TK for an IV Administered Drug

Dear Colleagues,

 

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A CRO just finished a teratology study with TK in which the drug was administered intravenously. The TK report addressed back-extrapolated Co instead of Cmax. In the previously conducted general tox studies in rats and dogs at a different CRO, their kineticist used Cmax, which of course, was always achieved at the first time-point (2 minutes). I am curious as to opinions/experience on using back-extrapolated Co vs. Cmax in the TK assessment for IV tox studies. Thanks.

 

Barry

___________________________________

Barry S. Levine, DSc

Diplomate, American Board of Toxicology

Levine Tox Consulting, LLC

Consultants in Toxicology

  and Nonclinical Development

2440 N. Lakeview Ave.

Suite 7EF

Chicago, IL 60614

Tel (773) 697-4846

Fax (312) 546-6334

Cell (312) 550-0100

email bslevine@LevineToxConsulting.com

website www.LevineToxConsulting.com

 

3 replies
  1. Steve Barton
    Steve Barton says:

    Roundtable of Toxicology Consultants | TK for an IV Administered DrugHi Barry I should make it clear that I am not an expert in this.
    Assuming this was a (fairly) rapid dose, there may be a short time before the plasma level equilibrates, in which case the 2 minute timepoint is probably correct. If the dose took some time to administer, which would be the case for more than about 1 mL/kg, the C0 calculation may be better.
    The added bonus of the C0 is that the calculation has been done, and you still know the Tmax from the plasma levels.
    The main question is how much difference does the different calculation methods produce. If small, then there is nothing to concern about.
    It is worth asking the CRO’s what their opinions are about the 2 methods. One may give a well-reasoned answer, which will be better than my attempt!
    Best regards Steve

    Steve Barton MSc CBiol MRSB DABT ERT

    BarTox Consulting Limited Tel: +44(0) 131 332 8624 or +44(0) 7790 834472 (mobile) email: steve@bartox.co.uk web: http://www.bartox.co.uk Skype: steve.bartox

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  2. Robin Guy
    Robin Guy says:

    Hi Barry,Also, remember if you are not doing what the protocol states (assuming this is GLP), you will need to have a protocol deviation and maybe an amendment.
    Best regards, Robin Robin Guy, MS, DABT, RQAP-GLPRobin Guy Consulting, LLCToxicology and GLP Consultingrobinguy@robinguy.com847.295.9250

  3. Archie Thurston
    Archie Thurston says:

    Barry:

    As a kineticist, I generally only calculate and report C0 for the first study being done in a program to provide some additional information back to the Sponsor (V, CL, t1/2, etc.), however, I would also report the Cmax (even though we all know that this is the first measured time point dose administration). After that initial study, I generally only report the Cmax and AUC values – as those are really the only parameters that are of interest in a tox program to demonstrate exposure.

    When assessing dose proportionality, I would recommend to use Cmax, as that is an actual measured value, rather than C0, which is an extrapolated value. If the Sponsor is not asking for this information (maybe they already have good PK characterization, I would then recommend that the CRO report the traditional Cmax and remove the C0 from the report, as this isn’t really useful for exposure assessments. When WinNonlin assesses AUC following IV administration, it automatically calculates C0 as a part of calculating the AUC (whereas for PO doses is assumes 0 – unless there is a pre-dose value). The C0 is calculated based on the slope from the first 3 points post dose administration, so depending upon your time points, the extrapolation may or may not be all that reliable.

    If you have any further questions – please contact me at your convenience.

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