Larger Dose Reductions of Vancomycin Required in Neonates with Patent Ductus Arteriosus Receiving Indomethacin versus Ibuprofen.

Ibuprofen and indomethacin are commonly used to induce ductus arteriosus closure in preterm neonates. Our group previously reported that ibuprofen decreased vancomycin clearance by 16%. In this study, we quantified the impact of indomethacin coadministration on vancomycin clearance by extending our vancomycin population pharmacokinetic model with a data set containing vancomycin concentrations measured in preterm neonates comedicated with indomethacin. The modeling data set includes concentration-time data of vancomycin administered alone or in combination with either ibuprofen or indomethacin collected in the neonatal intensive care units of UZ Leuven (Leuven, Belgium) and São Francisco Xavier Hospital (Lisbon, Portugal). The derived vancomycin pharmacokinetic model was subsequently used to propose dose adjustments that yield effective vancomycin exposure (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] between 300 to 550 mg·h/liter, with a probability of <0.1 of subtherapeutic exposure) in preterm neonates with patent ductus arteriosus. We found that indomethacin coadministration reduced vancomycin clearance by 55%. Model simulations showed that the most recent vancomycin dosing regimen, which was based on an externally validated model, requires 20% and 60% decreases of the loading and maintenance doses of vancomycin, respectively, when aiming for optimized exposure in the neonatal population. By analyzing vancomycin data from preterm neonates comedicated with indomethacin, we found a substantial decrease in vancomycin clearance of 55% versus a previously reported 16% for ibuprofen. This decrease in clearance impacts vancomycin dosing, and we anticipate that other drugs eliminated by glomerular filtration are likely to be affected to a similar extent as vancomycin.

Reliability of body-weight scalars on the assessment of propofol induction dose in obese patients.

BACKGROUND: Obese patients require specific perioperative care when compared with non-obese patients. The present study aimed to analyse the ability of size descriptors to estimate propofol induction dose in class II and III obese patients. METHODS: A cross-sectional study on adult patients with body mass index (BMI) equal to or greater than 35 kg/m2 and on adult patients with BMI lower than 35 kg/m2 was carried out. General anaesthesia was induced with remifentanil, propofol and rocuronium. Propofol infusion was started at 2000 mg/h until loss of consciousness. Bioelectrical impedance analysis and Brice modified interview was completed during pre- and post-operative evaluation, respectively. Measurements of propofol plasma concentration were performed using gas chromatography/ion trap-mass spectrometry. RESULTS: Forty patients were enrolled in the study. The median values of fat free mass (FFM) in BMI < 35 kg/m2 and BMI ≥ 35 kg/m2 groups were 70% and 55% of total body weight, respectively. Our results did not demonstrate a strong correlation level between the studied size descriptors and propofol induction dose in both groups. Nevertheless, when propofol doses were normalized by FFM, an apparent convergence of the empirical cumulative distribution functions was observed. CONCLUSION: None of the size descriptors was seen to be an effective predictor of the propofol induction dose in class II and III obese patients when a fixed infusion rate was used. Due to the observed variability between patients, guiding propofol induction dose against a clinical endpoint of unconsciousness appears more appropriate in order to avoid side effects related both with under or overdosing of propofol.

Usefulness of factor II and factor X as therapeutic markers in patients under chronic warfarin therapy.

Oral anticoagulation with warfarin is a widely used form of treatment for an increasing number of medical conditions. Nevertheless, appropriate therapeutic monitoring and dosage readjustments should be carried out in order to ensure its safety and efficacy. Although prothrombin time (usually expressed as International normalized ratio [INR]) is the most common warfarin response marker, clotting factors (namely factors II and X) are also indicated as alternative anticoagulant effect markers. In this paper, we examine the relationship between these warfarin response markers using information obtained from eighty 80 patients undergoing long-term warfarin therapy. Within the usual INR therapeutic range (2.0-3.5), a moderate inverse correlation between INR and both clotting factors II and X was observed. However, for INR values above 3.5, a non-proportional relationship were found between INR and both response markers. Therefore, it can be concluded that below critical clotting factor concentrations (20.6% and 15.6% of factors II and X activity, respectively), time required for clot formation becomes non-proportional and haemostasis will be jeopardised.

The maximal electroshock seizure (MES) model in the preclinical assessment of potential new antiepileptic drugs.

The choice of appropriate animal models for the initial in vivo testing of potential anticonvulsant compounds is one of the most important steps in the successful search for new antiepileptic drugs. The purpose of this paper is to describe the most important aspects to take into account when performing the maximal electroshock seizure (MES) test in the routine laboratory screening of new antiepileptics: the conventional and threshold MES test experimental procedures, the factors affecting experimental data (laboratory conditions, administration vehicles and drug formulations, time after drug administration, and stimulus duration and site of stimulation) and the assessment of anticonvulsant activity are discussed.

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.

Neuropharmacokinetic characterization of lamotrigine after its acute administration to rats.

The purpose of this study is to characterize the neuropharmacokinetics of lamotrigine following a single intraperitoneal dose. Adult male Wistar rats were given lamotrigine dose of 5, 10, or 20 mg/kg. Blood and brain samples were obtained at predetermined times over 120 h and analyzed by HPLC. The overall characteristics of plasma curves were determined by noncompartmental analysis with WINNONLIN. The kinetic characterization of lamotrigine distribution between plasma and brain was performed by indirect numerical deconvolution with MULTI(FILT). A linear disposition kinetics was observed within 5-20 mg/kg. The lamotrigine concentrations in brain homogenate were approx. twofold higher than in plasma. The following pharmacokinetic parameters were obtained for lamotrigine 5, 10, and 20 mg/kg, respectively: clearance of distribution from plasma to brain normalized with the volume of the brain, CL/V(h(-1)) = 4.64, 2.47, 2.40; brain-to-plasma partition coefficient, P = 0.40, 0.37, 0.34; first-order transfer rate constant from the brain to the plasma, K(h(-1)) = 11.68, 6.68, 5.96; single-pass mean transit time in the brain, MTT(h) = 0.086, 0.150, 0.168. These results indicate that lamotrigine plasma levels may be good indicators of lamotrigine levels in the brain and that higher response intensities could be expected with higher doses of lamotrigine, since efficacious concentrations are maintained for a longer period.

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.

Anorectic and behavioural effects of chronic Cissampelos sympodialis treatment in female and male rats.

Male and female rats were treated daily for 13 weeks with an ethanol extract of Cissampelos sympodialis leaves (9, 45 and 225 mg[sol ]kg). The food consumption, body weight and behavioural effects in the open-field test were evaluated by weekly monitoring. The results showed that the extract chronic treatment in female rats (45 and 225 mg[sol ]kg) reduced significantly the food intake and the body weight, and produced several alterations in the open-field test. These findings indicate that repeated oral administration of the extract may produce a sex-dependent difference in anoretic and behavioural effects.

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.

[Monitoring serum levels of gentamicin in neonates]. / Recém-nascidos e monitorização sérica de gentamicina.

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).

Population pharmacokinetics of digoxin in pediatric patients.

Digoxin pharmacokinetics were studied in a pediatric population with an age range of 6 days to 1 year using the population pharmacokinetic approach. Digoxin data were analyzed by mixed-effects modeling according to a one-compartment steady-state pharmacokinetic model using NONMEM software. The final model selected for the population prediction of digoxin clearance in pediatric patients was as follows: [equation: see text] Individual empirical Bayesian estimates were generated on the basis of the population estimates and were used to correlate the optimum dose of digoxin and patient age according to the following equation: [equation: see text] This equation and its derived nomogram may be used for the initial dosing of digoxin in children aged between 0 and 1 year. The use of this nomogram in routine monitoring requires further pharmacokinetic and clinical validation.

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.

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.

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.

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.

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.

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.

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.