A. M. Almeida

Lamotrigine analysis in blood and brain by high-performance liquid chromatography

A reversed-phase high-performance liquid chromatography assay was developed and validated to determine plasma and brain lamotrigine concentrations allowing pharmacokinetic-pharmacodynamic studies of this new antiepileptic drug in patients and laboratory animals. Lamotrigine and its internal standard were extracted, under alkaline conditions, from plasma and brain homogenate, into ethyl acetate; brain proteins were previously precipitated with trichloroacetic acid. The method was linear between 0.1 and 15.0 mg/l for plasma, with a detection limit of 0.008 mg/l, and between 0.1 and 5.0 mg/l for brain homogenate, with a detection limit of 0.023 mg/l. The method proved to be simple, useful and appropriate, not only for clinical and experimental research, but also for routine monitoring of lamotrigine concentrations in patients.

The Kinetic Profile of Gentamicin in Premature Neonates

The kinetic profile of gentamicin in premature infants has been studied to enable the development of optimized dosage schedules for neonatal intensive‐care units and to stress the relationship between the pharmacokinetic parameters and several demographic, developmental and clinical factors which might be associated with changes in gentamicin disposition.

A chiral liquid chromatography method for the simultaneous determination of oxcarbazepine, eslicarbazepine, R‐licarbazepine and other new chemical derivatives BIA 2–024, BIA 2–059 and BIA 2–265, in mouse plasma and brain

Recently, in silico models have been developed to predict drug pharmacokinetics. However, before application, they must be validated and, for that, information about structurally similar reference compounds is required. A chiral liquid chromatography method with ultraviolet detection (LC-UV) was developed and validated for the simultaneous quantification of BIA 2-024, BIA 2-059, BIA 2-265, oxcarbazepine, eslicarbazepine (S-licarbazepine) and R-licarbazepine in mouse plasma and brain. Compounds were extracted by a selective solid-phase extraction procedure and their chromatographic separation was achieved on a LiChroCART 250-4 ChiraDex column using a mobile phase of water-methanol (92:8, v/v) pumped at 0.7 mL/min. The UV detector was set at 235 nm. Calibration curves were linear (r(2)  ≥ 0.996) over the concentration ranges of 0.2-30 µg/mL for oxcarbazepine, eslicarbazepine and R-licarbazepine; 0.2-60 µg/mL for the remaining compounds in plasma; and 0.06-15 µg/mL for all the analytes in brain homogenate. Taking into account all analytes at these concentration ranges in both matrices, the overall precision did not exceed 9.09%, and the accuracy was within ±14.3%. This LC-UV method is suitable for carrying out pharmacokinetic studies with these compounds in mouse in order to obtain a better picture of their metabolic pathways and biodistribution.

The kinetic profile of vancomycin in neonates.

The pharmacokinetic parameters of vancomycin in a neonatal population have been characterized to enable development of optimum dosage guidelines for neonatal intensive‐care units and to examine the relationship between these pharmacokinetic parameters and various demographic, developmental and clinical factors which might be associated with changes in the kinetic profile of vancomycin.

Enantioselective assay for therapeutic drug monitoring of eslicarbazepine acetate: no interference with carbamazepine and its metabolites.

As add-on therapy, phase III clinical trials of eslicarbazepine acetate (ESL) conducted in patients with refractory partial-onset seizures have shown good efficacy, safety, and tolerability, even in patients taking carbamazepine (CBZ) at baseline (approximately 60% of the enrolled patients). Thus, considering the pharmacological disadvantages of CBZ and the similar efficacy spectrum of CBZ and ESL, switching to ESL may be successful in many patients. As ESL is a prodrug almost instantaneously converted to S-licarbazepine (S-Lic; approximately 95%), an interest in therapeutic drug monitoring (TDM) of S-Lic is likely to develop in the future. This study investigated the plasma concentrations of S-Lic and R-licarbazepine (R-Lic) enantiomers in patients under CBZ long-term treatment to assess the potential interference of CBZ or its metabolites in the enantioselective TDM of ESL (using S-Lic concentrations). A chiral high-performance liquid chromatography assay with ultraviolet detection (HPLC-UV) previously developed and validated by our research group was used. Twenty-four patients admitted to the Coimbra University Hospital and supposedly receiving CBZ long-term treatment were identified. Blood samples were collected from patients and serum CBZ concentrations were measured by the usual TDM protocol. Aliquots of plasma from such patients were also submitted to a chiral HPLC-UV analysis. The bioanalytical data indicated that S-Lic and R-Lic were not present at detectable concentrations in plasma samples of the CBZ-treated patients. The chromatograms generated by the analysis of patient plasma samples, when compared with those obtained from blank plasma samples spiked with S-Lic and R-Lic, clearly showed the absence of interferences at the retention times of both Lic enantiomers. These data support the usefulness of the chiral HPLC-UV method used for the enantioselective TDM of ESL (using S-Lic) for programs in which switching from CBZ to ESL is implemented.

Lamotrigine pharmacokinetic evaluation in epileptic patients submitted to VEEG monitoring

ObjectiveThe aim of the present study was to evaluate the pharmacokinetic profile of lamotrigine (LTG) in epileptic patients submitted to video-electroencephalography (VEEG) monitoring and, in addition, to investigate the influence of concomitant antiepileptic drugs (AEDs) on the kinetics of LTG.MethodsThe analysis assumed a one-compartment open model with first-order absorption and elimination. The kinetic estimates obtained in this population were validated by using the Prediction-Error approach. The influence of medication was also assessed by the calculation of the LTG concentration-to-dose ratio. Patients (n=135) were divided into four groups according to the co-medication: Group 1, patients taking LTG with enzyme-inducer agents; Group 2, patients receiving LTG with valproic acid; Group 3, patients receiving both inducers and inhibitors of LTG metabolism; Group 4, patients under AEDs not known to alter LTG metabolism.ResultsThe obtained estimates for clearance (CL) (L/h/kg) [0.075±0.029 (Group 1), 0.014±0.005 (Group 2), 0.025±0.008 (Group 3) and 0.044±0.011 (Group 4)] appear to be the most appropriate set to be implemented in clinical practice as prior information, as demonstrated by the accuracy and precision of the measurements. In addition, the influence of co-medication on the LTG profile was further confirmed by the basal LTG concentration-to-dose ratio.ConclusionThe results of the present investigation may contribute to achieving the goal of optimizing patients’ clinical outcomes by managing their medication regimen through measured drug concentrations. Patients submitted to VEEG monitoring may benefit from this study, as the results may be used to provide better drug management in this medical setting.

PKBase: A Population Approach-Oriented Database:

droxyrisperidone plasma concentrations after hospital day 40 with the fluvoxamine taper also suggests a potential drug interaction. Extrapyramidal side effects (EPS) and orthostatic hypotension are dose-related adverse effects associated with risperidone. It is anticipated that these adverse effects would be similarly related to 9-hydroxyrisperidone since this active metabolite shares a similar pharmacologic profile. These adverse effects may be particularly relevant to some geriatric populations that gain therapeutic benefit from lower risperidone doses (0.5–1.0 mg/d), but who may exhibit significant EPS and orthostatic hypotension at 2 mg/d.5 Increases in 9-hydroxyrisperidone plasma concentrations, which may occur on discontinuation of carbamazepine or initiation of fluvoxamine, may increase the risk of these adverse effects in some patients. However, formal pharmacokinetic studies investigating the potential interaction between fluvoxamine and risperidone are needed to confirm this finding. In summary, our case illustrates the complex interactions that may occur in patients receiving multiple medications. Knowledge of the CYP450 isoenzymes involved in the oxidative metabolism of a drug, as well as the inhibition and induction characteristics of a drug, can aid in predicting drug interactions; however, this information is either not known or is incomplete for many drugs. Furthermore, when multiple drugs with opposing actions (e.g., CYP450 inhibition and induction) are combined, the accuracy of predicting drug interactions diminishes. When such therapies are unavoidable, it is prudent to monitor plasma concentrations and clinical status during dose adjustments in these pat i e n t s .