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Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients

Authorized Users Only
2015
Authors
Vučićević, Katarina
Jovanović, Marija
Golubović, Bojana
Vezmar-Kovačević, Sandra
Miljković, Branislava
Martinović, Žarko J.
Prostran, Milica
Article (Published version)
Metadata
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Abstract
The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decre...ase in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

Keywords:
Phenobarbital / Interactions / Pharmacokinetics / Therapeutic drug monitoring / NONMEM
Source:
European Journal of Clinical Pharmacology, 2015, 71, 2, 183-190
Publisher:
  • Springer Heidelberg, Heidelberg
Funding / projects:
  • Basic and Clinical Pharmacological research of mechanisms of action and drug interactions in nervous and cardiovascular system (RS-175023)

DOI: 10.1007/s00228-014-1778-7

ISSN: 0031-6970

PubMed: 25380628

WoS: 000348148200007

Scopus: 2-s2.0-84922074826
[ Google Scholar ]
6
4
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/2408
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Vučićević, Katarina
AU  - Jovanović, Marija
AU  - Golubović, Bojana
AU  - Vezmar-Kovačević, Sandra
AU  - Miljković, Branislava
AU  - Martinović, Žarko J.
AU  - Prostran, Milica
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2408
AB  - The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.
PB  - Springer Heidelberg, Heidelberg
T2  - European Journal of Clinical Pharmacology
T1  - Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients
VL  - 71
IS  - 2
SP  - 183
EP  - 190
DO  - 10.1007/s00228-014-1778-7
ER  - 
@article{
author = "Vučićević, Katarina and Jovanović, Marija and Golubović, Bojana and Vezmar-Kovačević, Sandra and Miljković, Branislava and Martinović, Žarko J. and Prostran, Milica",
year = "2015",
abstract = "The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.",
publisher = "Springer Heidelberg, Heidelberg",
journal = "European Journal of Clinical Pharmacology",
title = "Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients",
volume = "71",
number = "2",
pages = "183-190",
doi = "10.1007/s00228-014-1778-7"
}
Vučićević, K., Jovanović, M., Golubović, B., Vezmar-Kovačević, S., Miljković, B., Martinović, Ž. J.,& Prostran, M.. (2015). Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients. in European Journal of Clinical Pharmacology
Springer Heidelberg, Heidelberg., 71(2), 183-190.
https://doi.org/10.1007/s00228-014-1778-7
Vučićević K, Jovanović M, Golubović B, Vezmar-Kovačević S, Miljković B, Martinović ŽJ, Prostran M. Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients. in European Journal of Clinical Pharmacology. 2015;71(2):183-190.
doi:10.1007/s00228-014-1778-7 .
Vučićević, Katarina, Jovanović, Marija, Golubović, Bojana, Vezmar-Kovačević, Sandra, Miljković, Branislava, Martinović, Žarko J., Prostran, Milica, "Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients" in European Journal of Clinical Pharmacology, 71, no. 2 (2015):183-190,
https://doi.org/10.1007/s00228-014-1778-7 . .

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