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J M Lanao

Publications and source records attributed to J M Lanao.

At least 19 recordsLinked to original sources
PubMed2005

Time-dependent pharmacokinetics of cyclosporine (Neoral) in de novo renal transplant patients.

PURPOSE: A model for the large scale temporal trend in the oral bioavailability of microemulsion cyclosporine (Neoral) (CsA) is established, with dependence on post-(renal) transplantation day (PTD). METHODS: Twenty de novo adult renal transplant recipients were monitored for CsA administered orally q12 h. A model development group (11 patients, 315 blood concentration samples) was screened at 2 h (C(2); n = 92), 3 h (C(3); n = 56) and at predose troughs (C(min); n = 167) over periods of up to 75 days. The final model was tested in nine patients with C(min) (n = 580) monitored across 4-5 years. The doses varied between 100 and 538 mg with an apparent hyperbolic trend in C(2)/dose vs. PTD. A nonlinear mixed effects modelling (NONMEM) approach was used to obtain population and individual patient one-compartment pharmacokinetic (PK) parameters for oral CsA, which carry implicit the bioavailability (F). RESULTS: In the final PK model (PK-f) the F was modelled via a simple function for the temporal (days) trend of the bioavailability after transplantation as, F(f) = 1-alpha * exp(-lambda * PTD) resulting in a 28% reduction in the unexplained intra-individual variability. The population PK-f parameters were, for apparent clearance [mean, 95% confidence interval (interindividual CV%)] Cl/F(f) = 17.0 (13.8-20.2) L/h (27%), apparent central compartment volume of distribution, V/F(f) = 134 L (108-160) (28%), and lambda = 0.037/day (0.005-0.069) (120%). The absorption rate k(a) and the parameter alpha were approximated iteratively as 4/h and 0.62 respectively. The PK-f was structurally superior to the base model in explaining part of the within subject (occasion) variability and predicting the exposure surrogates C(2) and C(3). Also, the PK-f was better than the base model with Bayesian fitting of individual profiles in that group. CONCLUSION: The PTD-dependent relative bioavailability model provides a rational means of steering dose titration of CsA in de novo renal transplantation patients by removing the large scale PK adjustment signal, either through nomograms or as a Bayesian prior.

Adult↗
PubMed2005

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.

Animals↗
PubMed2005

Drug tissue distribution: study methods and therapeutic implications.

Current interest in studies on tissue distribution stems from the limited capacity to predict tissue concentrations and the pharmacological response from plasma drug levels, and from the limitations - both methodological and deontological- involved in doing so, especially in humans. In this review we carry out a comparative analysis of the methods used for studying tissue distribution, placing special focus on recently developed non-invasive methods for the research of tissue distribution in humans, such as positron emission tomography and nuclear magnetic resonance spectroscopy. We describe the strategies of tissue distribution pharmacokinetic analysis that have evolved from analysis based on compartment and physiological models to analyses based on spatial and fractal models and, mainly, pharmacokinetic-pharmacodynamic models. Model-independent analysis based on the use of mean transit times or deconvolution strategies has become a good alternative for the pharmacokinetic analysis of tissue distribution. The need to increase the selectivity of many drugs justifies the desire to gain further insight into the design of new analogues prodrugs and carrier systems that will guarantee the specific delivery of a given drug to a particular organ or tissue, optimising the response. In silico models for drug distribution have become a helpful tool in drug discovery and development. The therapeutic implications of drug tissue distribution are also analysed, special reference being made to antiretroviral therapy and antitumoural gene therapy, among others.

Animals↗
PubMed2003

Population pharmacokinetics of high dose ibuprofen in cystic fibrosis.

AIMS: To evaluate ibuprofen population pharmacokinetics in a large series of data collected in children with cystic fibrosis (CF) treated with high doses of ibuprofen (59 patients; 2-18 years), and to identify the main causes responsible for the considerable interindividual variability in ibuprofen serum levels. METHODS: Blood samples were collected during routine clinical care; serum ibuprofen concentrations were determined by HPLC. Fitting of the concentration/time data to a one compartment kinetic population model was performed by a non-linear mixed effect regression method. RESULTS: Body weight, dose, and ibuprofen dosage form (lysinate salt or the free acid form), for elimination clearance (CL/F); and body weight, dose, and fasting status for the apparent distribution volume (Vd/F) proved to be the covariates with influence in the model. The four factors identified helped to explain part of the interindividual variability observed, but the remaining unexplained variability made therapeutic drug monitoring absolutely essential.

Administration, Oral↗
PubMed2002

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.

Algorithms↗
PubMed2000

A review of the isolated kidney as an experimental model for pharmacokinetic studies.

Traditional distribution studies have been based on methods affording steady-state partition coefficient or sparsely defined tissue profiles. Isolation organ techniques provide a methodology for complete description of drug disposition at any particular tissue; the kidney constitutes a case for importance for those drugs eliminated by renal excretion of those whose toxicological or pharmacological target space is located at this level. The aim of the present review is to analyze the use of the isolated perfused kidney in pharmacokinetic studies and its potential in this field.

Animals↗
PubMed1999

High-performance liquid chromatographic validated assay of doxorubicin in rat plasma and tissues.

A specific and selective high-performance liquid chromatography (HPLC) technique that requires few manipulations, and is readily adaptable to analysis for a large series of samples, has been developed for the determination of the concentration of the anticancer drug doxorubicin (DXR) in rat serum and tissues. The biological samples were efficiently deproteinised and resolved from a reversed-phase nucleosil C18 column with fluorescence detection. The validation study of the proposed method was successfully carried out in an assay range of between 5 and 5000 ng/ml and was subsequently implemented in a pharmacokinetic study of DXR in Wistar rats that were treated by intravenous administration of the drug.

Animals↗
PubMed1999

Distribution of ciprofloxacin in the isolated rat lung in the presence and absence of tissue oedema.

A series of experiments with the isolated perfused rat lung was carried out to study the distribution of ciprofloxacin in this tissue under different experimental conditions; the influence of drug administration rate and the presence of oedema were evaluated by comparison of the statistical moment and distribution coefficient values as well as the unit disposition function (UDF) profiles in the tissue. The polyexponential character of the outflow perfusate curves indicates a distribution behaviour which does not correspond to the 'well stirred model' but rather to the existence of some type of diffusion barriers and/or tissue binding. The presence of oedema in the tissue, induced by insufficient oxygenation of perfusate, significantly increases the distribution coefficient of ciprofloxacin and leads to relevant modifications in the unit disposition function (UDF) of the isolated lung, while administration rate does not significantly affect the kinetic behaviour of the drug in this tissue.

Animals↗
PubMed1999

Population pharmacokinetics of amikacin in patients with haematological malignancies.

The aim of this study was to analyse the pharmacokinetic behaviour of amikacin in patients with haematological malignancies using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 207 haematology patients divided into two groups: one for computing the population model (n = 134) and the other for validation (n = 73). A one-compartment model was used and the following covariates were tested for their influence on clearance and volume of distribution: age, gender, weight, parenteral nutrition, creatinine clearance, stage of antineoplastic treatment (induction, consolidation, intensification), number of weeks postchemotherapy, clinical diagnosis, Eastern Cooperative Oncology Group score, neutropenia, hypoalbuminaemia, concomitant medication (vancomycin and/or amphotericin B), overhydration, and autologous or allogenic bone marrow transplant. The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in these patients. Apart from bodyweight and renal function, acute myeloblastic leukaemia and hypoalbuminaemia proved to be the most important covariates explaining the interindividual variability in amikacin pharmacokinetics in patients with haematological malignancies. The predictive performance of this population model for amikacin serum concentrations seems suitable for clinical purposes.

Adult↗
PubMed1998

A comparative study of ofloxacin and ciprofloxacin erythrocyte distribution.

The present work deals with the in vitro and in vivo distribution of ofloxacin and ciprofloxacin in erythrocytes. In vitro studies were carried out in standard solutions prepared using fresh blood for a concentration range between 100 and 0.25 micrograms mL-1. A 5 mg kg-1 bolus dose was administered to rabbits and erythrocyte and plasma kinetics were determined over 8 h. A linear model was used to establish the relationship between plasma and erythrocyte concentrations of both quinolones in vitro. The mean partition coefficient values obtained were 1.04 +/- 0.02 and 1.32 +/- 0.03 for ofloxacin and ciprofloxacin, respectively. A decrease in the ciprofloxacin partition coefficient was observed at higher concentrations. Values ranged between 2.54 +/- 0.40 and 1.38 +/- 0.15 as the concentrations increased. The partition coefficients obtained from the linear relationship between plasma and erythrocyte concentrations established from the in vivo data were 0.80 +/- 0.58 for ofloxacin and 0.61 +/- 0.30 for ciprofloxacin. In vivo plasma and erythrocyte data analysis was performed by a deconvolution method and the theoretical transfer curves in erythrocytes were estimated. The distribution of both quinolones to erythrocytes is very rapid, probably due to a high permeability of erythrocyte membranes to these drugs. This was also confirmed by the parallelism between plasma and erythrocyte kinetics.

Animals↗
PubMed1998

Influence of diagnostic and treatment factors in the population pharmacokinetics of gentamicin.

Using the NONMEM program, the population kinetics of gentamicin were retrospectively studied in a series of 51 patients with different pathologies undergoing treatment (single or three daily doses) with gentamicin whose serum gentamicin levels were being monitored. Renal function, the type of treatment and cancer proved to be the covariates which affected drug clearance, while patient weight was found to govern the distribution volume. The distribution coefficient of gentamicin in the patients was 0.37 litres/kg, justifying gentamicin doses higher than those used conventionally. The optimized population model allowed us to simulate drug serum levels at 8 and 12h, as well as the area under the curve of gentamicin and its variability in patients with high distribution volumes when dosage regimens based on a single daily dose administration are implemented.

Abscess↗
PubMed1998

Influence of verapamil and digoxin on the in vitro binding of doxorubicin to the rat heart.

A study has been carried out to characterize the binding of doxorubicin to heart homogenates and subcellular fractions. The technique chosen to perform the study was equilibrium dialysis and the levels of anthracycline in the samples obtained from the dialysis were assessed using HPLC. Doxorubicin has high affinity to heart homogenates and subcellular fractions such as nuclear, mitochondrial and microsomal. The binding was saturable and dose-dependent. Doxorubicin binding is decreased in the presence of digoxin and especially verapamil.

Animals↗
PubMed1998

In vitro characterization of ciprofloxacin distribution in rat lung.

The binding of ciprofloxacin to both lung homogenate and isolated subcellular fractions, as well as the washout kinetics from lung homogenate of rats, was studied in vitro. Differences in the binding capacity of ciprofloxacin to subcellular fractions and total lung homogenate were observed. In vitro mean partition coefficient values (+/- SD) for nuclear, mitochondrial and microsomal fractions were 2.84 +/- 0.82, 2.32 +/- 0.69 and 2.72 +/- 0.75, respectively, with no statistical differences among these values. On the other hand, the partition coefficient obtained with lung homogenate showed a mean value (+/- SD) of 1.39 +/- 0.31, statistically lower than the values corresponding to the different cellular fractions. These results reveal a great affinity of ciprofloxacin for intracellular structures that may condition the distribution characteristics of the quinolone in lung and other body tissues, In washout studies, washout of ciprofloxacin from lung homogenate proved to be a monoexponential and first-order kinetic process.

Animals↗
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↗
PubMed1996

Influence of pharmacokinetic model on vancomycin peak concentration targets.

The aim of this study was to adapt the vancomycin therapeutic range to the kinetic models usually employed in clinical settings (one- and two-compartment models). Estimates of vancomycin pharmacokinetic parameters were obtained for both models in 22 hematologically malignant patients on vancomycin treatment using two serum concentrations and a bayesian algorithm. From these individually estimated pharmacokinetic parameters, an estimation of the maximum (Cssmax), 2 h postinfusion (Css2), and minimum (Cssmin) steady-state vancomycin serum concentrations for the one- and two-compartment models was made for a fixed 30 mg/kg/day dose. The linear regression equations between the predicted Css2 and Cssmin for the one- and two-compartment models do not differ significantly from the identity line, whereas the corresponding equation for Cssmax points to a 61% underestimation of Cssmax when the one-compartment model is used. From this latter regression equation, it is possible to define 20 mg/L (range of 18-21 mg/L) as a target Cssmax vancomycin serum concentration when a one-compartment model is used to monitor vancomycin therapy. Another practical approach would be to define the target concentration by a desired range at 2 h, which corresponds to a Cssmax value of 30-40 mg/L.

Anti-Bacterial Agents↗
PubMed1996

Pharmacokinetics of amikacin in intensive care unit patients.

OBJECTIVE: To characterize the population pharmacokinetics of amikacin in intensive care unit (ICU) patients and to analyse whether these patients show different kinetic behaviour on the basis of their clinical diagnoses. METHOD: The patient population comprised 104 medical ICU patients on amikacin treatment for several presumed or documented Gram-negative infections. Four study groups were defined according to patients' clinical diagnosis: sepsis group (n = 39), trauma group (n = 20), pneumonia group (n = 21) and 'other diagnosis' group (n = 24). The pharmacokinetic parameters for amikacin in these patients were then compared. RESULTS: The ICU patients were found to have increased values for the amikacin volume of distribution (0.52 +/- 0.21 litres/kg), whereas total amikacin clearance expressed as a linear function of creatinine clearance was Cl (ml/min/kg) = 0.13 +/- 0.86 ClCR, which is not significantly different from other estimations reported in the literature. However, this relationship revealed statistically significant differences among the four groups of ICU patients. Moreover, the septic and trauma patients showed higher (but not statistically significant) values for the amikacin volume of distribution. CONCLUSION: The amikacin pharmacokinetic parameters obtained should allow Bayesian individualization of amikacin doses in patients admitted to medical ICUs, on the basis of their clinical diagnoses.

Adult↗
PubMed1996

Bayesian forecasting in paediatric populations.

Bayesian forecasting offers several important advantages for dosage individualisation in children, although, unlike for adults, its use in this population is much lower. Indeed, currently Bayesian methods are underused in this patient population. The paucity of paediatric population pharmacokinetic parameters, and the unavailability of specific clinical pharmacokinetic software for the whole paediatric population, are the main limitations to the application of Bayesian methods in these patients. When these problems have been overcome, this approach will allow clinicians to achieve therapeutic concentrations more readily, faster and more precisely, thus making the methodology highly attractive in the paediatric setting.

Adolescent↗