Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: A population approach

Francisco J. Flores-Murrieta, Hui C. Ko, Dora M. Flores-Acevedo, Francisco J. López-Muñoz, William J. Jusko, Mark E. Sale, Gilberto Castañeda-Hernández

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50of 9.22 μg/ml. This IC50is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 μg/ml). The present results demonstrate that mechanisin-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.
Original languageAmerican English
Pages (from-to)547-557
Number of pages491
JournalJournal of Pharmacokinetics and Biopharmaceutics
StatePublished - 1 Jan 1998
Externally publishedYes

Fingerprint

Tolmetin
Pharmacokinetics
Population
Prostaglandins
Intra-Articular Injections
Nociception
Bayes Theorem
Hindlimb
Uric Acid
Pharmaceutical Preparations

Cite this

Flores-Murrieta, Francisco J. ; Ko, Hui C. ; Flores-Acevedo, Dora M. ; López-Muñoz, Francisco J. ; Jusko, William J. ; Sale, Mark E. ; Castañeda-Hernández, Gilberto. / Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: A population approach. In: Journal of Pharmacokinetics and Biopharmaceutics. 1998 ; pp. 547-557.
@article{85a07a20fd874ef3940287758d035d58,
title = "Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: A population approach",
abstract = "The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76{\%} and an IC50of 9.22 μg/ml. This IC50is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 μg/ml). The present results demonstrate that mechanisin-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.",
author = "Flores-Murrieta, {Francisco J.} and Ko, {Hui C.} and Flores-Acevedo, {Dora M.} and L{\'o}pez-Mu{\~n}oz, {Francisco J.} and Jusko, {William J.} and Sale, {Mark E.} and Gilberto Casta{\~n}eda-Hern{\'a}ndez",
year = "1998",
month = "1",
day = "1",
language = "American English",
pages = "547--557",
journal = "Journal of Pharmacokinetics and Biopharmaceutics",
issn = "0090-466X",
publisher = "Kluwer/Plenum Publishers",

}

Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: A population approach. / Flores-Murrieta, Francisco J.; Ko, Hui C.; Flores-Acevedo, Dora M.; López-Muñoz, Francisco J.; Jusko, William J.; Sale, Mark E.; Castañeda-Hernández, Gilberto.

In: Journal of Pharmacokinetics and Biopharmaceutics, 01.01.1998, p. 547-557.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: A population approach

AU - Flores-Murrieta, Francisco J.

AU - Ko, Hui C.

AU - Flores-Acevedo, Dora M.

AU - López-Muñoz, Francisco J.

AU - Jusko, William J.

AU - Sale, Mark E.

AU - Castañeda-Hernández, Gilberto

PY - 1998/1/1

Y1 - 1998/1/1

N2 - The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50of 9.22 μg/ml. This IC50is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 μg/ml). The present results demonstrate that mechanisin-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.

AB - The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2, or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50of 9.22 μg/ml. This IC50is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 μg/ml). The present results demonstrate that mechanisin-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0032423511&origin=inward

UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=0032423511&origin=inward

M3 - Article

SP - 547

EP - 557

JO - Journal of Pharmacokinetics and Biopharmaceutics

JF - Journal of Pharmacokinetics and Biopharmaceutics

SN - 0090-466X

ER -