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Hi,
We've injected increasing bolus doses of baclofen in the intrathecal
spaces of goats and calculated Clearance, VDss, and MRT using non
compartimental analysis. Thalf was calculated from Lz using the last
three points. We found no significative linear relation between the dose
and Clearance or VD (assessed by spearman rank correlation test) but it
was not the case for MRT or Thalf. In fact MRT or Thalf increased with
the dose injected (R>0,7 and p<0,05 for MRT and Thalf) as if the PK was
not linear within the dose range tested (150-560 ug) but in this case
Clearance should not be constant in the dose range tested ? If we look
at the formulas, it is as if AUMC increased more rapidly with the dose
than AUC (thus AUMC/AUC ratio increases with the dose). Have you
experienced this phenomena and how can it be explained ?
Thank very much you to everyone who will be able to help me on this.
F. Lagarce
--
Frederic Lagarce, Pharm-D, Ph-D
Inserm you 646, Ingenierie de la vectorisation particulaire
10 rue A Boquel, 49100 Angers
tel 33 (2) 41 73 58 55
fax 33 (2) 41 73 58 53
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Are you using the same 3 time points to calculate Lz? For eg. conside a
sampling scheme of 0,1,2,4,6,8,10,12,14,16 hours; If the Lz is
calculated using 8,10,12 hours for the lower doses (14 and 16 conc are
BLQ) and 12,14,16 hours for the higher doses, then it could very well
be that at the lower doses you are not capturing the terminal phase and
hence a lower T1/2 is observed.
Rajeev
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Hi,
I agree with Rajeev. You need to take a better look at your data. NCA
could be misleading depending on the nature of the data and complexity
of the problem.
You said:- Clearance (CL) versus dose did not show any trend.
I am assuming CL was calculated using CL=Dosei.v./AUC
Therefore, it looks like AUC increases dose proportionally. No
surprises!
Also, I am assuming AUC and AUMC are calculated by numerical
integration using trapezoidal rule. Did you look at the contribution
of the area in the extrapolated region for these two
calculations?(last sampling time to infinity)? It is my first
impression that there is considerable error propagation while
calculating the area under the first moment (that is one of the
reasons we limit ourselves from going beyond the first moment...refer
Gibaldi and Perrier). Although, I have been convinced that I should
never look at R^2, given the R^2=0.49 (R=0.7???), I could be wrong.
Pravin
--
Pravin Jadhav
Graduate Student
Department of Pharmaceutics
MCV/Virginia Commonwealth University
DPE1/CDER/OCPB/Food and Drug Administration
Phone: (301) 594-2623
Fax: (301) 480-3212
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Dear, Rajeev and Pravin
First of all thank you very much for tou answers. Half life was always
calculated using the same last three points. AUC and AUMC were
calculated using the trapezo*dal rule. CL was calculated from
dose/AUC
so, AUC increases proportionaly with the dose. But at the same Time MRT
and terminal Half life increased with the dose. Having a closer look at
the data I observed that AUMC increased faster than AUC if the dose was
higher. Assuming that one can trust the model and the data, is it
possible to have a clearance constant in a dose range and at the same
time MRT or Thalf not constant ? if yes how could this phenomena be
explained ?
thank you for your kind help
Frederic
--
Frederic Lagarce, Pharm-D, Ph-D
Inserm you 646, Ingenierie de la vectorisation particulaire
10 rue A Boquel, 49100 Angers
tel 33 (2) 41 73 58 55
fax 33 (2) 41 73 58 53
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Dear Frederic,
You can try the following to check for linear kinetics :
1) Plot AUC v Dose - if Linear, then CL is constant, and hence linear
PK.
You can also calculate AUC/Dose .. if this is constant then CL is
constant.
2) Dose normalize the curves - if the curves are superimposable then CL
constant. If not this a clear case of non-linear PK.
Since MRT= Vss/CL, if Vss is constant and CL decreases then certainly
MRT
will increase.
Ramesh
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Dear Frederic,
I think that concomitant flip-flop phenomenom and an absorption rate
that increase with increasing dose could explain your results.
Kind regards,
Nicolas.
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Hi
Don't overlook a simple cause for linearity with CL and apparent
non-linearity with half-life, as being due to poor assay performance at
lower concentrations - resulting in inaccurate estimates of half-life at
lower doses which becomes more accurate at higher doses...
Steve
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane 4072
Australia
Tel +61 7 3365 8808
Fax +61 7 3365 1688
University Provider Number: 00025B
Email: sduffull.at.pharmacy.uq.edu.au
www: http://www.uq.edu.au/pharmacy/sduffull/duffull.htm
PFIM: http://www.uq.edu.au/pharmacy/sduffull/pfim.htm
MCMC PK example: http://www.uq.edu.au/pharmacy/sduffull/MCMC_eg.htm
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Dear Frederic,
MRT=Vd/cl
T1/2=0.693/Kel or T1/2=0.693*vd/cl Or T1/2=0.693*MRT
If you look at the above two equation, MRT and T1/2 are dependent on 2
factors i.e., Volume of distribution and Clearance. If you tell that CL
was
constant across doses was Vd constant across the dose range studied?
If Vd is different they it will explain the phenomena which you have
seen.
Regards,
Suresh.B.L
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