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Biomedical subjects

A C Falcão

Publications and source records attributed to A C Falcão.

At least 19 recordsLinked to original sources
PubMed2006

Lamotrigine pharmacokinetic evaluation in epileptic patients submitted to VEEG monitoring.

OBJECTIVE: The 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. METHODS: The 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. RESULTS: The 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. CONCLUSION: The 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.

Adolescent↗
PubMed2005

Lamotrigine pharmacokinetic/pharmacodynamic modelling in rats.

The aim of this study was to perform a pharmacokinetic/pharmacodynamic (PK/PD) modelling of lamotrigine following its acute administration to rats. Adult male Wistar rats were given 10 mg/kg of lamotrigine intraperitoneally. Plasma and brain samples were obtained at predetermined times over 120 h post-dose and analysed by liquid chromatography. The anticonvulsant profile against maximal electroshock seizure stimulation was determined over 48 h after dosing. As a linear relationship between lamotrigine plasma and brain profiles was observed, only the plasma data set was used to establish the PK/PD relationship. To fit the effect-time course of lamotrigine, the PK/PD simultaneous fitting link model was used: the pharmacokinetic parameters and dosing information were used in the one-compartment first-order model to predict concentrations, which were then used to model the pharmacodynamic data with the sigmoid Emax model, in order to estimate all the parameters simultaneously. The following parameters were obtained: Vd = 2.00 L/kg, k(abs) = 8.50 h(-1), k(el) = 0.025 h(-1), k(e0) = 3.75 h(-1), Emax = 100.0% (fixed), EC50 = 3.44 mg/L and gamma = 8.64. From these results, it can be stated that lamotrigine is extensively distributed through the body, its plasma elimination half-life is around 28 h and a lamotrigine plasma concentration of 3.44 mg/L is enough to protect 50% of the animals. When compared with humans, the plasma concentrations achieved with this dose were within the therapeutic concentration range that had been proposed for epileptic patients. With the present PK/PD modelling it was possible to fit simultaneously the time-courses of the plasma levels and the anticonvulsant effect of lamotrigine, providing information not only about the pharmacokinetics of lamotrigine in the rat but also about its anticonvulsant response over time. As this approach can be easily applied to other drugs, it becomes a useful tool for an explanatory comparison between lamotrigine and other antiepileptic drugs.

Animals↗
PubMed2004

Lamotrigine kidney distribution in male rats following a single intraperitoneal dose.

As it has been previously shown that lamotrigine (LTG) accumulates in the kidney of male rats, the purpose of the present investigation was to characterize the kidney profiles of LTG and its kidney distribution pattern in male rats, in order to confirm if a preferential distribution exists and to analyse if it does or does not affect the LTG systemic pharmacokinetics. Adult male Wistar rats were intraperitoneally injected with 5, 10 and 20 mg/kg of LTG. The concentration-time profiles of LTG in plasma and whole kidney were determined over 120 h postdose. The distribution of LTG in the rat kidney was investigated in another group of rats by measuring LTG levels in the renal cortex and medulla. The LTG plasma concentration-time profiles revealed a linear relationship with dose. However, a slight increase in the LTG elimination half-life with dose was observed. In contrast, a nonlinear relationship was established between LTG kidney levels and the dose administered. Consequently, nonparallel patterns were observed between LTG plasma and kidney profiles. The LTG kidney distribution pattern revealed an accumulation of LTG in the renal cortex. The present study demonstrated that LTG distributes preferentially to the kidneys of the male rat in a dose-dependent manner and suggests that such distribution may slightly affect the systemic kinetics of the drug.

Animals↗
PubMed2003

[Monitoring serum levels of gentamicin in neonates].

Newborn infants in intensive care units demonstrated a higher incidence of gestational age below 31 week. Obstetrical and neonatal diseases procedures required for the management of critically ill neonates are associated with an increased risk of infections. Gentamicin is an aminoglycoside antibiotic often used to treat gram-negative bacillary infections and suspected sepsis in neonates. The risk of toxicity or poor efficacy is further increased due to the recognised wide intra and interpatient variability of the newborn. The present work involved 49 infants of 31.3 +/- 4.1 (mean +/- SD) weeks of gestational age, weighing 1.7 +/- 0.8 kg and were treated with standard doses of gentamicin (3.8 +/- 0.9 mg/kg/day). Routine clinical care data were retrospectively collected from the medical records in the neonatal intensive-care unit at Coimbra University Hospital. Data analysis demonstrated that potentially toxic serum levels were observed in 49% of newborn infants (trough > 2 mg/L). Additionally, the obtained results also showed that 7.5% of peak concentrations were found to be higher than 10 mg/L. Potentially sub-therapeutic concentrations were observed in 15% of the patients (peak > 6 mg/L).

Critical Care↗
PubMed2002

Linear regression for calibration lines revisited: weighting schemes for bioanalytical methods.

When the assumption of homoscedasticity is not met for analytical data, a simple and effective way to counteract the greater influence of the greater concentrations on the fitted regression line is to use weighted least squares linear regression (WLSLR). The purpose of the present paper is to stress the relevance of weighting schemes for linear regression analysis and to show how this approach can be useful in the bioanalytical field. The steps to be taken in the study of the linear calibration approach are described. The application of weighting schemes was shown by using a high-performance liquid chromatography method for the determination of lamotrigine in biological fluids as a practical example. By using the WLSLR, the accuracy of the analytical method was improved at the lower end of the calibration curve. Bioanalytical methods data analysis was improved by using the WLSLR procedure.

Calibration↗
PubMed2002

Influence of administration vehicles and drug formulations on the pharmacokinetic profile of lamotrigine in rats.

Given that administration vehicles and drug formulations can affect drug bioavailability, their influence on the pharmacokinetic profile of lamotrigine (LTG), a new-generation anti-epileptic drug, was studied in rats. Three different formulations administered intraperitoneally at a dose of 10 mg/kg were used: (1) LTG suspended in a 0.25% methylcelulose solution, (2) LTG dissolved in a 50% propylene glycol solution, and (3) LTG isethionate dissolved in distilled water. Plasma and brain homogenate levels were determined in order to evaluate vehicle-dependent drug absorption. The results demonstrated rapid absorption of LTG when it was administered as an aqueous solution, in contrast to a slower and more erratic absorption after the injection of either the lipophilic solution or the suspension. A plasma peak was achieved 15 min post-dose with the aqueous solution, with a brain peak being achieved 15 min later, while with the other formulations both plasma and brain homogenate peaks were reached 2 h after LTG administration. This study suggests that LTG isethionate dissolved in distilled water is the most suitable formulation for successful LTG pharmacokinetic studies in rats.

Animals↗
PubMed2001

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.

Animals↗
PubMed2001

Population kinetics of tobramycin in neonates.

The population kinetics of tobramycin were studied in 140 neonates (100/40 patients for the index/validation groups, respectively) of 30 to 42 weeks' gestational age and 0.8 to 4.25 kg current body weight in their first 2 weeks of life, undergoing routine therapeutic drug monitoring of their tobramycin serum levels. The 365 tobramycin concentration measurements obtained were analyzed by use of NONMEM according to a one-compartment open model with zero-order absorption and first-order elimination. The effect of a variety of demographic, developmental, and clinical factors (gender, height, birth weight, current weight, gestational age, postnatal age, postconceptional age, and serum creatinine concentration) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. The final pharmacostatistical model with influential covariates was as follows (full population): clearance (L/h) = 0.0508 x current weight (kg), multiplied by 0.843 if birth weight was 2.5 kg or less (low-birthweight infants), and volume of distribution (L) = 0.533 x current weight (kg). Using the proportional error model for the random-effects parameters, interindividual variability for clearance and for volume of distribution was determined to be 25.8% and 21.9%, respectively, and the residual variability was 19.2%. In this study, the use of the NONMEM gave significant and consistent information on the pharmacokinetics and the determinants of the pharmacokinetic variability of tobramycin in neonates when compared with available bibliographic information. Moreover, the final population pharmacokinetic model may be used to design a priori recommendations for tobramycin and to improve the dosing readjustments through Bayesian estimation.

Anti-Bacterial Agents↗
PubMed2000

Theophylline pharmacokinetics with concomitant steroid and gold therapy.

BACKGROUND: Theophylline has been used for several decades in the treatment of asthma. In recent years, however, with the appreciation of the importance of inflammation in the pathogenesis of asthma, new therapeutic approaches have arisen, including beta2-agonists, steroid and nonsteroidal anti-inflammatory drugs, such as gold salts. OBJECTIVE: In the present work we studied the kinetic behaviour of theophylline administered concomitantly with methylprednisolone (steroid compound) and auranofin (oral gold) in six adult female patients. METHOD: Drug concentration data for patients under routine care were collected. The kinetic analysis (Bayesian Approach) was done using two different commercial software packages, PKS (Abbott Diagnostics) and CAPCIL (SIMKIN Inc., courtesy of Dade-Behring). A one-compartment open model with first-order absorption (ka for PKS=0. 5/h; ka for CAPCIL=0.3/h ) and first- order elimination. Default CL, t1/2 and Vd values were used for each program was assumed. The measured and predicted theophylline concentrations were used to calculate percentage prediction errors defined as %PE=[(predicted conc. - measured conc.)/measured conc.] x 100. A linear regression analysis was also carried out for the observed concentrations and those predicted by each method (PKS vs. CAPCIL). RESULTS: The predicted concentrations indicating persistently over-predicted the observed theophylline serum levels (results expressed as median and interquartile range; %PE for PKS=58.1 [37.1-126.0]; %PE for CAPCIL=34.0 [12.5-93.8]). The regression analysis confirmed the same tendency, showing an intercept significantly different from zero using both PKS and CAPCIL. CONCLUSION: The results suggest a possible interaction between theophylline and auranofin. Both PKS and CAPCIL failed to predict theophylline serum levels based exclusively on population pharmacokinetic parameters. The lower observed concentrations than expected have obvious implications in practice. Periodic theophylline serum determinations are advisable until further studies provide the necessary clarification about the kinetic profile of theophylline in patients taking concomitant steroids and gold salts.

Adult↗
PubMed2000

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. Sixty-eight newborn patients of 24- to 34-weeks gestational age and 600-3,100 g current weight in their first week of life, undergoing routine therapeutic drug monitoring of their gentamicin serum levels, were included in this retrospective analysis. Gentamicin pharmacokinetic parameters were determined through non-linear regression by using a single-compartment open model. By regression analysis the current weight (g) was shown to be the strongest co-variate, and both gentamicin clearance (L h(-1)) and volume of distribution (L) had to be normalized. Additionally, gentamicin clearance depended on gestational age with a cut-off at 30 weeks, which allowed the division of the overall population into two subsets (< 30 weeks and between 30-34 weeks of gestational age). The younger neonates (<30 weeks of gestational age) showed a lower gentamicin clearance (0.0288 vs 0.0340 L h(-1) kg(-1)), a slightly higher volume of distribution (0.464 vs 0.435 L kg(-1)), and a longer half-life (11.17 vs 8.88 h) compared with the older subgroup (30-34 weeks of gestational age). On the basis of the pharmacokinetic parameters obtained, we suggest loading doses of 3.7 and 3.5 mg kg(-1) for the two subgroups of neonates (<30 weeks and 30-34 weeks of gestational age), respectively. The appropriate maintenance doses in accordance with the characteristics of the patients should be 2.8 mgkg(-1)/24h and 2.6 mg kg(-1)/18 h for neonates < 30 weeks and between 30-34 weeks of gestational age, respectively. Finally, when compared with previous studies, the information obtained on the pharmacokinetics and determinants of the pharmacokinetic variability of gentamicin in neonates was shown to be consistent.

Age Factors↗
PubMed2000

Therapeutic monitoring of warfarin: the appropriate response marker.

Warfarin is a 4-hydroxycoumarin anticoagulant drug used for the prevention and management of thromboembolic and vascular diseases. It acts through the inhibition of the vitamin K-dependent transcarboxylation reactions that convert precursors of clotting factors into their active form. Appropriate use of warfarin requires patient monitoring and dosage adjustments, to ensure its safety and efficacy. The aim of this work was to clarify the relationship between traditional (prothrombin time, usually expressed as the international normalized ratio; INR) and alternative (clotting factors II and X) warfarin response markers to establish their usefulness for therapeutic drug monitoring. Seventy adult outpatients, aged between 31 and 86 years old, were involved in the study. All subjects received warfarin in a monotherapy regimen and had been on a stable dosing schedule for at least two weeks to assure a steady-state condition. A total of 81 prothrombin times (expressed as INR), and factor II and factor X activity were simultaneously determined. Eleven patients presented repeated measurements at different time periods under the same dosing regimen. The results obtained from regression and cluster analysis showed a close relationship between factors II and X (r = 0.73), a weak correlation between INR and both factor II (r = -0.35) and factor X (r = -0.36), and a very slight dependency between warfarin and the response markers used. In addition, it seems that independent of the selected response marker, in long-term warfarin therapy, reproducible responses can be obtained over time if a steady-state condition is achieved. The coefficients of variation for factors II and X were greater (35.44 and 37.93%, respectively) than INR (14.50%), indicating that INR is a more precise measure than either factor II or factor X. In conclusion, INR appears to be the most appropriate warfarin response marker for therapeutic drug monitoring due to its universality, objectivity as a direct physiological effect measurement, and the available information regarding appropriate endpoints. However, when INR values are not in accordance with patient response therapy, factor II and factor X should be considered as an alternative to optimize warfarin therapy.

Adult↗
PubMed1999

Predictive capacity of carbamazepine pharmacokinetic parameters in a Portuguese outpatient population.

The individualization of anticonvulsant therapy regimens can contribute to the implementation of appropriate carbamazepine (CBZ) maintenance doses in epileptic patients. An accurate method for the prediction of concentrations based on a determination of parameters and serum concentrations could be of clinical relevance in the management of epilepsy. In this study, we retrospectively evaluated the predictive performance in an adult outpatient population of six different methods, representing six sets of CBZ pharmacokinetic parameters selected according to the literature using a Bayesian computer program (PKS System; Abbott Laboratories, Abbott Park, IL, USA). The study involved 50 patients with two or more available concentrations selected under several inclusion criteria. The patients were taking CBZ (between 200 and 1600 mg/d) in monotherapy or polytherapy regimens and had no hepatic or renal disease. Steady state concentrations were predicted according to the use of prior information and using one and two feedback patient concentrations. Accuracy and precision were assessed by mean prediction error (ME), mean squared prediction error (MSE) and root mean squared prediction error (RMSE). The analysis showed CL = 0.067 L/hour/kg and Vd = 1.19 L/kg as the most accurate and precise set of pharmacokinetic parameters, presenting the highest percentage of clinically acceptable estimates (error < 2 microg/mL). Additionally, predictions based on one measured feedback concentration were found to be more accurate and precise than prior population-based predictions; the use of two previous patient concentrations further improved predictive capacity but failed to show a significant difference when compared with predictions based on one measured feedback concentration. In conclusion, the adoption of the previously mentioned set of parameters as population estimates and the use of at least one feedback concentration through the Bayesian approach seems to be essential for a better CBZ use in clinical practice. Finally, despite the obtained results, we believe that the Portuguese pharmacokinetic parameter determination of antiepileptics should be carried out to improve the rationale and cost-effectiveness of anticonvulsant therapy.

Adolescent↗
PubMed1998

Kinetic profile of carbamazepine in an adult Portuguese outpatient population.

OBJECTIVE: The aim of our work was to define the kinetic profile of carbamazepine (CBZ), in order to improve on dosing schedules through a Bayesian approach. METHOD: Carbamazepine dose/steady-state trough concentrations data pairs and associated information were collected retrospectively on a population of adult epileptic patients. RESULTS: Fifty patients (index population) with two or more available concentrations (total of 174 determinations) met our inclusion criteria. Patients were taking CBZ (200-1800 mg/day) in mono- or polytherapy regimens. The analysis assumed a one-compartmental model with first-order absorption and elimination. Due to the data source (only trough concentrations were measured as part of hospital routine), the volume of distribution was fixed at 1.19 l/kg. The final estimates for CL were: 0.075 +/- 0.027 (mono- and polytherapy), 0.069 +/- 0.020 (monotherapy), and 0.106 +/- 0.037 l/h/kg (polytherapy). In order to validate these results, we assessed their predictive capacity using 18 new patients (validation population), submitted to the same inclusion criteria and using Prediction-Error analysis. The results suggested a different CL value for our population compared to earlier published clearance values. The results also pointed to an increased metabolic rate associated with polytherapy. The prediction capacity of the optimization method derived from a Portuguese population made in an a priori evaluation indicated a low error (-0.04 microg/ml), close to the theoretical zero value. CONCLUSION: Our results provide specific data on CBZ disposition in a Portuguese population and given the wide variability in the literature values, our data may help improve dosing of CBZ in Portuguese patients.

Adult↗
PubMed1998

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. Forty-four infants (twenty-five males and nineteen females) with suspected or proven Gram-positive infection and who received intravenous vancomycin between October 1993 and December 1996 were included in this retrospective analysis. Gestational age ranged from 25 to 40 weeks and postconceptional age at the time of the study ranged from 28 to 45 weeks. Sixty case-studies were obtained from the forty-four patients, with one period of study corresponding to one week or one cycle of therapy. Vancomycin pharmacokinetic parameters were determined by use of a one-compartment model. By regression analysis the current weight (g) was shown to be the stronger covariate, and both vancomycin clearance (L h(-1)) and volume of distribution (L) had to be normalized. The vancomycin volume of distribution depended on the postconceptional age with a cut-off at 32 weeks, whereas vancomycin clearance depended on the presence or absence of concomitant treatment with indomethacin or of mechanical ventilation, or both. On the basis of the pharmacokinetic parameters obtained we suggest initial dosage guidelines for vancomycin ranging from 10 mg kg(-1) every 8 h to 10 mg kg(-1) every 12 h, depending on the demographic and clinical characteristics of the patients. The results obtained enabled application of better a priori and a posteriori dosage schedules to infants in neonatal intensive-care units by use of the Bayesian approach, although further prospective study is recommended before direct extrapolation to patients in other settings.

Body Weight↗
PubMed1997

Population pharmacokinetics of caffeine in premature neonates.

OBJECTIVE: To determine population pharmacokinetic parameters of caffeine in premature neonates. METHODS: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modeling) according to a one-compartment open model with either zero or first-order absorption and first-order elimination. The effect of a variety of developmental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. RESULTS: The final pharmacostatistical model with influential covariates were as follows: clearance (m1.h-1) = 5.81-current weight (kg) + 1.22.postnatal age (weeks), multiplied by 0.757 if gestational age < or = 28 weeks and 0.836 if the current primary source of patients' nutrition is parenteral nutrition, and volume of distribution (ml) = 911.current weight (kg). The inter-individual variability in clearance and the residual variability, expressed as coefficients of variation, were 14.8%, and 18.44%, respectively. Due to the lack of information on the data set we were unable to characterize the interindividual variability for volume of distribution. CONCLUSION: In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibliographic information. Additionally, parenteral nutrition and low gestational age (< or = 28 weeks) may even come to be considered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premature infants.

Caffeine↗
PubMed1997

Carbamazepine population pharmacokinetics in children: mixed-effect models.

The aim of the authors' study was to investigate the factors affecting carbamazepine (CBZ) clearance (CL) in children with epilepsy. The factors evaluated were total body weight (TBW), age, dose, sex, and phenobarbital (PB) and valproic acid (VA) comedication. A total of 387 steady-state serum concentration samples was analyzed. These were collected during CBZ therapy from 201 children, aged 1-14 years and weighting 9-78 kg. Population CL was calculated by using NONMEM, with a one-compartment model with first-order absorption and elimination. The absorption rate, bioavailability, and volume of distribution were set at values found in the literature. The model found best to describe the data was CL = (0.0122 TBW + 0.0467 Dose) Age0.331 (1.289 PB). The interindividual variability in CL had a variation coefficient (CV) of 11.8%, and the residual error, described by using an additive model, was 1.5 mg/l. The results show that CL increases linearly with TBW and nonlinearly with age; thus older children have a lower CL with respect to TBW than do younger ones. Likewise CL was seen to increase with the increase in the CBZ dose, suggesting a dose-dependent autoinduction of CBZ metabolism. Concomitant PB administration affected CL: however, sex and VA comedication did not affect it significantly. The final regression model for CL, was validated in a different group of 74 children. The standarized prediction error (SPE) was not significantly different from zero (SPE = 0.028), indicating that the model proposed for CL can be used to make accurate dosage recommendations. With these population estimates, CBZ doses that would be suitable for pediatric patients of different ages are proposed.

Adolescent↗