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Re: Parallel first order and Michaelis-Menten elimination

From: Nick Holford <n.holford>
Date: Tue, 30 Mar 2010 13:42:47 -0700

Leonid,

I accept that the unit volume parameterization of VM is quite reasonable
if you think that all elimination occurs in the same volume as the
distribution volume. This is the usual test tube model that gives rise
to the unit volume belief system. It is not a realistic view of
elimination from the human body

I would also accept that if all elimination occurs in some blood cell
distribution volume (e.g.white cells) then this will be highly
correlated with the drug distribution volume and the unit volume
parameterization will appear to work fine but will fail if there is some
covariate that determines blood cell volume distribution differently
from drug distribution volume.

However, I don't accept that the elimination of a biological can be
independent of weight if we refer to the actual mass eliminated per unit
time. The first order part of the model for elimination which uses
clearance is certainly not independent of weight so why would you
imagine that the mixed order elimination process would be independent of
weight?

Note that the oldest example of a mixed order elimination process is for
ethanol (Widmark essentially invented the science of pharmacokinetics
with a mixed order elimination model). Ethanol elimination largely
occurs in the liver while it distributes in total body water. Liver
metabolism scales allometrically in a different way from total body
water so I do not believe that the mixed order elimination of ethanol
should be described with the unit volume belief system. I much prefer
the unit body belief system.

Sorry - I was confused by your residual error model which at first sight
seemed to be a transform both sides model. However, the model you use
restricts all residual errors to be non-negative which is not a
realistic description of any non-censored residual error process. All
real world uncensored measurement errors should have an error
distribution on both sides of zero when the true value is zero.

Nick

Leonid Gibiansky wrote:
> Hi Nick
>
> This form of equations can be derived from the target-mediated drug
> disposition equations. In that, VM=Kint*Rmax, where Kint is the
> internalization rate and Rmax is the concentration of the target
> (receptor). Target-mediated clearance is believed to be carried out in
> the central volume (in that particular form of the equations), and
> thus, VM is coming from the enzyme theory equations (maximum reaction
> rate). In my experience, if you follow parametrization that I use, VM
> is independent on weight (and thus, random effect on volume does not
> correlate with the random effect on VM - if the one is needed- unlike
> the parameterization that you propose). For biologics, if we believe
> that the mechanism of non-linear clearance is TMDD, it is more
> mechanistic to use parameterization suggested in my e-mail.
>
> Alternatively, the same MM equation can be derived from TMDD using
> slightly different assumptions. In that form, VM=ksyn, where ksyn is
> the target production rate per unit volume. Both forms (Vm=ksyn or
> VM=Kint*Rmax) interpret MM constants in terms of mechanistic
> parameters of the TMDD system.
>
> As to the error model, I used non-transformed variables but borrowed
> the error model from the log-transformed case. I like it because it
> would not deliver negative results on simulations.
>
> While the log-transformation may or may not provide much benefits, it
> is the only way to implement true exponential (rather than
> proportional) error model in nonmem. This is purely technical
> (mathematical-statistical-numerical method-related) problem, no
> biology behind this transformation, so I cannot see much sense to
> argue for or against using this trick.
>
> Any way, the question was about MM part, not the error model. We can
> supplement MM model with any more conventional error model of personal
> choice (hopefully supported by the data and confirmed by the VPC).
>
> Best !
> Leonid
>
>
>
>
> --------------------------------------
> Leonid Gibiansky, Ph.D.
> President, QuantPharm LLC
> web: www.quantpharm.com
> e-mail: LGibiansky at quantpharm.com
> tel: (301) 767 5566
>
>
>
>
> Nick Holford wrote:
>> Leonid,
>>
>> Thanks for the code example which illustrates one side of a religious
>> debate which took place a few weeks ago on PharmPK. The essence of
>> this debate was should one normalize PK parameters to a unit volume
>> or to a unit body.
>>
>> The unit volume believers feel that the rate constant is the
>> 'natural' way to describe pharmacokinetics while the unit body
>> believers feel that clearance is more 'natural'. Both groups agree
>> that the two systems are just reparameterizations and make identical
>> numerical predictions.
>>
>> Your coding of Vmax for the mixed order elimination process has the
>> implicit units of mass/time per unit volume e.g. mg/h/L. This is the
>> unit volume belief system.
>>
>> I am a unit body believer so I would code this system differently
>> with a very simple change- substituting A(1) with C1 to multiply the
>> mixed order expression. I have also changed VM to VMUB to indicate
>> that the dimensions of the Vmax parameter are per unit body i.e. mg/h
>> per body.
>>
>> DADT(1) = -K10*A(1)-C1*VMUB/(KM+C1)-K12*A(1)+K21*A(2)
>>
>> It could also be written like this to emphasize that the mixed order
>> process has the same units as CL (for unit body believers) when C1
>> tends to 0:
>>
>> DADT(1) = -C1*(CL+VMUB/(KM+C1) - K12*A(1)+K21*A(2)
>>
>> I note also that your residual error model implies that the DV has
>> been log transformed. This reflects yet another belief system which I
>> think you have shown has little, if any, practical merit. I prefer to
>> keep the DV in the original units.
>>
>> Best wishes,
>>
>> Nick
>>
>>
>>
>> Leonid Gibiansky wrote:
>>> ADVAN6 ADVAN8 or (nm7) ADVAN13
>>>
>>> The code is below
>>>
>>> Leonid
>>>
>>> -------------------
>>> $SUBROUTINE ADVAN6 TOL=9
>>>
>>> $MODEL
>>> NCOMP = 2
>>> COMP = (CENTRAL) ;1
>>> COMP = (PERIPH) ;2
>>>
>>> $PK
>>> CL= THETA(1)*EXP(ETA(1))
>>> V1= THETA(2)*EXP(ETA(2))
>>> Q = THETA(3)*EXP(ETA(3))
>>> V2= THETA(4)*EXP(ETA(4))
>>> VM= THETA(5)*EXP(ETA(5))
>>> KM= THETA(6)
>>>
>>> K10 = CL/V1
>>> K12 = Q/V1
>>> K21 = Q/V2
>>> S1 = V1
>>> S2 = V2
>>>
>>> $DES
>>> C1 = A(1)/S1
>>> DADT(1) = -K10*A(1)-A(1)*VM/(KM+C1)-K12*A(1)+K21*A(2)
>>> DADT(2) = K12*A(1)-K21*A(2)
>>>
>>> $ERROR
>>> TY = A(1)/V1
>>> IPRED=TY
>>> W = SQRT(THETA(7)**2/TY**2+THETA(8)**2)
>>> Y = IPRED*EXP(W*ERR(1))
>>>
>>> $THETA
>>> .....
>>>
>>> $OMEGA
>>> .....
>>>
>>> $SIGMA
>>> 1 FIX ; ~ERR
>>>
>>> --------------------------------------
>>> Leonid Gibiansky, Ph.D.
>>> President, QuantPharm LLC
>>> web: www.quantpharm.com
>>> e-mail: LGibiansky at quantpharm.com
>>> tel: (301) 767 5566
>>>
>>> chenyuhong
>>>> Dear All,
>>>>
>>>> I am working with a Biologic and would like to have a PK model with
>>>> parallel first order and Michaelis-Menten elimination. Any
>>>> suggestion about which subroutine I am supposed to use? If you can
>>>> share an example for the control stream, that will be a great help.
>>>>
>>>> Thanks,
>>>>
>>>> Yuhong
>>>>
>>>>
>>>>
>>
>> --
>> Nick Holford, Professor Clinical Pharmacology
>> Dept Pharmacology & Clinical Pharmacology
>> University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
>> tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
>> email: n.holford
>> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
>>

--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email: n.holford
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford


Received on Tue Mar 30 2010 - 16:42:47 EDT

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