Dear All,
I'm working on the population pharmacokinetics of a mAb, in this study
4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested
different models, but none of them fit well; that's why I decided to
find for each dose level the best model. I found the two lower dose
levels fitted to Michaelis Menten + CL linear model and the two higher
dose levels fitted to QSS Rtot model.
I think if I use this code, I'll find the best model for my data, so I
appreaciate your suggestions:
$PK
TVCL= THETA(1)
TVV1= THETA(2)
TVQ = THETA(3)
TVV2 = THETA (4)
TVKM = 0
TVVM = 0
IF(DOS.LT.200) THEN
TVKM = THETA (5)
TVVM = THETA (6)
TVKSS = 0
TVKINT = 0
TVKDEG = 0
TVRMAX = 0
IF(DOS.GT.100) THEN
TVKSS = THETA (7)
TVKKINT = THETA(8)
TVRMAX = THETA(9)
ENDIF
K = CL/V1
K12 = Q/V1
K21 = Q/V2
S1 = V1
;----------------------------------
$DES
CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1)
DADT(1) =
-(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC)
DADT(2) = K12*CONC*V1-K21*A(2)
Thank you,
Regards,
Niurys de Castro
--
MSc Niurys de Castro Suárez
Profesor Asistente Farmacometría
Investigador Agregado
Departamento Farmacia
Instituto de Farmacia y Alimentos, Universidad de La Habana
Cuba
Help with a PK code
Generally speaking, the portion which undergoes saturatable clearance due
to ligand or receptor engagement will be negligible at high concentrations.
Therefore, it is recommend to use one saturable equation without needs of
dose dependent “IF .. THEN … ENDIF “ Statement
The followings are some programming comments in NONMEM coding.
IF(DOS.LT.200) THEN;; This assumes DOSE below 50 and 100 not 200
;;; LT = less than
;;; LE = less than or Equal to
TVKM = THETA (5)
TVVM = THETA (6)
;; THIS needs to be end in order to next if Then statement effective
*ENDIF;;*
;;;
TVKSS = 0
TVKINT = 0
TVKDEG = 0
TVRMAX = 0
IF(DOS.GT.100) THEN;;; This assumes that DOS 200 and 400
;;; GT = Greater than
;;; GE = Great or Equal to
TVKSS = THETA (7)
TVKKINT = THETA(8)
TVRMAX = THETA(9)
ENDIF
....
$DES
CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1)
;; CONC is simply A(1)/V1 and RMAX and KSS are undefined variables.
Hope it helps.
Quoted reply history
On Tue, Apr 23, 2019 at 8:49 AM Niurys.CS <amaranthfan_at_gmail.com> wrote:
> Dear All,
>
> I'm working on the population pharmacokinetics of a mAb, in this study
> 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested
> different models, but none of them fit well; that's why I decided to
> find for each dose level the best model. I found the two lower dose
> levels fitted to Michaelis Menten + CL linear model and the two higher
> dose levels fitted to QSS Rtot model.
> I think if I use this code, I'll find the best model for my data, so I
> appreaciate your suggestions:
>
> $PK
>
> TVCL= THETA(1)
> TVV1= THETA(2)
> TVQ = THETA(3)
> TVV2 = THETA (4)
>
> TVKM = 0
> TVVM = 0
>
> IF(DOS.LT.200) THEN
> TVKM = THETA (5)
> TVVM = THETA (6)
>
> TVKSS = 0
> TVKINT = 0
> TVKDEG = 0
> TVRMAX = 0
>
> IF(DOS.GT.100) THEN
>
> TVKSS = THETA (7)
> TVKKINT = THETA(8)
> TVRMAX = THETA(9)
>
> ENDIF
>
>
> K = CL/V1
> K12 = Q/V1
> K21 = Q/V2
> S1 = V1
>
> ;----------------------------------
> $DES
>
> CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V
1)
>
> DADT(1)
> -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CON
C)
> DADT(2) = K12*CONC*V1-K21*A(2)
>
>
> Thank you,
>
> Regards,
> Niurys de Castro
>
> --
>
> MSc Niurys de Castro Suárez
> Profesor Asistente Farmacometría
> Investigador Agregado
> Departamento Farmacia
> Instituto de Farmacia y Alimentos, Universidad de La Habana
> Cuba
>
>
Generally speaking, the portion which undergoes saturatable clearance due
to ligand or receptor engagement will be negligible at high concentrations.
Therefore, it is recommend to use one saturable equation without needs of
dose dependent “IF .. THEN … ENDIF “ Statement
The followings are some programming comments in NONMEM coding.
IF(DOS.LT.200) THEN;; This assumes DOSE below 50 and 100 not 200
;;; LT = less than
;;; LE = less than or Equal to
TVKM = THETA (5)
TVVM = THETA (6)
;; THIS needs to be end in order to next if Then statement effective
*ENDIF;;*
;;;
TVKSS = 0
TVKINT = 0
TVKDEG = 0
TVRMAX = 0
IF(DOS.GT.100) THEN;;; This assumes that DOS 200 and 400
;;; GT = Greater than
;;; GE = Great or Equal to
TVKSS = THETA (7)
TVKKINT = THETA(8)
TVRMAX = THETA(9)
ENDIF
....
$DES
CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1)
;; CONC is simply A(1)/V1 and RMAX and KSS are undefined variables.
Hope it helps.
Quoted reply history
On Tue, Apr 23, 2019 at 8:49 AM Niurys.CS <[email protected]> wrote:
> Dear All,
>
> I'm working on the population pharmacokinetics of a mAb, in this study
> 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested
> different models, but none of them fit well; that's why I decided to
> find for each dose level the best model. I found the two lower dose
> levels fitted to Michaelis Menten + CL linear model and the two higher
> dose levels fitted to QSS Rtot model.
> I think if I use this code, I'll find the best model for my data, so I
> appreaciate your suggestions:
>
> $PK
>
> TVCL= THETA(1)
> TVV1= THETA(2)
> TVQ = THETA(3)
> TVV2 = THETA (4)
>
> TVKM = 0
> TVVM = 0
>
> IF(DOS.LT.200) THEN
> TVKM = THETA (5)
> TVVM = THETA (6)
>
> TVKSS = 0
> TVKINT = 0
> TVKDEG = 0
> TVRMAX = 0
>
> IF(DOS.GT.100) THEN
>
> TVKSS = THETA (7)
> TVKKINT = THETA(8)
> TVRMAX = THETA(9)
>
> ENDIF
>
>
> K = CL/V1
> K12 = Q/V1
> K21 = Q/V2
> S1 = V1
>
> ;----------------------------------
> $DES
>
> CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1)
>
> DADT(1) =
> -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC)
> DADT(2) = K12*CONC*V1-K21*A(2)
>
>
> Thank you,
>
> Regards,
> Niurys de Castro
>
> --
>
> MSc Niurys de Castro Suárez
> Profesor Asistente Farmacometría
> Investigador Agregado
> Departamento Farmacia
> Instituto de Farmacia y Alimentos, Universidad de La Habana
> Cuba
>
>
The code will work as written (if you add ENDIF after TVVM = THETA (6), and define all parameters CL, V1, Q, V2, KINT, ...) but mechanistically, this is not a good idea to have two models for two dose levels. You may want to try QSS model with non-constant Rtot (MM model is usually good when Rtot is low, while QSS is good when Rtot has accumulation, so may be this is why you see MM model at low doses and QSS at high doses).
Also, what is measured, is it free or total concentration? This part of the code was not shown, and it depends on the assay (for QSS part of the model).
Thanks
Leonid
Quoted reply history
On 4/23/2019 8:34 AM, Niurys.CS wrote:
> Dear All,
>
> I'm working on the population pharmacokinetics of a mAb, in this study
> 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested
> different models, but none of them fit well; that's why I decided to
> find for each dose level the best model. I found the two lower dose
> levels fitted to Michaelis Menten + CL linear model and the two higher
> dose levels fitted to QSS Rtot model.
> I think if I use this code, I'll find the best model for my data, so I
> appreaciate your suggestions:
>
> $PK
>
> TVCL= THETA(1)
> TVV1= THETA(2)
> TVQ = THETA(3)
> TVV2 = THETA (4)
>
> TVKM = 0
> TVVM = 0
>
> IF(DOS.LT.200) THEN
> TVKM = THETA (5)
> TVVM = THETA (6)
>
> TVKSS = 0
> TVKINT = 0
> TVKDEG = 0
> TVRMAX = 0
>
> IF(DOS.GT.100) THEN
>
> TVKSS = THETA (7)
> TVKKINT = THETA(8)
> TVRMAX = THETA(9)
>
> ENDIF
>
> K = CL/V1
> K12 = Q/V1
> K21 = Q/V2
> S1 = V1
>
> ;----------------------------------
> $DES
>
> CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1)
>
> DADT(1) =
> -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC)
> DADT(2) = K12*CONC*V1-K21*A(2)
>
> Thank you,
>
> Regards,
> Niurys de Castro
Dears Leonid and Saeheum,
First of all, thank you for your suggestions, they are very useful and
cleared up some queries I had.
Leonid, regarding your question about measurement of free or total
ligand concentration, in this study we only measured the free ligand
concentration.
Thank so much,
Regards,
Niurys
Quoted reply history
2019-04-23 12:00 GMT-05:00, Leonid Gibiansky <[email protected]>:
> The code will work as written (if you add ENDIF after TVVM = THETA (6),
> and define all parameters CL, V1, Q, V2, KINT, ...) but mechanistically,
> this is not a good idea to have two models for two dose levels. You may
> want to try QSS model with non-constant Rtot (MM model is usually good
> when Rtot is low, while QSS is good when Rtot has accumulation, so may
> be this is why you see MM model at low doses and QSS at high doses).
>
> Also, what is measured, is it free or total concentration? This part of
> the code was not shown, and it depends on the assay (for QSS part of the
> model).
>
> Thanks
> Leonid
>
>
> On 4/23/2019 8:34 AM, Niurys.CS wrote:
>> Dear All,
>>
>> I'm working on the population pharmacokinetics of a mAb, in this study
>> 4 dose levels (50, 100, 200 and 400 mg) were evaluated. I tested
>> different models, but none of them fit well; that's why I decided to
>> find for each dose level the best model. I found the two lower dose
>> levels fitted to Michaelis Menten + CL linear model and the two higher
>> dose levels fitted to QSS Rtot model.
>> I think if I use this code, I'll find the best model for my data, so I
>> appreaciate your suggestions:
>>
>> $PK
>>
>> TVCL= THETA(1)
>> TVV1= THETA(2)
>> TVQ = THETA(3)
>> TVV2 = THETA (4)
>>
>> TVKM = 0
>> TVVM = 0
>>
>> IF(DOS.LT.200) THEN
>> TVKM = THETA (5)
>> TVVM = THETA (6)
>>
>> TVKSS = 0
>> TVKINT = 0
>> TVKDEG = 0
>> TVRMAX = 0
>>
>> IF(DOS.GT.100) THEN
>>
>> TVKSS = THETA (7)
>> TVKKINT = THETA(8)
>> TVRMAX = THETA(9)
>>
>> ENDIF
>>
>>
>> K = CL/V1
>> K12 = Q/V1
>> K21 = Q/V2
>> S1 = V1
>>
>> ;----------------------------------
>> $DES
>>
>> CONC=0.5*(A(1)/V1-RMAX-KSS)+0.5*SQRT((A(1)/V1-RMAX-KSS)**2+4*KSS*A(1)/V1)
>>
>> DADT(1) =
>> -(K+K12)*CONC*V1+K21*A(2)-KINT*RMAX*CONC*V1/(KSS+CONC)-VM*CONC*V1/(KM+CONC)
>> DADT(2) = K12*CONC*V1-K21*A(2)
>>
>>
>> Thank you,
>>
>> Regards,
>> Niurys de Castro
>>
>
--
MSc Niurys de Castro Suárez
Profesor Asistente Farmacometría
Investigador Agregado
Departamento Farmacia
Instituto de Farmacia y Alimentos, Universidad de La Habana
Cuba
"Una estrella brilla en la hora de nuestro encuentro"