The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling
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2009
Authors
Vučićević, KatarinaMiljković, Branislava
Pokrajac, Milena
Prostran, Milica
Martinović, Žarko J.
Grabnar, Iztok
Article (Published version)
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Monitoring valproic acid (VPA) concentrations is especially challenging due to its highly variable pharmacokinetics (PK) and complex interactions with other antiepileptic drugs. We used sparse routine therapeutic drug monitoring data (n = 200) from 129 adults with epilepsy to develop a population PK model of VPA, and determine the factors that influence its clearance (CL/F). Patients were on mono VPA therapy, or were concomitantly treated with carbamazepine, phenobarbital, topiramate (TPR), lamotrigine or benzodiazepines. A one-compartment model with first-order absorption and elimination was used to fit the concentration-time VPA data. Estimates generated by NONMEM indicated that VPA CL/F was influenced by the patients' body weight (increases with the 0.556 exponent), VPA daily dose (if it is greater than 1000 mg/day, CL/F increases by 43%), and co-therapy with TPR (lowering CL/F for 23%). The interindividual variability in VPA CL/F was modeled with exponentional error model. The esti...mated coefficient of variation was 31.9%, while the residual variability was 23.8% for the proportional and 13.2 mg/l for the additive component. The model was validated in a separate set of 24 patients, and the predictive performance was evaluated, that indicated unbias and acceptable precision. This study confirms the interaction of VPA with TPR, which is presumably dependent on VPA dose.
Keywords:
Valproic acid / Topiramate / Interaction / Therapeutic drug monitoring / Population pharmacokinetics / NONMEMSource:
European Journal of Pharmaceutical Sciences, 2009, 38, 5, 512-518Publisher:
- Elsevier Science BV, Amsterdam
Funding / projects:
DOI: 10.1016/j.ejps.2009.09.017
ISSN: 0928-0987
PubMed: 19804822
WoS: 000272572900011
Scopus: 2-s2.0-70449553615
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PharmacyTY - JOUR AU - Vučićević, Katarina AU - Miljković, Branislava AU - Pokrajac, Milena AU - Prostran, Milica AU - Martinović, Žarko J. AU - Grabnar, Iztok PY - 2009 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1211 AB - Monitoring valproic acid (VPA) concentrations is especially challenging due to its highly variable pharmacokinetics (PK) and complex interactions with other antiepileptic drugs. We used sparse routine therapeutic drug monitoring data (n = 200) from 129 adults with epilepsy to develop a population PK model of VPA, and determine the factors that influence its clearance (CL/F). Patients were on mono VPA therapy, or were concomitantly treated with carbamazepine, phenobarbital, topiramate (TPR), lamotrigine or benzodiazepines. A one-compartment model with first-order absorption and elimination was used to fit the concentration-time VPA data. Estimates generated by NONMEM indicated that VPA CL/F was influenced by the patients' body weight (increases with the 0.556 exponent), VPA daily dose (if it is greater than 1000 mg/day, CL/F increases by 43%), and co-therapy with TPR (lowering CL/F for 23%). The interindividual variability in VPA CL/F was modeled with exponentional error model. The estimated coefficient of variation was 31.9%, while the residual variability was 23.8% for the proportional and 13.2 mg/l for the additive component. The model was validated in a separate set of 24 patients, and the predictive performance was evaluated, that indicated unbias and acceptable precision. This study confirms the interaction of VPA with TPR, which is presumably dependent on VPA dose. PB - Elsevier Science BV, Amsterdam T2 - European Journal of Pharmaceutical Sciences T1 - The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling VL - 38 IS - 5 SP - 512 EP - 518 DO - 10.1016/j.ejps.2009.09.017 ER -
@article{ author = "Vučićević, Katarina and Miljković, Branislava and Pokrajac, Milena and Prostran, Milica and Martinović, Žarko J. and Grabnar, Iztok", year = "2009", abstract = "Monitoring valproic acid (VPA) concentrations is especially challenging due to its highly variable pharmacokinetics (PK) and complex interactions with other antiepileptic drugs. We used sparse routine therapeutic drug monitoring data (n = 200) from 129 adults with epilepsy to develop a population PK model of VPA, and determine the factors that influence its clearance (CL/F). Patients were on mono VPA therapy, or were concomitantly treated with carbamazepine, phenobarbital, topiramate (TPR), lamotrigine or benzodiazepines. A one-compartment model with first-order absorption and elimination was used to fit the concentration-time VPA data. Estimates generated by NONMEM indicated that VPA CL/F was influenced by the patients' body weight (increases with the 0.556 exponent), VPA daily dose (if it is greater than 1000 mg/day, CL/F increases by 43%), and co-therapy with TPR (lowering CL/F for 23%). The interindividual variability in VPA CL/F was modeled with exponentional error model. The estimated coefficient of variation was 31.9%, while the residual variability was 23.8% for the proportional and 13.2 mg/l for the additive component. The model was validated in a separate set of 24 patients, and the predictive performance was evaluated, that indicated unbias and acceptable precision. This study confirms the interaction of VPA with TPR, which is presumably dependent on VPA dose.", publisher = "Elsevier Science BV, Amsterdam", journal = "European Journal of Pharmaceutical Sciences", title = "The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling", volume = "38", number = "5", pages = "512-518", doi = "10.1016/j.ejps.2009.09.017" }
Vučićević, K., Miljković, B., Pokrajac, M., Prostran, M., Martinović, Ž. J.,& Grabnar, I.. (2009). The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling. in European Journal of Pharmaceutical Sciences Elsevier Science BV, Amsterdam., 38(5), 512-518. https://doi.org/10.1016/j.ejps.2009.09.017
Vučićević K, Miljković B, Pokrajac M, Prostran M, Martinović ŽJ, Grabnar I. The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling. in European Journal of Pharmaceutical Sciences. 2009;38(5):512-518. doi:10.1016/j.ejps.2009.09.017 .
Vučićević, Katarina, Miljković, Branislava, Pokrajac, Milena, Prostran, Milica, Martinović, Žarko J., Grabnar, Iztok, "The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling" in European Journal of Pharmaceutical Sciences, 38, no. 5 (2009):512-518, https://doi.org/10.1016/j.ejps.2009.09.017 . .