Biomedical subjects

Saïk Urien

Publications and source records attributed to Saïk Urien.

15 recordsLinked to original sources

PubMed2006

Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years.

The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.

Adolescent↗

PubMed2006

Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy.

PURPOSE: A population pharmacokinetic model was developed to describe dose-exposure relationships of methotrexate (MTX) in adults with lymphoid malignancy; this is in order to explore the interindividual variability in relationship with the different physiopathological variables. The final model was applied to the Bayesian estimation of MTX concentrations using two blood samples. METHODS: Fifty-one patients receiving 136 courses of MTX (1-6 per patient) were included in this study. The data was analysed using NONMEM software. A linear two-compartment model with linear elimination best described the data. Setting mean parameters values and variabilities to population values, we obtained Bayesian prediction of MTX pharmacokinetic parameters and concentrations. The predictive performance was evaluated by comparing the Bayesian estimated and observed concentrations and the Bayesian estimated parameters with the individual final model estimated parameters. RESULTS: The population pharmacokinetic parameters and the inter-subject variablities expressed as coefficient of variation were: the total body clearance CL, 7.1 l h-1 (22%), the volume of the central and peripheral compartments V1, 25.1 l (22.5%), V2, 2.7 l (64%), respectively, and the transfer constant Q, 2.7 (51%) l h-1. Inter-course variability was only significant on CL. Age and serum creatinine had significant effects on CL and was included in the final model. A good correlation was obtained between Bayesian estimated and experimental concentrations (r2=0.85).

Adult↗

PubMed2006

Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients.

Statins are the most commonly prescribed agents for the treatment of hypercholesterolaemia. This is due to their efficacy in reducing low-density lipoprotein cholesterol (LDL) level which is the primary goal of the treatment especially for patients with multiple risk factors or with established coronary heart diseases. The purpose of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the LDL-lowering process in patients with hypercholesterolaemia treated with atorvastatin, fluvastatin or simvastatin. A total of 100 patients were studied retrospectively. They received atorvastatin (n = 57), fluvastatin (n = 26) or simvastatin (n = 17). As no pharmacokinetic data were available, the absorption rate was fixed to 1/h and atorvastatin, simvastatin and fluvastatin elimination half-lives were fixed to 14, 2 and 2.5 h respectively. A total of 309 LDL levels were measured and the data were analysed by nonmem v. The time course of the LDL-lowering effect of statins was described by an indirect-response model with precursor (LDL synthesis, input rate K(in)) and response (circulating LDL, input and output rates K) compartments. The following parameters were estimated: LDL input rate (K(in)) 0.14 +/- 0.015 g/L/day (mean +/- SD); inhibition fraction of K(in) (INH) 0.21 +/- 0.017; and dose producing 50% increase of LDL removal (D50), 26 +/- 7.8, 1.3 +/- 0.48 and 15 +/- 5.25 mg for atorvastatin, simvastatin and fluvastatin, respectively. Gender, bodyweight, age, calories/day, sugar/day, lipids/day, hyperlipidaemia types and waist/hip circumference, renal and hepatic functions had no effect on the pharmacodynamic parameters. The pharmacodynamic parameters for the three statins were accurately estimated. The PK/PD model developed successfully predicted the time course of the LDL-lowering effect of statins.

Adolescent↗

PubMed2006

Pregnancy-related effects on nelfinavir-M8 pharmacokinetics: a population study with 133 women.

A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h(-1); absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL(10)/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL(1M)/F), 0.65 liters/h (69%); and M8 elimination rate constant (k(M0)), 3.3 h(-1) (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h(-1)) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

Adult↗

PubMed2006

Age-related effects on nelfinavir and M8 pharmacokinetics: a population study with 182 children.

As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, nelfinavir pharmacokinetics was investigated in order to optimize the individual treatment schedule in a pediatric population. A population pharmacokinetic model was developed to describe the concentration-time course of nelfinavir and its active metabolite M8. Individual characteristics were used to explain the large interindividual variability in children. Data from therapeutic drug monitoring in 182 children treated with nelfinavir were analyzed with NONMEM. Then Food and Drug Administration (FDA) current recommendations were evaluated estimating the percentage of children who reached the target minimum plasma concentration (0.8 mg/liter) by using Bayesian estimates. Nelfinavir pharmacokinetics was described by a one- compartment model with linear absorption and elimination. Pharmacokinetic estimates and the corresponding intersubject variabilities for the model were as follows: nelfinavir total clearance, 0.93 liters/h/kg (39%); volume of distribution, 6.9 liters/kg (109%); absorption rate, 0.5 h(-1); formation clearance fraction to hydroxy-tert-butylamide (M8), 0.025; M8 elimination rate, 1.88 h(-1) (49%). Apparent nelfinavir total clearance and volume of distribution decreased as a function of age. M8 elimination rate was increased by concomitant administration of nevirapine or efavirenz. Our data confirm that the FDA recommendations for children from 2 to 13 years are optimal and that the dose recommended for children younger than 2 years is adequate for the children from 2 months to 2 years old. However, in children younger than 2 months, the proposed nelfinavir newborn dose of 40 mg/kg of body weight twice daily is inadequate and we suggest increasing the dose to 50 to 60 mg/kg administered thrice daily. This assumption should be further evaluated.

Aging↗

PubMed2006

Population pharmacokinetics of ceftriaxone and pharmacodynamic considerations in haemodialysed patients.

OBJECTIVES: To determine the pharmacokinetic parameters of ceftriaxone following an infusion in haemodialysed outpatients and to use these parameters for an optimisation of dosing based on pharmacodynamic indices. METHODS: Fifty haemodialysed patients were enrolled in a single-centre, prospective, open-label study. They received short intravenous infusions of ceftriaxone 1 or 2 g every 48 hours for bronchopneumonia immediately after the dialysis session. Total plasma concentrations of ceftriaxone were analysed with a population pharmacokinetic approach using nonlinear mixed-effects modelling. Free drug concentrations were derived from published binding parameters in order to estimate the time when they exceed the minimum inhibitory concentration (MIC). RESULTS: The pharmacokinetics were best described by a two-compartment model. None of the covariates tested (age, bodyweight, height, sex, body mass index, albumin) influenced the pharmacokinetic parameters. The estimated population pharmacokinetic parameters (interindividual variability [percentage of coefficient of variation]) were clearance 0.36 L/h (48%), volume of distribution of the central compartment 4.53 L (47%), intercompartmental clearance 10.8 L/h and volume of distribution of the peripheral compartment 9.54 L (63%). The terminal elimination half-life (t(1/2)beta) from plasma was 27.5 hours. The mean (range) times when the free drug concentration exceeded the MIC (T>MIC) following ceftriaxone 1 g infusion were 60.3 (53.0-67.7) hours and 2.5 (1.0-3.9) hours for the breakpoints 1 and 8 mg/L (based on free drug concentration), respectively. After administration of ceftriaxone 2 g, the T>MIC was 88.5 (78.8-98.3) hours and 17.7 (13.3-22.0) hours for the breakpoints 1 and 8 mg/L, respectively. The simulated free drug concentrations (median, first and third quartile) for 48 and 72 hours following the first dose of ceftriaxone 1g were 1.11, 0.63 and 1.89 mg/L, and 0.63, 0.28 and 1.18 mg/L, respectively. For ceftriaxone 2g infusion, the simulated free concentrations (median, first and third quartile) at 48 and 72 hours were 2.50, 1.40 and 4.52 mg/L, and 1.37, 0.60 and 2.70 mg/L, respectively. CONCLUSIONS: On the basis of decreased clearance in haemodialysed patients, it can be argued that the dose of ceftriaxone should be decreased or the delay between doses should be increased. However, taking into account pharmacodynamic considerations, this study showed that following intravenous administration of ceftriaxone 1 g after each dialysis session, some patients were at risk of achieving a concentration below the MIC (1 mg/L), particularly if the second administration occurred 72 hours after the first dosing. Thus, a dose of ceftriaxone 2 g intravenously is recommended immediately following dialysis, particularly in patients with severe infections or when the dosing interval will be higher than 48 hours.

Adult↗

PubMed2005

Population pharmacokinetics of tacrolimus in full liver transplant patients: modelling of the post-operative clearance.

OBJECTIVE: To investigate the population pharmacokinetics of tacrolimus in an adult liver transplant cohort using routine drug monitoring data and to identify patient characteristics that influence pharmacokinetic parameters. METHODS: Tacrolimus pharmacokinetics was studied in 37 adult patients using a population approach performed with NONMEM. RESULTS: A one-compartment open model with linear absorption and elimination adequately described the data. The apparent clearance (CL) was approximately zero in the immediate post-operative days (PODs) and then rapidly increased as a function of POD to reach a plateau. This was modelled as a sigmoid relationship with the characteristic parameters CL(max) (plateau), TCL(50) (time to obtain 50% of the plateau) and gamma (coefficient of sigmoidicity). This clearance model was thought to describe the hepatic function regeneration after transplantation. Typical population estimates (percentage inter-individual variability) of CL(max), TCL50, and gamma and apparent distribution volumes (V) were 36 l/h (43%), 6.3 days (33%), and 4.9 l and 1870 l (49%), respectively. The CL(max) was negatively related to plasma albumin, and TCL50 was positively related to aspartate amino transferase (ASAT). Bayesian estimations performed at different POD times indicated that acceptable precisions in individual pharmacokinetic predictions could be obtained after the 15th POD. CONCLUSION: Tacrolimus clearance modelling showed that there was a large variation in individual CL estimates up to the 15th day post-surgery. After this period, the mean error resulting from the Bayesian estimation was strongly decreased and this estimation method could be applicable and should limit tacrolimus monitoring.

Bayes Theorem↗

PubMed2005

Dosing strategy in patients with renal failure receiving enoxaparin for the treatment of non-ST-segment elevation acute coronary syndrome.

BACKGROUND: Enoxaparin therapy is recommended for the initial treatment of patients with non-ST-segment elevation acute coronary syndrome. However, little dosing information is available regarding the use of enoxaparin in patients with renal impairment. METHODS: We conducted a population pharmacokinetic analysis using anti-Xa activities measured in 532 patients (normal renal function in 34%, mild renal impairment in 36%, moderate renal impairment in 20%, and severe renal impairment in 10%) receiving subcutaneous enoxaparin (mean weight-corrected dose [+/-SD], 0.83 +/- 0.19 mg x kg(-1) x 12 h(-1) for an acute coronary syndrome. Simulations were then performed to develop a dosing strategy for patients with renal impairment. RESULTS: A 1-compartment model with first-order kinetics best fit the data. The covariate analysis showed that enoxaparin clearance was related to renal function and volume of distribution to total body weight. Enoxaparin clearance was decreased by 31% in patients with moderate renal impairment and by 44% in patients with severe renal impairment, resulting in a significant accumulation with the use of the standard 1 mg . kg(-1) x 12 h(-1) dosing regimen. Simulations showed that a first unadjusted dose of 1 mg/kg followed by a regimen of 0.8 mg . kg(-1) x 12 h(-1) in patients with moderate renal impairment or 0.66 mg . kg(-1) x 12 h(-)1 in patients with severe renal impairment should avoid accumulation of enoxaparin and keep peak anti-Xa activities between 0.5 and 1.2 IU/mL for a large majority of patients. CONCLUSIONS: An enoxaparin dosage reduction should be considered in acute coronary syndrome patients with creatinine clearance lower than 50 mL/min. A simple dosing protocol for enoxaparin to avoid significant accumulation in patients with moderate or severe renal impairment is proposed.

Adult↗

PubMed2005

Anti-factor Xa kinetics after intravenous enoxaparin in patients undergoing percutaneous coronary intervention: a population model analysis.

AIM: Recent studies have suggested that intravenous (i.v.) enoxaparin could be used as antithrombotic therapy in patients ongoing percutaneous coronary intervention (PCI). However, anti-Xa pharmacokinetics following different i.v. dosing regimens is not clearly established. METHODS: A population pharmacokinetic analysis was developed using anti-Xa activities measured in 546 patients who received a single 0.5 mg kg(-1) i.v. dose of enoxaparin immediately before PCI. Effects of higher doses (0.75 mg kg(-1) and 1 mg kg(-1)) and/or additional bolus after the initial administration were similarly simulated. RESULTS: Enoxaparin anti-Xa time profiles were best described by a one-compartment model with zero-order kinetics. Mean population parameters (intersubject variability, %) were CL 1.2 l h(-1) (33), V 2.9 l (30) and zero-order input 0.25 h (24). With a single bolus of 0.5 mg kg(-1), the totality of the patients reached an effective anticoagulation level (anti-Xa >0.5 IU ml(-1)) and only 2.5% reached levels above 1.5 IU ml(-1). Simulations showed that greater doses (0.75 mg kg(-1) and 1 mg kg(-1)) prolonged the duration of anticoagulation (3.4 and 4.1 h, respectively) compared with the 0.5 mg kg(-1) bolus (2.7 h) and markedly increased the proportion (48% and 79%, respectively) of patients with anti-Xa levels >1.5 IU ml(-1). For delayed and/or prolonged procedures, patients could be administered a second bolus of half the initial dose in a time interval between 90 min to 2 h after in order to maintain similar anticoagulation profile levels. CONCLUSIONS: A single 0.5 mg kg(-1) i.v. dose of enoxaparin reached anticoagulation levels adequately and should be safer compared with greater doses for anticoagulation in patients undergoing an elective PCI. An additional second bolus could be proposed in patients with delayed or prolonged procedures.

Adult↗

PubMed2005

Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy.

The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (V(c)/F), peripheral distribution volume (V(p)/F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 297 +/- 28.5 [corrected] liters, 848 +/- 209 [corrected] liters, 80 +/- 15 [corrected] liters/h and 50.5 +/- 3.1 [corrected] liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/S(CR)) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC(0-24)). In patients without tubular dysfunction, AUC(0-24) values markedly decreased from 6.7 to 1.4 mg . h/liter for BW/S(CR) increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/S(CR) should be further evaluated.

Adenine↗

PubMed2005

Abacavir pharmacokinetics in human immunodeficiency virus-infected children ranging in age from 1 month to 16 years: a population analysis.

Abacavir pharmacokinetics was studied in 105 children by a population approach performed with NONMEM. A 1-compartment open model with linear absorption and elimination adequately described the data. Typical population estimates (percent interindividual variability) of absorption rate constant, apparent distribution volume, and apparent plasma clearance were 1.79 h(-1) (58%), 42.9 L (53%), and 24.3 L/h (30%), respectively. Apparent plasma clearance was positively related to body weight. Individual Bayesian estimates of apparent plasma clearance were used to calculate individual abacavir area under the concentration curve (AUC). For the current weight-based regimen, abacavir exposure was found to be constant throughout the age range of the study, with an overall mean AUC value of 8.5 +/- 2.5 mg x h/L, which is slightly greater than the mean AUC value reported in adults. This study confirms the relevance of the current weight-based abacavir dosage regimen in pediatric patients.

Adolescent↗

PubMed2004

Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment.

The use of weight-adjusted enoxaparin dosage in patients with renal failure results in increased bleeding complications. The authors investigated the impact of patient-related factors such as renal function on the pharmacokinetics of enoxaparin. Anti-Xa activity was measured in the blood of 60 patients (74 +/- 10 years, body weight 72 +/- 15 kg, men 60%, creatinine clearance 56 +/- 24 mL/min) with acute coronary syndromes receiving subcutaneous administration of enoxaparin. A population-based approach with limited sampling strategy was used. A 1-compartment model with first-order absorption and elimination best fitted the data. The mean clearance (CL/F) and distribution volume (V/F) were 0.72 L/h and 6.65 L, respectively. V/F was influenced by body weight. CL/F was mainly related to the renal function, decreasing with increasing levels of serum creatinine, and lower in women than in men. The elimination half-life was thus estimated to be 6.4 and 9.2 hours in male and female patients, respectively. The final covariate submodel was then: [Equation included in full-text article]. Maximal anti-Xa activity was predicted to rise above 1.5 IU/mL in case of mild elevation of serum creatinine according to gender and body weight. Renal function is the main factor affecting enoxaparin pharmacokinetics. In patients with decreased renal function, enoxaparin dose should be adjusted on the basis of body weight, serum creatinine, and gender to reach a target anticoagulation level assessed by maximal anti-Xa activity in steady-state conditions.

Acute Disease↗

PubMed2003

Population pharmacokinetics of moxifloxacin in plasma and bronchial secretions in patients with severe bronchopneumonia.

OBJECTIVE: Our objective was to construct a population pharmacokinetic model for moxifloxacin disposition in plasma and bronchial secretions in patients with severe bronchopneumonia who were mechanically ventilated. METHODS: Seventeen patients receiving 400 mg moxifloxacin intravenously daily were enrolled in this multicenter, prospective, open-label study. Blood and bronchial samples were collected on days 1 and 4. The population pharmacokinetic modeling was performed with NONMEM. RESULTS: Moxifloxacin rapidly appeared in bronchial secretions and reached maximum concentrations within 1 to 2 hours. The concentrations achieved in plasma and bronchial secretions showed parallel profiles versus time on days 1 and 4. The pharmacokinetics was best described by a 2-compartment model with a link to bronchial secretions. The population pharmacokinetic parameters were as follows (given as estimate with percent interindividual variability in parentheses except where otherwise indicated): clearance, 14.3 L/h (25%); central distribution volume, 62.9 L (14%); intercompartmental clearance, 27.2 L/h (36%); peripheral distribution volume; 71 L (32%); fraction of moxifloxacin clearance to bronchial secretions, 0.11 (range, 0.06-0.16); and elimination rate constant for bronchial secretions, 1.7 h(-1) (40%). The plasma terminal half-life was 6.7 hours. The bronchial-to-plasma exposure ratio was 1.0 (range, 0.6-2.0). With a conservative 90% minimum inhibitory concentration (MIC(90)) of 0.25 mg/L, the maximum concentration/MIC(90) ratios were higher than 10 and the area under the curve/MIC(90) ratios were roughly 100 for plasma and bronchial secretions. CONCLUSIONS: This study showed the fast diffusion of moxifloxacin into the lungs in ventilated patients with severe respiratory infection. The bronchial secretions reached bactericidal levels for common germs found in respiratory tract infections.

Adult↗

PubMed2003

Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.

1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.

Animals↗

PubMed2002

Weekly administration of paclitaxel: theoretical and clinical basis.

The rationale for weekly administration of paclitaxel, which acts on microtubules to arrest mitosis, is that more frequent delivery of moderate doses may achieve greater efficacy than standard doses every 3 weeks, through more sustained exposure of dividing tumor cells to its cytotoxic effects. This dose-dense approach to treatment may inhibit tumor regrowth between cycles and limit the emergence of malignant cell populations resistant to chemotherapy. More frequent exposure to paclitaxel may also enhance its apoptotic and antiangiogenic effects. Paclitaxel activity is considered to be independent of p53 status, in contrast to anticancer drugs that produce lesions on DNA, which achieve a better response if p53 is functional. Weekly therapy also has advantages in terms of improving paclitaxel therapeutic index. Clinical studies show that weekly paclitaxel is effective and that toxicity is acceptable. The response rates of single-agent paclitaxel varied from 21 to 86% in breast cancer, from 20% to 65% in ovarian cancer and from 30% to 56% in non-small cell lung cancer.

Antineoplastic Agents, Phytogenic↗