1 reply to this topic

[Florian Kopp]

Hi everybody,

Has anyone done some modeling regarding target-mediated drug disposition (TMDD) in the WNL classic code? I am interested in a simulation tool where you can enter KD, target expression rate and receptor turnover, which will predict concentration over time plots depending on the respective dose.

Thanks in advance for your help!

Best wishes

Florian

[Simon Davis]

Florian, I'm back in the office today and I had a quick look around - the examples we have in house are focussed on doing this in Phoenix and certainly when you get to simulating I think you'll find that a lot easier in PML than in WNL classic. We have a project that implements Krzyanski and Mager's TMDD model from I think 2005.

/extranet/media/kunena/attachments/legacy/images/tmmd3.jpg
Some example code looks like;

test(){
dosepoint(Atot)

deriv(At = (Kpt * C * Vc - Ktp * At))

C = 0.5 * ((Ctot - Rtot - Kd) + sqrt((Ctot - Rtot - Kd)^2 + 4 * Kd * Ctot))

deriv(Atot = - Kint * Atot - (Kel + Kpt - Kint) * C * Vc + Ktp * At)

Ctot = Atot / Vc

Ksyn = Kdeg * R0
deriv(Rtot = (Ksyn - (Kint - Kdeg) * (Ctot - C) - Kdeg * Rtot))
sequence { Rtot = R0; }

error(CEps = 1)
observe(CObs = C + CEps)

stparm( Kel = tvKel, Vc = tvVc, Ktp = tvKtp, Kpt = tvKpt, Kd = tvKd, R0 = tvR0, Kint = tvKint, Kdeg = tvKdeg)
fixef(tvKel = c(, 1.49, ), tvVc = c(, 51.2, ), tvKtp = c(, .389, ), tvKpt = c(, .389, ), tvKd = c(, 1.22, ), tvR0 = c(, 8.19, ), tvKint = c(, 3.16, ), tvKdeg = c(, 0.67, ))

}

but I guess you could take these formula back into WNL classic if you desired.

Simon.

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Edited by Simon Davis, 12 November 2015 - 01:27 PM.