Hi Yaming,
I have not done it so I do not have the code, but here is the possible way
1. There is an ADVAN9 routine that allows for equilibrium compartments.
Equilibrium compartment is essentially a solution of something like
S(t)=u1, or it possibly can be tricked to solving this equation. Another
possibility is to add the external fortran code to solve algebraic equation.
2. For dose, I cannot think of the way to have dose event at the
dynamically determined time. But this can be implemented by something
like a delta function (short impulse with high rate) to the right-hand
side of the differential equation. It will not be bolus but it can be
short infusion with high rate. The time of infusion start can be
controlled on the fly, in $DES block
CODE = 0
IF(T > T1 and T < T1+duration) CODE = 1
DADT()= P*CODE
where duration is a parameter (1 hour, 1 min, whatever is short in your
scale but preferably large relative to the integration steps) and
P=DOSE/duration.
Not straightforward but doable
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
On 4/4/2013 11:16 AM, Yaming Hang wrote:
Dear Leonid, Nick and Bill,
Thank you very much for responding to my question! Sorry my original question
was not detailed enough, let me try it again:
I have a hazard function h(t) which is concentration dependent:
h(t)=h0(t)*(1-CP(t)/(EC50+CP(t))), where CP(t) is the drug exposure at time t,
h0(t) is the baseline hazard function without drug (may be a constant).
Definition of EC50 is as usual.
The cumulative hazard H(t) is integral of h(x) from time 0 to t, and the
survival function S(t)=exp(-H(t)).
Let's make it simple, assume the concentration follows a one-compartment model
and it's a bolus IV dose, CL and V are known. Also assume h0(t) is a constant
lambda, along with EC50 are known. Every time a dose is introduced, the amount
is the same. Here is how I intend to simulate the event (repeated) history for
one subject:
At time 0, a unit dose is introduced, CP(t) can be determined, therefore S(t)
can be determined (maybe through the $DES, not necessarily a closed form). The
time of first event will be simulated by first generating a random number u1
from Uniform[0,1], and then solve the equation S(t1)=u1. That's why I need to
inverse the survival function. Right at time t1 following the first event, I'll
introduce another unit dose. Because most likely the concentration coming from
the first dose has not reached zero by time t1, the survival function starting
from t1 could be different than the survival function starting from the first
dose (time 0). I'll follow the same procedure to simulate a t2, which is the
time from first event to second event, and another unit dose will be introduced
at time t1+t2. This process will continue until a certain cut-off time point
has been met. That's why I said the dosing is dynamic.
Hope this time I've stated it clear enough. It's just one thought on how to do
the simulation, I'd like to get some advice on how this can be accomplished in
NONMEM.
Kind Regards,
Yaming
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Leonid Gibiansky
Sent: Wednesday, April 03, 2013 5:39 PM
To: Yaming Hang
Subject: Re: [NMusers] seeking help on NONMEM code for simulation of Repeated
Time to Event Data
Yaming
Could you, please, add some more details about the procedure to determine the time
of the event/dose. Is it some numerical integral of hazard, and when it reaches
some value (integral from 0 to T0) then the dose is given at T0 ? Or you can
determine it earlier, say by time T1 <
T0 (where T1 is known in advance)?
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
On 4/3/2013 4:35 PM, Yaming Hang wrote:
Dear NONMEM Users,
I have some questions about how to accomplish the following tasks in
NONMEM, would you kindly share your experience with me or provide some
suggestions? I'm trying to make a simulation that involves dynamic
dosing. Here is the algorithm of simulation: at time 0, a dose is
given, then the time to the first event will be simulated based on a
certain survival function which depends on the drug exposure. Next,
conditioning on that simulated first event time, a second dose will be
introduced, and again time to the second event will be simulated. This
will be repeated until a certain cut off time point.
My specific questions are:
1. since the dosing history will be depending on the simulated event
time, I cannot construct the dosing history in NONMEM data set a
prior, how can this be done?
2. The survival function is a function of the time-varying drug
exposure, therefore I need to inverse an integral which does not have
a closed form (i.e. only expressed in differential equation), how can
I do that?
Your help will be much appreciated!
Yaming Hang
