Natalícia de Jesus Antunes

Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs

Introduction: Epilepsy is a chronic neurological disease manifesting as recurrent seizures. Despite the availability of numerous antiepileptic drugs (AEDs), one-third of the patients are not responsive to treatment. Such inter-individual variability in the response to AEDs may be partly explained by genetic differences. This review summarizes the pharmacogenetics (PGx) of AEDs. In addition, a model-based approach is presented that enables the integration of PGx data with other relevant sources of variability, such as demographic characteristics and co-medications. Areas covered: A comprehensive overview is provided of the data available in the literature on the evidence for correlations between genetic mutations and pharmacokinetic (PK) and/or pharmacodynamics (PD) of AEDs. This information is then used in an integrated manner in the second part, where PGx differences are parameterized as covariates in PK and PKPD models. Expert opinion: Polymorphisms are profuse in the PK and PD of AEDs. However, understanding of their clinical implication remains limited due to the lack of methodologies that discriminate the contribution of other sources of variability in CNS exposure to drugs. A model-based approach, in which other intrinsic (e.g., demographic covariates) and extrinsic (e.g., drug–drug interactions) factors are evaluated concurrently is needed to ensure optimization and individualization of treatment in epileptic patients.

Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients.

PurposeThis study investigated the influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol administered intravenously or orally.MethodsThirty hypertensive women during the last trimester of pregnancy were divided into four groups: non-diabetic and diabetic women treated with intravenous or oral labetalol.ResultsThe pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women receiving the drug intravenously. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the β-blocker (RR) than for the other enantiomers in both diabetic and non-diabetic women. Gestational diabetes mellitus caused changes in the kinetic disposition of the labetalol stereoisomers when administered orally. The AUC values for the less potent adrenoceptor antagonist (SS) and for the α-blocking (SR) isomers were higher in diabetic than in non-diabetic pregnant women.ConclusionsThe approximately 100% higher AUC values obtained for the (SR) isomer in diabetic pregnant women treated with oral labetalol may be of clinical relevance in terms of the α-blocking activity of this isomer.

Analysis of oxcarbazepine and the 10-hydroxycarbazepine enantiomers in plasma by LC-MS/MS: application in a pharmacokinetic study.

Oxcarbazepine is a second-generation antiepileptic drug indicated as monotherapy or adjunctive therapy in the treatment of partial seizures or generalized tonic-clonic seizures in adults and children. It undergoes rapid presystemic reduction with formation of the active metabolite 10-hydroxycarbazepine (MHD), which has a chiral center at position 10, with the enantiomers (S)-(+)- and R-(-)-MHD showing similar antiepileptic effects. This study presents the development and validation of a method of sequential analysis of oxcarbazepine and MHD enantiomers in plasma using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Aliquots of 100 μL of plasma were extracted with a mixture of methyl tert-butyl ether: dichloromethane (2:1). The separation of oxcarbazepine and the MHD enantiomers was obtained on a chiral phase Chiralcel OD-H column, using a mixture of hexane:ethanol:isopropanol (80:15:5, v/v/v) as mobile phase at a flow rate of 1.3 mL/min with a split ratio of 1:5, and quantification was performed by LC-MS/MS. The limit of quantification was 12.5 ng oxcarbazepine and 31.25 ng of each MHD enantiomer/mL of plasma. The method was applied in the study of kinetic disposition of oxcarbazepine and the MHD enantiomers in the steady state after oral administration of 300 mg/12 h oxcarbazepine in a healthy volunteer. The maximum plasma concentration of oxcarbazepine was 1.2 µg/mL at 0.75 h. The kinetic disposition of MHD is enantioselective, with a higher proportion of the S-(+)-MHD enantiomer compared to R-(-)-MHD and an AUC(0-12) S-(+)/R-(-) ratio of 5.44.

Analysis of unbound plasma concentration of oxcarbazepine and the 10-hydroxycarbazepine enantiomers by liquid chromatography with tandem mass spectrometry in healthy volunteers

HighlightsThe method was linear in the range of 4.0–2.0 &mgr;g/mL plasma for OXC.The method was linear in the range of 20.0–6.0 &mgr;g/mL plasma for the MHD enantiomers.The free fraction was 0.27 for OXC, 0.37 for S‐(+)‐MHD and 0.42 for R‐(−)‐MHD.The free fraction of MHD was enantioselective. ABSTRACT This study describes the development and validation of a method for the analysis of unbound plasma concentrations of oxcarbazepine (OXC) and of the enantiomers of its active metabolite 10‐hydroxycarbazepine (MHD) [S‐(+)‐ and R‐(−)‐MHD] using liquid chromatography with tandem mass spectrometry (LC–MS/MS). Additionally, the free fraction of the drug is described in healthy volunteers (n = 12) after the oral administration of 300 mg OXC/12 h for 5 days. Plasma aliquots of 200 &mgr;L were submitted to ultrafiltration procedure and 50 &mgr;L of the ultrafiltrate were extracted with a mixture of tert‐butyl methyl ether:dichloromethane (2:1, v/v). OXC and the MHD enantiomers were separated on a OD‐H chiral phase column. The method was linear in the range of 4.0–2.0 &mgr;g/mL for OXC and of 20.0–6.0 &mgr;g/mL plasma for the MHD enantiomers. The limit of quantification was 4 ng for OXC and 20 ng for each MHD enantiomer/mL plasma. The intra‐ and inter‐day precision and inaccuracy were less than 15%. The free fraction at the time of peak plasma concentration of OXC was 0.27 for OXC, 0.37 for S‐(+)‐MHD and 0.42 for R‐(−)‐MHD. Enantioselectivity in the free fraction of MHD was observed, with a higher proportion of R‐(−)‐MHD compared to S‐(+)‐MHD.

Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects

Abstract Oxcarbazepine is indicated for the treatment of partial or generalised tonic‐clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10‐hydroxycarbazepine (MHD), which can exist as R‐(−)‐ and S‐(+)‐MHD enantiomers. Here we describe the influence of the P‐glycoprotein (P‐gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P‐gp substrates. Healthy subjects (n = 12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300 mg b.i.d. and 80 mg t.i.d., respectively. Blood samples (n = 185) were collected over a period of 12 h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta‐analytical approach. The pharmacokinetics of oxcarbazepine was described by a two‐compartment model with absorption transit compartments and first‐order elimination. The concentration‐time profiles of both MHD enantiomers were characterised by a one‐compartment distribution model. Clearance estimates (95% CI) were 84.9 L/h (69.5–100.3) for oxcarbazepine and 2.0 L/h (1.9–2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131 L (97–165)) as compared to R‐(−)‐ and S‐(+)‐MHD (23.6 L (14.4–32.8) vs. 31.7 L (22.5–40.9), respectively). Co‐administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10–28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P‐glycoprotein inhibition. Graphical abstract No caption available.

Erratum to: Metformin pharmacokinetics in nondiabetic pregnant women with polycystic ovary syndrome

It came to our attention that a spelling mistake occurred in the name of one of the authors, Elaine Christine Dantas Moisés.