RE: [NMusers] truncation & simulation

Ron,

 

Truncation can also introduce bias so you should check for this in your
simulations as well. Also, if your model based on 100 patients results =
in
simulations of CL/F ranging from 1 – 300 L/hr but the post hoc =
estimates of
CL/F range from 5 – 30 L/hr then you may want to further assess the
appropriateness of your model before using it to conduct clinical trial
simulations. Sounds like you are over-estimating the variance. You =
might
want to look at a histogram of the ETAs for CL/F and look for departures
from normality.

 

Ken

 

From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] =
On
Behalf Of Nick Holford
Sent: Tuesday, April 22, 2008 4:04 PM
To: Ron Mathôt
Cc: nmusers_at_globomaxnm.com
Subject: Re: [NMusers] truncation & simulation

 

Ron,

When you truncate the simulated parameter distribution it can lead to a
major violation of the assumptions of maximum likelihood i.e. that all
random effects are normally distributed. This means that the likelihood
ratio test will have a larger Type 1 error than expected from using the
chi-2 distribution assumption. You should use a randomization test in =
order
to determine what change in OFV is needed in order to reject the null =
under
your desired hypothesis.

Nick

Ron Mathôt wrote:

Dear NONMEM users,

Currently I am working on the simulation of a bio-equavalence trial. For =
the
reference compound a population PK model has been derived on basis of =
data
from 100 patients. Values for between-and within-patient variability are
available for all PK parameters. The simulation comprises a randomized
cross-over study with 12 patients taking the test and reference =
compound.
Two-hunderd trials are simulated and summarized. During the simulations =
I
noticed that truncation of the simulated of PK parameters significantly
influences the power of the study to confirm bio-equivalence. For =
instance
truncation of simulated oral clearances of both compounds from a range =
of
1-300 L/hr to 5 - 30 L/hr doubled the number of positive trials (due to
decreased within- patient variability). Post-hoc estimates form the =
popPK
study indicated that clearance values of the reference compound are all
within the latter range of 5 to 30 L/hr. I expect that oral clearance of =
the
test compound will not differ more than 5% from the reference compound. =
In
my opinion simulation of trials with the smallest range will produce =
more
reliable estimates of the power to detect bio-equivalence.

I would greatly appreciate your comments on this subject.
Best regards,

Ron Mathôt

Department of Hospital Pharmacy and Clincal Pharmacology
Erasmus University Medical Center
Rotterdam
The Netherlands








--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New =
Zealand
n.holford_at_auckland.ac.nz tel:+64(9)373-7599x86730 fax:+64(9)373-7090
www.health.auckland.ac.nz/pharmacology/staff/nholford
 


Received on Tue Apr 22 2008 - 16:27:31 EDT