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I would appreciate your opinion/ suggestions (excluding PK
disproportionality) regarding the following issue:
What could be the reasons for prolongation of half-life from around
1hr (in the clinical dose) to about 7 hrs (in 6-fold higher dose)?
The concentrations vs. time graph suggests a bi-compartmental model.
Thank You,
Kind regards,
A.
[Is it possible that you are only seeing the alpha (faster) at lower
doses because of assay limitations, otherwise saturable elimination
(metabolism) - db]
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The following message was posted to: PharmPK
1) saturation of clearance pathway
2) saturation of catabolic pathway
3) storage then slow release from another compartment
4) a combination of any of the above
Ed O'Connor, PhD
Technical Director, Immunoanalytical
Tandem Laboratories
115 Silvia Street
West Trenton, New Jersey
609-228-0243
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Hi 'A',
Presumably the AUC also increases disproportionately at the x6 higher
dose? (I agree with David B.'s explanation.)
- Peter
Peter W. Mullen, PhD, FCSFS
KEMIC BIORESEARCH (www.kemic.com)
Kentville
Nova Scotia, B4N 4H8
Canada
Tel. (902) 678-8195 Fax (902) 678-2839 E-mail pmullen.-a-.kemic.com
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Is your compound dosage an oral or IV formulated dose? Is there an
alteration in the absorption characteristics indicating a flip-flop
condition? What are the general physicochemical characteristics of
the compound, is it amenable to dosage at a 6-fold higher dose in the
similar form in which you dose at the lowered dose. Ed's input is
also very valuable in this case and could interplay with the
suggestions in this email.
Sanjeev Thohan, PhD
Director, DMPK
Exelixis, Inc
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