Bioequivalence and Bioavailability Forum

jag009 ★★★ NJ, 2012-04-02 18:50 (4844 d 07:27 ago) Posting: # 8370 Views: 6,032	PK Modelling for OROS drug profile [PK / PD] Post reply
	Hello, Has anyone ever tried to model a OROS drug profile like Exalgo (Hydromphone)? The profile looks crazy... Any advice? Thanks John

Helmut
★★★

Vienna, Austria,
2012-04-02 21:38
(4844 d 04:39 ago)

@ jag009
Posting: # 8372
Views: 5,049

Blood, Sweat, and Tears

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Hi John!

❝ Has anyone ever tried to model a OROS drug profile like Exalgo (Hydromphone)?

Sure – if you mean hydromorphone… :-D

❝ The profile looks crazy... :confused:

Not uncommon for osmotic pumps. Remember that the absorption phase is never first-order (like in conventional ev formulations) but zero-order.

❝ Any advice?

Start with a model describing infusion, rather than an oral dose; include a model parameter f (bioavailability).
Modify the model in such a way that the ‘infusion rate’ (or alternatively the end of infusion) is not a constant term but becomes a parameter of the model.
OROS tablets can be quite complicated (multi-layered). I have seen only mean curves of Exalgo; if these secondary peak(s) are consistently seen in spaghetti plots as well, consider:
If you know the technology of Exalgo: Divide the dose into an early part (zero-order input) and a later part (first-order input) according to the amounts contained.
If you don’t have a clue: Set the the amount released in the first part to f × D and the second one to (1–f) × D. Estimate f in the model.
You also have a lag-time of ~2 h (and maybe another one for the second part).
Now you have a working model, but the estimates are imprecise (if you get convergence at all). The number of parameters approach the number of sampling times points. You run out of degrees of freedom.
You open a can of worms and go with PopPK…

Be prepared for blood, sweat, and tears. To get an idea what can be done with such formulations see the models described by Paixão et al.^*

Paixão P, Gouveia LF, and JAG Morais
An alternative single dose parameter to avoid the need for steady-state studies on oral extended-release drug products
Eur J Pharm Biopharm 80/2, 410–7 (2012)

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jag009 ★★★ NJ, 2012-04-03 22:17 (4843 d 04:01 ago) @ Helmut Posting: # 8381 Views: 4,951	Blood, Sweat, and Tears Post reply
	Hi Helmut, Thanks for the article reference! It really helps! John

SDavis
★★

UK,
2012-04-17 12:50
(4829 d 13:28 ago)

@ jag009
Posting: # 8425
Views: 5,064

Example Zero Order code for Phoenix WNL

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There was some discussion about various ways to do this on the Phoenix user forum a while back.

http://pharsight.com/extranet/index.php?option=com_kunena&Itemid=55&func=view&catid=51&id=821&limit=6&limitstart=6#835

here is a simple example of modelling Rate of abs.

test(){

# the pk model e.g. no. of compartments

   deriv(A1 = - Ke * A1)

   C = A1 / V



# DOse point, EDITED to model RATE of Absorbtion, total dose 20000, tmax approx 4 hours)

   dosepoint(A1,rate=zrate)



# addtive residual error statement, i.e equiv of weightingin WNL classic

error(CEps = 1)

   observe(CObs = C + CEps)



# Setting up POPULATION estimates

# tv =Typical Value, REDUNDANT in this model

   stparm(V = tvV)

   stparm(Ke = tvKe)



# Initialising the paramters

   fixef(tvV = c(, 100, ))

   fixef(tvKe = c(, 0.441, ))

fixef(zrate = c(, 5001, ))

}

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PK Modelling for OROS drug profile [PK / PD]

Blood, Sweat, and Tears

Blood, Sweat, and Tears

Example Zero Order code for Phoenix WNL