- On 15 Oct 2004 at 12:10:43, Frederic Lagarce (frederic.lagarce.-at-.st-serge.univ-angers.fr) sent the message

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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 - On 15 Oct 2004 at 12:24:56, "menon, rajeev" (rmenon.-a-.kospharm.com) sent the message

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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 - On 15 Oct 2004 at 20:28:23, Pravin Jadhav (pravinj.at.gmail.com) sent the message

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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 - On 17 Oct 2004 at 15:59:13, Frederic Lagarce (frederic.lagarce.at.st-serge.univ-angers.fr) sent the message

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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 - On 18 Oct 2004 at 08:34:18, "Ramesh, Jayaram" (ramesh.jayaram.-a-.astrazeneca.com) sent the message

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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 - On 18 Oct 2004 at 17:36:49, gregoire nicolas (icrgregoire.-a-.yahoo.com) sent the message

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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. - On 19 Oct 2004 at 08:12:07, "Steve Duffull" (sduffull.-a-.pharmacy.uq.edu.au) sent the message

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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 - On 19 Oct 2004 at 10:21:41, "Suresh, Lakshminarayan" (suresh.lakshminarayan.-at-.astrazeneca.com) sent the message

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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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