- On 7 Sep 2000 at 13:07:03, "Ossig, Dr. Joachim" (Joachim.Ossig.aaa.grunenthal.de) sent the message

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Dear pk-professionals,

In the moment I have a problem with the interpretation of serum

concentration profiles of a new drug. More than 90% of the drug is

metabolized by conjugation, the conjugate is excreted renally:

After 2-min infusion of increasing doses (by infusion pump using an

indwelling cannula) some subjects showed tmax-values up to 0.5 or even 1

hour. The cmax is lower than predicted from 15 min infusion data. The

analytical method (HPLC with fluorescence detection) is selective (checked

by LC-MS-MS), there is no evidence for enterohepatic circulation after oral

dosing.

Here are 2 examples:

time [h], c_10_mg, c_20_mg, c_40_mg

0.050, 4.3, 20.2, 76.0

0.083, 55.3, 37.4, 98.0

0.167, 66.7, 53.8, 90.7

0.250, 36.3, 36.5, 75.6

0.500, 19.2, 34.8, 76.8

1.000, 14.2, 35.3, 73.7

2.000, 11.2, 27.4, 63.6

4.000, 7.8, 17.0, 48.6

6.000, 5.0, 12.0, 27.5

10.00, 2.8, 5.8, 13.6

time [h], c_10_mg, c_20_mg, c_30_mg

0.050, 15.2, 26.3, 61.4

0.083, 29.2, 37.4, 47.9

0.167, 23.1, 33.5, 43.5

0.250, 22.4, 32.1, 52.9

0.500, 18.4, 37.5, 57.2

1.000, 15.6, 41.5, 56.5

2.000, 12.4, 31.7, 49.8

4.000, 9.1, 24.2, 35.7

6.000, 5.5, 15.0, 22.5

10.00, 2.4, 4.9, 8.2

Is there anybody able to help me to find the (may be trivial) explanation?

I had expected some turbulence in the first sample points (3, 5 and 10

minutes) but no increasing concentrations .... - On 8 Sep 2000 at 10:57:55, "Hoffmann, Gerhard {PRNS~Basel}" (GERHARD.HOFFMANN.-at-.roche.com) sent the message

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Dear Dr. Ossig,

what is the solubility of the drug? Are you sure that there is no

precipitation after infusion?

Subsequent systemic dissolution can create profiles like the ones you saw.

Gerhard H.

Roche, Basel - On 8 Sep 2000 at 10:58:28, ml11439.aaa.goodnet.com sent the message

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Group,

Lipid soluble benzodiazepines and barbiturates undergo redistribution

after IV administration, where uptake into less vascular tissues (especially

muscle and fat) leads to a decline in the concentration of durg in the

plasma and brain. A similar redistribution phenomenon could be taking

place here.

Two compartment analysis of the data as if an infusion took place up

until the peak plasma concentrations, indicates that there is a decrease

in to two compartment characteristics with Increasing doses. The k12 and

k12 decrease with increasing doses indicating a saturation of the peripheral

compartment.

Although I have only read about similar phenomenon,,this type of data

might indicate an initial distribution into a preferred compartment, and

then redistibution into the plasma. It would appear at least, that there

is change in the distribution properties of the drug with increasing doses.

Ko=10mg/0.03333hr= 300mg/hr for T=0.03333hr

A= RXo(alpha)/Ko(1-e-alphaT) 10mg dose Sub 1

58.18494153

B= SXo(beta)/Ko(1-e-betaT)

17.22363161

Vc= Xo/(A+b) 49.01273 R

0.132610917 10.59955 alpha

k21= (alphaA +betaB)/(A+b) 17.16428 S

8.224536062 0.20125 beta

K10=alpha*beta/k21

0.259365398

K12= alpha+ beta-k21-k10

2.316899877

Vb=k10*Vc/beta

0.170905228

Ko=40mg/0.03333hr= 1200mg/hr for T=0.03333hr

A= RXo(alpha)/Ko(1-e-alphaT) 40mg Dose Sub 1

53.70058

B= SXo(beta)/Ko(1-e-betaT)

32.24054

Vc= Xo/(A+b) 53.53319 R

0.465435 0.181437 alpha

k21= (alphaA +betaB)/(A+b) 32.14004 S

0.181437 0.181437 beta

K10=alpha*beta/k21

0.181437

K12= alpha+ beta-k21-k10

0

Vb=k10*Vc/beta

0.465435

Mike Leibold, PharmD, RPH

ML11439.-a-.goodnet.com

References

1) Gibaldi, M., Perrier, D., Pharmacokinetics, New York, Marcel Dekker

1975

2) Gibaldi, M., Perrier, D., Pharmacokinetics 2nd ed, New York, Marcel Dekker

1982

3) Wagner, J., Fundamentals of Clinical Pharmacokinetics, Hamilton, Drug

Intelligence Publications 1975

4) Godfrey, Keith, Compartment Models and Their Application, New York,

Academic Press 1983

5) Wagner, J.G., Pharmacokinetics for the Pharmaceutical Scientist, Lancaster,

Technomic Publishing Co 1993 - On 8 Sep 2000 at 20:42:24, ml11439.at.goodnet.com sent the message

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Group,

Here is a slight change in the two compartment analysis as

if an infusion took place up until 0.5 hours in subject 1, at

two different doses of 10mg and 40mg, which resulted in the

following change in the data. Basically, the same decrease in two

compartment characteristics occurs in the data, again indicating

a change in distribution properties (a saturation of a

preferred compartment?).

Ko=10mg/0.03333hr= 300mg/hr for T=0.03333hr

A= RXo(alpha)/Ko(1-e-alphaT) 10mg dose Sub 1

13.77935

B= SXo(beta)/Ko(1-e-betaT)

15.34182

Vc= Xo/(A+b) 13.10631 R

0.343393 3.024355 alpha

k21= (alphaA +betaB)/(A+b) 15.2945 S

1.525579 0.179443 beta

K10=alpha*beta/k21

0.355734

K12= alpha+ beta-k21-k10

1.322485

Vb=k10*Vc/beta

0.680753

Ko=40mg/0.03333hr= 1200mg/hr for T=0.03333hr

A= RXo(alpha)/Ko(1-e-alphaT) 40mg Dose Sub 1

51.18065

B= SXo(beta)/Ko(1-e-betaT)

29.72178

Vc= Xo/(A+b) 51.02111 R

0.494423 0.181437 alpha

k21= (alphaA +betaB)/(A+b) 29.62913 S

0.181437 0.181437 beta

K10=alpha*beta/k21

0.181437

K12= alpha+ beta-k21-k10

1.09E-13

Vb=k10*Vc/beta

0.494423

Mike Leibold, PharmD,RPh

ML11439.aaa.goodnet.com

References

1) Gibaldi, M., Perrier, D., Pharmacokinetics, New York, Marcel Dekker

1975

2) Gibaldi, M., Perrier, D., Pharmacokinetics 2nd ed, New York, Marcel Dekker

1982

3) Wagner, J., Fundamentals of Clinical Pharmacokinetics, Hamilton, Drug

Intelligence Publications 1975

4) Godfrey, Keith, Compartment Models and Their Application, New York,

Academic Press 1983

5) Wagner, J.G., Pharmacokinetics for the Pharmaceutical Scientist, Lancaster,

Technomic Publishing Co 1993 - On 9 Sep 2000 at 17:10:38, David_Bourne (david.aaa.boomer.org) sent the message

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Group,

When including the plasma levels before the peak, the best

fitting model is a two compartment with a first order dissolution term.

That is, a model which allows for dissolution of the IV administered

drug in the plasma after it has been administered. This is the only

model which fits the increase in plasma concentrations that occurs

before the peak.

Here is the triexpoenential model which was fitted to the data,

but the first term is negative, representing the first order dissolution

term of the equation. An ordinary three compartment model would not fit

the plasma concentrations before the peak.

Nonlinear Regression of Cp = Qe-pt + Re-at +Se-bt

Q pi R alpha S

-835.0134346 18.99610185 551.7020564 11.43598543

16.97809179 beta

0.178897821

Predicted Conc Time Concentration

SS function Minimized

5.270679896 0.05 4.3 0.000292109

57.70270585 0.083 55.3 0.035570097

63.19889347 0.167 66.7 0.301764167

40.63117962 0.25 36.3 0.311086177

17.27579577 0.5 19.2 0.423790259

14.20288683 1 14.2 0.050400387

11.87135267 2 11.2 0.000132097

8.300639105 4 7.8 2.39696E-06

5.803939269 6 5 0.041752943

2.83756301 10 2.8 0.006232451

1.171023083 Sum

Mike Leibold, PharmD, RPh

ML11439.-a-.goodnet.com

References

1) Gibaldi, M., Perrier, D., Pharmacokinetics, New York, Marcel Dekker

1975

2) Gibaldi, M., Perrier, D., Pharmacokinetics 2nd ed, New York, Marcel Dekker

1982

3) Wagner, J., Fundamentals of Clinical Pharmacokinetics, Hamilton, Drug

Intelligence Publications 1975

4) Godfrey, Keith, Compartment Models and Their Application, New York,

Academic Press 1983

5) Wagner, J.G., Pharmacokinetics for the Pharmaceutical Scientist, Lancaster,

Technomic Publishing Co 1993

---

Sender: PharmPK.at.boomer.org

Reply-To: ml11439.aaa.goodnet.com (Michael J. Leibold)

From: ml11439.-a-.goodnet.com (Michael J. Leibold)

Date: Sat, 9 Sep 2000 03:17:30 -0700 (MST)

To: david.aaa.boomer.org

Subject: Re: PO-kinetics after 2-min infusion?

Group,

Fitting the data to a triexpoential equation with the

first term being a negative first order dissolution term seems

to fit the data adequately. The first order dissolution with

a two compartment model can predict the initial low plasma

concentrations which increase to a peak, as well as explain

what seemed to be decrease in two compartment characteristics

with the higher 40mg dose. This would be mathematically

equivalent to the two compartment first order absorption model,

and kinetically similar to activation of a prodrug.

The following data resulting from a 40mg dose in subject

one were fitted to a triexponential equation with a negative

first order dissolution term. The fit seemed as good as

with the 10mg dose, and the fit indicated the same two

compartment characteristics.

40mg dose Sub 1

2min Infusion

Nonlinear Regression of Cp = Qe-pt + Re-at +Se-bt

Q pi R alpha S

-866.3538907 33.86616619 521.9578591 24.85520409

85.38710337 beta

0.175312971

Predicted Conc Time Concentration

SS function Minimized

81.70453204 0.05 76 4.62601E-05

100.2539897 0.083 98 0.00138804

88.22444089 0.167 90.7 0.073684107

82.59464127 0.25 75.6 0.645936614

78.22308832 0.5 76.8 0.026369485

71.65637351 1 73.7 0.056667696

60.13362278 2 63.6 0.188927218

42.34893146 4 48.6 0.804029999

29.82411358 6 27.5 0.196418325

14.79168741 10 13.6 0.104420506

2.097888249 Sum

SSW 1/C Function Minimized

2.097888249

Mike Leibold, PharmD, RPh

ML11439.-a-.goodnet.com - On 10 Sep 2000 at 19:01:45, matthew.-a-.md.huji.ac.il sent the message

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Dear Dr. Joachim!

I met similar problems with Cmax achieved some time following IV bolus

administration while injecting VPA derivatives to dogs. The problem to my

understanding was solubility of the compound in plasma. So what may happen

after the injection is that the compound will sediment inside the blood

vessel and afterwards redissolve in the blood current over a period of

several minutes, which will subsequently cause Cmax achievement not in time

zero. On the other hand if your compound is freely water soluble it is

probably some other reason that caused this particular phenomenon of yours.

Matthew Wasserman. - On 11 Sep 2000 at 12:37:04, ml11439.-a-.goodnet.com sent the message
Dissolution+/-Prodrug? Corrected text

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Joachim,

When including the plasma levels before the peak, the best

fitting model is a two compartment with a first order dissolution term.

That is, a model which allows for dissolution of the IV administered

drug in the plasma after it has been administered. This is the only

model which fits the increase in plasma concentrations that occurs

before the peak.

Here is the triexpoenential model which was fitted to the data,

but the first term is negative, representing the first order dissolution

term of the equation. An ordinary three compartment model would not fit

the plasma concentrations before the peak.

Nonlinear Regression of Cp = Qe-pt + Re-at +Se-bt

Q pi R alpha S

-835.0134346 18.99610185 551.7020564 11.43598543

16.97809179 beta

0.178897821

Predicted Conc Time Concentration

SS function Minimized

5.270679896 0.05 4.3 0.000292109

57.70270585 0.083 55.3 0.035570097

63.19889347 0.167 66.7 0.301764167

40.63117962 0.25 36.3 0.311086177

17.27579577 0.5 19.2 0.423790259

14.20288683 1 14.2 0.050400387

11.87135267 2 11.2 0.000132097

8.300639105 4 7.8 2.39696E-06

5.803939269 6 5 0.041752943

2.83756301 10 2.8 0.006232451

1.171023083 Sum

Fitting the data to a triexpoential equation with the

first term being a negative first order dissolution term seems

to fit the data adequately. The first order dissolution with

a two compartment model can predict the initial low plasma

concentrations which increase to a peak, as well as explain

what seemed to be decrease in two compartment characteristics

with the higher 40mg dose. This would be mathematically

equivalent to the two compartment first order absorption model,

and kinetically similar to activation of a prodrug.

The following data resulting from a 40mg dose in subject

one were fitted to a triexponential equation with a negative

first order dissolution term. The fit seemed as good as

with the 10mg dose, and the fit indicated the same two

compartment characteristics.

40mg dose Sub 1

2min Infusion

Nonlinear Regression of Cp = Qe-pt + Re-at +Se-bt

Q pi R alpha S

-866.3538907 33.86616619 521.9578591 24.85520409

85.38710337 beta

0.175312971

Predicted Conc Time Concentration

SS function Minimized

81.70453204 0.05 76 4.62601E-05

100.2539897 0.083 98 0.00138804

88.22444089 0.167 90.7 0.073684107

82.59464127 0.25 75.6 0.645936614

78.22308832 0.5 76.8 0.026369485

71.65637351 1 73.7 0.056667696

60.13362278 2 63.6 0.188927218

42.34893146 4 48.6 0.804029999

29.82411358 6 27.5 0.196418325

14.79168741 10 13.6 0.104420506

2.097888249 Sum

SSW 1/C Function Minimized

2.097888249

Mike Leibold, PharmD, RPh

ML11439.-at-.goodnet.com

References

1) Gibaldi, M., Perrier, D., Pharmacokinetics, New York, Marcel Dekker

1975

2) Gibaldi, M., Perrier, D., Pharmacokinetics 2nd ed, New York, Marcel Dekker

1982

3) Wagner, J., Fundamentals of Clinical Pharmacokinetics, Hamilton, Drug

Intelligence Publications 1975

4) Godfrey, Keith, Compartment Models and Their Application, New York,

Academic Press 1983

5) Wagner, J.G., Pharmacokinetics for the Pharmaceutical Scientist, Lancaster,

Technomic Publishing Co 1993

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