Download No effect of carbamazepine daily dose on phenobarbital

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p
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Structural model
Exponential model
Linear model
Power model
Interindividual variability - exponential model
TVCL= CL; CL=TVCL*EXP( CL)
TVV= V * WT; V=TVV*EXP( V)
TVKA= Ka; KA=TVKA*EXP( Ka)
Log-linear model
Categorical covariate (0-present; 1-non present)
Residual variability - proportional model
C=CPRED*(1+ )
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J Clin Pharm Ther
Eur J Clin Pharmacol
P.5.d.003
No effect of carbamazepine daily dose on phenobarbital elimination in adult epileptic patients - population
pharmacokinetic analysis
M. Jovanovic 1, K. Vucicevic1, B. Golubovic 1, S. Vezmar Kovacevic 1, M. Prostran 2, Z. Martinovic3, B. Miljkovic1
1Faculty of Pharmacya Department of Pharmacokinetics and Clinical Pharmacya Belgradea Serbia
2Faculty of Medicinea Department of Pharmacology Clinical Pharmacology and Toxicologya Belgradea Serbia
3Institute
of Mental Healtha Department of Epilepsy and Clinical Neurophysiologya Belgradea Serbia
Objectives: The aim of the study was to explore impact of carbamazepine aCBZ) daily dose on phenobarbital
aPB) oral clearance aCL/F) in adult patients with epilepsy. The influence of CBZ is indefinite as previous results
indicate variable effects on PB disposition. Decrease of PB CL/F in the presence of CBZ was recorded mostly in
population of children [1,2].
Methods: A total of 205 measured PB concentrations wereused for analysis. Data were collected during routine
therapeutic drug monitoring at the Unit for Antiepileptic Drugs at the Institute of Mental Health, Belgrade, Serbia.
PB was administered either as monotherapy or in combination with other antiepileptic drugs. Patients a42±13
years) included in the study were at least three weeks on stable dosing regimens, for the assurance that the
steady-state was reached for each of the antiepileptic drugs included in the therapy. Daily doses of PB were in
the range from 25 to 300mg and dosage regimens were once, twice or three times a day. Eighty-one patients
were co-treated with CBZ whose dose was in the range from 200 to 2000mg/day. Data analysis was performed by
nonlinear mixed effects modelling approach using NONMEM ® software aversion 7.2, Icon Development Solutions,
Ellicott City, MD, USA). The first-order conditional estimation method with interaction aFOCEI) was used for
parameter estimation. Due to insufficient data in the absorption and distribution phase, only CL/F was
estimated. Additive, proportional and exponential error model were tested for describing interindividual
variability. For residual intraindividual variability of PB concentration additive, proportional and combination error
models were evaluated.
Results: An average daily dose of CBZ was 801.2±416.4mg. A one-compartment model with first-order
absorption and elimination was used as a structural model. The interindividual variability was evaluated by an
exponential model while residual variability was best described by proportional model. Objective function value
aOFV) for base model was 966.7. Influence of CBZ daily dose was explored as categorical and continuous
covariate. Covariate was tested against the base model and if OFV was significantly changed aat least 3.84,
p<0.05) covariate was included in the model. Correlation between CBZ daily dose and PB CL/F was investigated
using power, exponential, linear and log-linear model. However, there were not significant changes in OFV
values, as well as in interindividual variability. The estimate of CL/F for a typical patient was in the range
0.261–0.321 l/h for the final model. Average CL/F of patients co-treated with CBZ was 0.320 l/h.
Conclusion: In the present study inclusion of CBZ daily dose in the base model did not significantly improve data
fitting. This confirms that CBZ does not contribute to interindividual variability of PB elimination. Therefore, in
clinical practice adjustment of PB dose is not needed in the presence of CBZ.
1. Yukawa, E., 1999. Population-based investigations of drug relative clearance using nonlinear mixed-effect
modelling from information generated during the routine clinical care of patients. J Clin Pharm Ther 24a2),
103–113.
2. Yukawa, E.L., To, H., Ohdo, S., Higuchi, S., Aoyama, T., 1998. Detection of a drug–drug interaction on
population-based phenobarbitone clearance using nonlinear mixed-effects modeling. Eur J Clin Pharmacol 54a1),
69–74.
Citation: Eur Neuropsychopharmacol. 2014;24aSuppl 2):S645
Keywords
Pharmacokinetics
Epilepsy
Drug monitoring