04-26 17:54 (5158 d 13:17 ago) @ jagankm Posting: # 8464 Views: 4,744 |
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Dear jagankm If you have two different formulation with several strengths each then you have to perform for each formulation one BE study with the highest strength, i.e. according to your example formulation A with 100 mg and formulation B with 300 mg and for the other strengths you can apply a biowaiver. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
Ing. Helmut Schütz