RE: [NMusers] how to obtain steady-state individual PK parameters in NONMEM

Dear Juli,

 

Below are analytical solutions to Cmax, Tmax, Cmin and AUCtau for a
one-compartment model with first order absorption. Write the solutions in
$PK and output the calculated parameters in a table.

 

If your posthoc parameter estimates are based on sparse data I would advice
you to look into what magnitude of shrinkage these estimates are suffering
from (See: Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin
Pharmacol Ther. 2007 Jul;82(1):17-20.). If the posthoc parameter estimates
are heavily shrunk the same will go for your secondary calculated PK
parameters.

 

If you want to simulate steady state profiles the easiest way is to use a
data-set with the SS data item (Steady State dose) and II data item (Inter
dose Interval = TAU). See the NONMEM manual for further details on the use
of these data items.

 

; ------------------------------------------------------------------------

 

Cmax,ss = (F *
DOSE)/V*(1/(1-EXP(-KE)))*((KA*(1-EXP(-KE*TAU)))/(KE*(1-EXP(-KA*TAU))))**(KE/
(KE-KA))

 

Tmax,ss = (1/(KA-KE))*LN((KA*(1-EXP(-KE*TAU)))/(KE*(1-EXP(-KA*TAU))))

 

Cmin,ss = (F *
DOSE)/V*(KA/(KA-KE))*((EXP(-KE*TAU)/(1-EXP(-KE*TAU)))-(EXP(-KA*TAU)/(1-EXP(-
KA*TAU))))



(Or insert dummy data point into the data set (EVID=2))

 

AUCtau = F*DOSE/CL = F*DOSE/KE*V

 

(Assumes regular dosing schedule and fix dose during treatment. In other
cases an integration approach is necessary.)

 

; ------------------------------------------------------------------------

 

F = bioavailability (NONMEM code F1, if only oral data is used F1 is
assumed to be 1 and apparent oral V and CL are estimated)

 

TAU = Inter dosing interval

 

KA = Absorption rate constant

 

KE = Elimination rate constant (CL/V)

 

V = Distribution volume

 

In the code above I have written LN() to represent the natural logarithm of
an expression. In NONMEM this should written LOG(). ** is used both here and
in NONMEM to code for raised to the power of.

 

; ------------------------------------------------------------------------

 

Good luck!

 

Kind regards,

 

Martin Bergstrand, MSc, PhD student

-----------------------------------------------

Division of Pharmacokinetics and Drug Therapy,
Department of Pharmaceutical Biosciences,
Uppsala University

-----------------------------------------------

P.O. Box 591

SE-751 24 Uppsala

Sweden

-----------------------------------------------

martin.bergstrand_at_farmbio.uu.se

-----------------------------------------------

Work: +46 18 471 4639

Mobile: +46 709 994 396

Fax: +46 18 471 4003

 

 

----- Original Message -----

From: <mailto:juli.zachy_at_gmail.com> Juli Zachy

To: <mailto:nmusers_at_globomaxnm.com> nmusers_at_globomaxnm.com

Sent: Friday, May 09, 2008 4:22 PM

Subject: [NMusers] how to obtain steady-state individual PK parameters in
NONMEM

 

Dear NONMEM users,

 

I have a one-compartment model with first order absorption with ADVAN2
TRANS2. Is there an easy way to obtain steady-state individual PK parameters
(e.g., Cmax, Cmin, AUCtau) in NONMEM based on the posthoc estimates?

 

Alternately, is there a way to simulate the steady-state concentration-time
profiles NONMEM based on the posthoc estimates?

 

Thank you for your input in advance.

 

Juli




Received on Mon May 12 2008 - 09:16:55 EDT