Hi Yaming,
Another approach is to fill your dataset with dummy doses and then only
set F to a non-zero value in your code whenever you actually need a
dose. It's a little clumsy but it can work quite well, especially if
you know a dose can only occur at a finite number of visits to the clinic.
Best regards, James
On 04/04/2013 16:36, Leonid Gibiansky wrote:
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
--
James G Wright PhD,
Scientist, Wright Dose Ltd
Tel: UK (0)772 5636914
