Saik Urien | Université Paris Descartes (original) (raw)
Papers by Saik Urien
European Journal of Pharmacology, 2006
Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant prote... more Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in mutant transport-deficient (TR−) rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population nonlinear mixed effect modeling. The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR− rats (0.03 ± 0.02l/ h) than in normal control (0.09 ± 0.05l/h), in normal probenecid (0.10 ± 0.07 l/h) and in TR− control rats (0.13 ± 0.07 l/h). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.
The Lancet Neurology, 2016
Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are t... more Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2·5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10·3%, 95% CI -24·0 to 3·4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. UCB Pharma.
Molecular Imaging and Biology, 2015
Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were... more Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy. Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-deoxy-3&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-[(18)F]fluorothymidine ([(18)F]FLT), single photon emission tomography (SPECT) with [(99m)Tc]TcO4 ([(99m)Tc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [(18)F]FDG and [(99m)Tc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel-treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed. All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [(99m)Tc]TEC and [(18)F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [(18)F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [(18)F]FDG and [(99m)Tc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week(-1) in untreated, doxorubicin, and docetaxel groups, respectively. Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [(18)F]FDG-PET and [(99m)Tc]TEC SPECT monitor tumor response to chemotherapy.
Journal of the National Cancer Institute, Apr 21, 2004
Anticancer research
Cisplatin toxicity could be decreased by adjusting its dosage to each patient. For this purpose, ... more Cisplatin toxicity could be decreased by adjusting its dosage to each patient. For this purpose, a limited sampling method was established and validated based on a Bayesian approach taken using the values of assays during a 5-day continuous infusion of cisplatin. Using this method, a dosing model to achieve a target plasma concentration of total platinum (Pt) was evaluated retrospectively; the calculated dose of cisplatin was 95.0 to 104.8% of the actual dose. This model was then studied prospectively and the actual plasma Pt concentration reached at the end of the infusion was 94.9% of the target concentration. A strong correlation was observed between the clearance of Pt and the calculated clearance of creatinine or Cockroft index (p = 1.7 x 10(-11), and this correlation was used to develop another cisplatin dosing model. With this model the actual concentration reached at the end of the infusion was 85.3% of the theoretical concentration. The Bayesian approach gave reliable results for most clinical uses, whereas the creatinine based model has to be improved.
Anticancer research
ABSTRACT
Anticancer research
ABSTRACT
Journal of Critical Care, 2015
Models are mathematical tools used to describe real-world features. Therapeutic interventions in ... more Models are mathematical tools used to describe real-world features. Therapeutic interventions in the field of critical care medicine may easily be translated into such models. Indeed, numerous variables influencing drug pharmacokinetics and pharmacodynamics are systematically documented in the intensive care unit over time. Organ failure, fluid shifts, other drug administration, and renal replacement therapy may cause changes in physiological values, such as body weight and composition, temperature, serum protein levels, arterial pH, and renal or hepatic function. Trials assessing the efficacy and safety of novel drugs usually exclude critically ill patients, and guidelines regarding drug dosage rarely apply to such patients. Modeling in the critically ill may allow physicians to inform decisions related to therapeutic interventions, particularly relating to infectious diseases. However, few clinicians are familiar with these methods. Here, we present a current overview of population pharmacokinetic and pharmacodynamic models applicable in critically ill patients aimed at nonspecialists and then emphazize recent potential of modeling for optimizing treatments and care in the intensive care unit.
The Lancet Oncology, 2015
Clinical Research and Regulatory Affairs, 1994
ABSTRACT
Pharmaceutical Research, Sep 1, 1995
European Journal of Clinical Pharmacology, Mar 1, 2013
No information on optimal cholecalciferol dosing in kidney transplant patients is currently avail... more No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30-80 ng/mL during the first year post-transplantation. Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration. The mean population parameter estimates and the associated between-subject variability were: formation rate constant (k(f)), 0.11 day(-1); clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V(C)/F), 237 L; basal concentration (C(0)),12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients.
J Pharmacokinet Pharmacodyn, 2005
To model the biotransformation steps of 5-FU production from capecitabine and identify patient ch... more To model the biotransformation steps of 5-FU production from capecitabine and identify patient characteristics that may influence the drug disposition. Blood samples and demographic data were collected from two phase I studies in which adult patients received oral capecitabine for various malignancies. Capecitabine, 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-deoxy-5-fluorocytidine (5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFCR), 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-deoxy-5-fluorouridine (5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFUR) and 5-fluorouracile (5-FU) concentration-time data were analysed via a population approach using NONMEM. Forty patients and 75 pharmacokinetic time-courses were available for analysis. Capecitabine pharmacokinetics was ascribed to a one compartment model from which 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFCR, 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFUR and 5-FU were sequentially produced. Capecitabine oral absorption was characterized by a rapid first order input (K(a)=2.1 +/- 0.3 hr(-1)) with a lag time (0.28 +/- 0.11 hr), but related inter-occasion (IOV) and inter-subject (ISV) variabilities for these parameters, 167% and 110%, indicated that this oral absorption was highly variable. The capecitabine CL (CL10 = 218+/- 18 L/hr, ISV = 18%) and 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFUR elimination rate constant (K34 = 5.3 +/- 2.0 hr(-1), ISV = 25%) were influenced by total bilirubin (BILT). The elimination rate constant of plasma 5-FU (K40) was 66 +/- 24 hr(-1) (ISV = 34%). The final pharmacokinetic model was validated using 2000 bootstrap runs and provided non-parametric statistics of the parameters (median, 2.5th and 97.5th percentiles). This study supported the possibility of modelling a complex sequential metabolic pathway which produces pharmacologicaly active compounds from a prodrug. Only BILT significantly influenced the pharmacokinetics but this effect was not considered as relevant for dosing adjustment.
Anti Cancer Drugs, Dec 1, 2003
Our aim was to develop a population pharmacokinetic model of ultrafilterable oxaliplatin in metas... more Our aim was to develop a population pharmacokinetic model of ultrafilterable oxaliplatin in metastatic cancer patients. Oxaliplatin was administered by 2- or 4-h infusions, 50, 65, 75, 85, 100 or 130 mg/m2 to 56 patients. Blood samples were collected over 28 h. Plasma concentrations of ultrafilterable oxaliplatin were determined by flameless atomic absorption spectrophotometry. Population pharmacokinetic analysis was performed using a non-linear mixed-effects modeling method. Ultrafilterable oxaliplatin concentration-time profiles showed a secondary peak or a shoulder aspect post-infusion, attributed to the existence of an enterohepatic recirculation (EHR). They were best described by a two-compartment model incorporating an EHR component. Plasma clearance (CL) was related positively to body weight (BW) and negatively to serum creatinine (SCr), and was greater in male patients than in female patients. This covariate modeling resulted in a decrease in the interindividual variability for CL from 104 to 62%. The central distribution volume (V1) and inter-compartmental clearance (Q) were related to BW. Typical population estimates of CL, central distribution volume (V1), input rate constant into gallbladder (k1B) and lag time for drug reabsorption (TLAG) were 14.1 or 8.5 l/h (male or female patients), 24.9 l, 1.8 h-1 and 2.0 h, respectively. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. We conclude that a two-compartment with EHR model adequately described ultrafilterable oxaliplatin pharmacokinetics, explaining a secondary transient increase in concentration. This study identified combined-covariate-effects ultrafilterable oxaliplatin clearance, supporting dose adjustment of oxaliplatin based on BW, gender and corrected for SCr level, if drug exposure is thought to be related to therapeutic or toxic issues.
European journal of rheumatology and inflammation
The binding of benoxaprofen to human serum albumin (HSA) was investigated by equilibrium dialysis... more The binding of benoxaprofen to human serum albumin (HSA) was investigated by equilibrium dialysis at pH 7.4 and 37 degrees C. As most acidic drugs, almost completely ionized at plasma pH, benoxaprofen was avidly bound to HSA (7.5 x 10(-6) M) with the following parameters: n1 = 3.3 and K1 = 325 x 10(3) M-1; n2 = 16.2 and K2 = 2.1 x 10(3) M-1 At normal HSA plasma concentration in humans benoxaprofen was more than 99.5% bound, either when a pure HSA solution or when a pooled serum was used. Such results were obtained within a wide range of benoxaprofen concentrations and benoxaprofen binding did not significantly differ whatever its concentration might be. The influence of liver failure on benoxaprofen serum binding was investigated in five patients whose bilirubinaemia was from 15 to 28 x 10(-6) M, and the results were compared to those of five normal volunteers. There was no difference between the two groups: 99.30 +/- 0.30% versus 99.62 +/- 0.30%. However, in four other patients whose bilirubinaemia was greater than 130 x 10(-6) M, the binding of benoxaprofen decreased to 98.0 +/- 1.6% (p] less than 0.05). Addition of FFA (palmitic acid, 2000 . 10(-6) M) to H SA (580 x 10(-6) M) involved a slight decrease in HSA binding of benoxaprofen: 99.8 +/- 0.1 versus 99.66 +/- 0.03%. Serum binding of benoxaprofen was not affected by therapeutic levels of tolbutamide, was slightly decreased from 99.7 to 9.2% by furosemide, to 99.4% by CPIB, and to 99.4% by salicylic acid. At the reverse, therapeutic plasma levels of benoxaprofen did not displace warfarin and acenocoumarol, but they displaced CPIB from 90.1 to 86.1%, glibenclamide from 95.2 to 94.2% and phenylbutazone 99.6 to 93.0%.
Molecular Pharmacology
The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lower... more The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lowering and water-insoluble drug, probucol, was investigated in in vitro studies. [14C]Probucol was incubated in whole human blood, a serum pool, individual diluted sera, and isolated protein and lipoprotein fractions. In whole blood, about 90% partitioned in plasma. Following ultracentrifugal fractionation of the serum, it was found that less than 5% distributed in the d greater than 1.20 protein fraction (albumin-rich fraction) and more than 95% in the lipoprotein fractions. The distribution of probucol in the lipoprotein fractions correlated with the lipoprotein total lipid volume under saturation conditions (incubation of isolated lipoprotein fractions) as well as nonsaturation conditions (fractionation of serum exposed to [14C]probucol). Incubation of the albumin-rich fraction and of apolipoproteins originating from the isolated lipoprotein fractions showed that they account for a negligible part in the interaction of probucol with blood components. The probucol uptake of individual sera was shown to be correlated to the lipid content of the serum. When probucol was incubated in erythrocyte suspensions containing variable amounts of lipoproteins, probucol partitioned less in erythrocytes as the lipoprotein concentration increased in the suspension.
Nouvelle revue française d'hématologie
International journal of clinical pharmacology, therapy, and toxicology
The binding parameters of valproic acid (VPA) to human serum albumin (HSA) were determined by equ... more The binding parameters of valproic acid (VPA) to human serum albumin (HSA) were determined by equilibrium dialysis and computed using non-linear regression. However unclassic, it was observed that the binding parameters of VPA varied according to the concentration of the HSA solutions used. At 580 microM HSA, VPA is bound to two classes of binding sites with the association constants K1 = 56000 M(-1) and K2 = 750 M(-1), and their respective numbers of binding sites n1 = 2 and n2 = 5. Free serum fraction of VPA is significantly increased by 500, 1000 and 1500 microM palmitate, 250 microM clofibrate, 320 microM phenylbutazone, or 360 microM salicylate. In any case, the increase of the VPA serum free fraction is highly correlated with the inhibitor concentration. On the other hand, the free serum fraction of warfarin is increased by 600 microM VPA (100 micrograms/ml). In patients with liver disease, the variations of the free serum fraction of VPA are correlated to the albumin and to the bilirubin concentrations. Serum binding of VPA is significantly decreased in the two groups of patients as compared with the control group.
European Journal of Pharmacology, 2006
Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant prote... more Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in mutant transport-deficient (TR−) rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population nonlinear mixed effect modeling. The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR− rats (0.03 ± 0.02l/ h) than in normal control (0.09 ± 0.05l/h), in normal probenecid (0.10 ± 0.07 l/h) and in TR− control rats (0.13 ± 0.07 l/h). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.
The Lancet Neurology, 2016
Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are t... more Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2·5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10·3%, 95% CI -24·0 to 3·4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. UCB Pharma.
Molecular Imaging and Biology, 2015
Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were... more Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy. Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-deoxy-3&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-[(18)F]fluorothymidine ([(18)F]FLT), single photon emission tomography (SPECT) with [(99m)Tc]TcO4 ([(99m)Tc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [(18)F]FDG and [(99m)Tc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel-treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed. All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [(99m)Tc]TEC and [(18)F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [(18)F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [(18)F]FDG and [(99m)Tc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week(-1) in untreated, doxorubicin, and docetaxel groups, respectively. Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [(18)F]FDG-PET and [(99m)Tc]TEC SPECT monitor tumor response to chemotherapy.
Journal of the National Cancer Institute, Apr 21, 2004
Anticancer research
Cisplatin toxicity could be decreased by adjusting its dosage to each patient. For this purpose, ... more Cisplatin toxicity could be decreased by adjusting its dosage to each patient. For this purpose, a limited sampling method was established and validated based on a Bayesian approach taken using the values of assays during a 5-day continuous infusion of cisplatin. Using this method, a dosing model to achieve a target plasma concentration of total platinum (Pt) was evaluated retrospectively; the calculated dose of cisplatin was 95.0 to 104.8% of the actual dose. This model was then studied prospectively and the actual plasma Pt concentration reached at the end of the infusion was 94.9% of the target concentration. A strong correlation was observed between the clearance of Pt and the calculated clearance of creatinine or Cockroft index (p = 1.7 x 10(-11), and this correlation was used to develop another cisplatin dosing model. With this model the actual concentration reached at the end of the infusion was 85.3% of the theoretical concentration. The Bayesian approach gave reliable results for most clinical uses, whereas the creatinine based model has to be improved.
Anticancer research
ABSTRACT
Anticancer research
ABSTRACT
Journal of Critical Care, 2015
Models are mathematical tools used to describe real-world features. Therapeutic interventions in ... more Models are mathematical tools used to describe real-world features. Therapeutic interventions in the field of critical care medicine may easily be translated into such models. Indeed, numerous variables influencing drug pharmacokinetics and pharmacodynamics are systematically documented in the intensive care unit over time. Organ failure, fluid shifts, other drug administration, and renal replacement therapy may cause changes in physiological values, such as body weight and composition, temperature, serum protein levels, arterial pH, and renal or hepatic function. Trials assessing the efficacy and safety of novel drugs usually exclude critically ill patients, and guidelines regarding drug dosage rarely apply to such patients. Modeling in the critically ill may allow physicians to inform decisions related to therapeutic interventions, particularly relating to infectious diseases. However, few clinicians are familiar with these methods. Here, we present a current overview of population pharmacokinetic and pharmacodynamic models applicable in critically ill patients aimed at nonspecialists and then emphazize recent potential of modeling for optimizing treatments and care in the intensive care unit.
The Lancet Oncology, 2015
Clinical Research and Regulatory Affairs, 1994
ABSTRACT
Pharmaceutical Research, Sep 1, 1995
European Journal of Clinical Pharmacology, Mar 1, 2013
No information on optimal cholecalciferol dosing in kidney transplant patients is currently avail... more No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30-80 ng/mL during the first year post-transplantation. Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration. The mean population parameter estimates and the associated between-subject variability were: formation rate constant (k(f)), 0.11 day(-1); clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V(C)/F), 237 L; basal concentration (C(0)),12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients.
J Pharmacokinet Pharmacodyn, 2005
To model the biotransformation steps of 5-FU production from capecitabine and identify patient ch... more To model the biotransformation steps of 5-FU production from capecitabine and identify patient characteristics that may influence the drug disposition. Blood samples and demographic data were collected from two phase I studies in which adult patients received oral capecitabine for various malignancies. Capecitabine, 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-deoxy-5-fluorocytidine (5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFCR), 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-deoxy-5-fluorouridine (5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFUR) and 5-fluorouracile (5-FU) concentration-time data were analysed via a population approach using NONMEM. Forty patients and 75 pharmacokinetic time-courses were available for analysis. Capecitabine pharmacokinetics was ascribed to a one compartment model from which 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFCR, 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFUR and 5-FU were sequentially produced. Capecitabine oral absorption was characterized by a rapid first order input (K(a)=2.1 +/- 0.3 hr(-1)) with a lag time (0.28 +/- 0.11 hr), but related inter-occasion (IOV) and inter-subject (ISV) variabilities for these parameters, 167% and 110%, indicated that this oral absorption was highly variable. The capecitabine CL (CL10 = 218+/- 18 L/hr, ISV = 18%) and 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-DFUR elimination rate constant (K34 = 5.3 +/- 2.0 hr(-1), ISV = 25%) were influenced by total bilirubin (BILT). The elimination rate constant of plasma 5-FU (K40) was 66 +/- 24 hr(-1) (ISV = 34%). The final pharmacokinetic model was validated using 2000 bootstrap runs and provided non-parametric statistics of the parameters (median, 2.5th and 97.5th percentiles). This study supported the possibility of modelling a complex sequential metabolic pathway which produces pharmacologicaly active compounds from a prodrug. Only BILT significantly influenced the pharmacokinetics but this effect was not considered as relevant for dosing adjustment.
Anti Cancer Drugs, Dec 1, 2003
Our aim was to develop a population pharmacokinetic model of ultrafilterable oxaliplatin in metas... more Our aim was to develop a population pharmacokinetic model of ultrafilterable oxaliplatin in metastatic cancer patients. Oxaliplatin was administered by 2- or 4-h infusions, 50, 65, 75, 85, 100 or 130 mg/m2 to 56 patients. Blood samples were collected over 28 h. Plasma concentrations of ultrafilterable oxaliplatin were determined by flameless atomic absorption spectrophotometry. Population pharmacokinetic analysis was performed using a non-linear mixed-effects modeling method. Ultrafilterable oxaliplatin concentration-time profiles showed a secondary peak or a shoulder aspect post-infusion, attributed to the existence of an enterohepatic recirculation (EHR). They were best described by a two-compartment model incorporating an EHR component. Plasma clearance (CL) was related positively to body weight (BW) and negatively to serum creatinine (SCr), and was greater in male patients than in female patients. This covariate modeling resulted in a decrease in the interindividual variability for CL from 104 to 62%. The central distribution volume (V1) and inter-compartmental clearance (Q) were related to BW. Typical population estimates of CL, central distribution volume (V1), input rate constant into gallbladder (k1B) and lag time for drug reabsorption (TLAG) were 14.1 or 8.5 l/h (male or female patients), 24.9 l, 1.8 h-1 and 2.0 h, respectively. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. We conclude that a two-compartment with EHR model adequately described ultrafilterable oxaliplatin pharmacokinetics, explaining a secondary transient increase in concentration. This study identified combined-covariate-effects ultrafilterable oxaliplatin clearance, supporting dose adjustment of oxaliplatin based on BW, gender and corrected for SCr level, if drug exposure is thought to be related to therapeutic or toxic issues.
European journal of rheumatology and inflammation
The binding of benoxaprofen to human serum albumin (HSA) was investigated by equilibrium dialysis... more The binding of benoxaprofen to human serum albumin (HSA) was investigated by equilibrium dialysis at pH 7.4 and 37 degrees C. As most acidic drugs, almost completely ionized at plasma pH, benoxaprofen was avidly bound to HSA (7.5 x 10(-6) M) with the following parameters: n1 = 3.3 and K1 = 325 x 10(3) M-1; n2 = 16.2 and K2 = 2.1 x 10(3) M-1 At normal HSA plasma concentration in humans benoxaprofen was more than 99.5% bound, either when a pure HSA solution or when a pooled serum was used. Such results were obtained within a wide range of benoxaprofen concentrations and benoxaprofen binding did not significantly differ whatever its concentration might be. The influence of liver failure on benoxaprofen serum binding was investigated in five patients whose bilirubinaemia was from 15 to 28 x 10(-6) M, and the results were compared to those of five normal volunteers. There was no difference between the two groups: 99.30 +/- 0.30% versus 99.62 +/- 0.30%. However, in four other patients whose bilirubinaemia was greater than 130 x 10(-6) M, the binding of benoxaprofen decreased to 98.0 +/- 1.6% (p] less than 0.05). Addition of FFA (palmitic acid, 2000 . 10(-6) M) to H SA (580 x 10(-6) M) involved a slight decrease in HSA binding of benoxaprofen: 99.8 +/- 0.1 versus 99.66 +/- 0.03%. Serum binding of benoxaprofen was not affected by therapeutic levels of tolbutamide, was slightly decreased from 99.7 to 9.2% by furosemide, to 99.4% by CPIB, and to 99.4% by salicylic acid. At the reverse, therapeutic plasma levels of benoxaprofen did not displace warfarin and acenocoumarol, but they displaced CPIB from 90.1 to 86.1%, glibenclamide from 95.2 to 94.2% and phenylbutazone 99.6 to 93.0%.
Molecular Pharmacology
The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lower... more The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lowering and water-insoluble drug, probucol, was investigated in in vitro studies. [14C]Probucol was incubated in whole human blood, a serum pool, individual diluted sera, and isolated protein and lipoprotein fractions. In whole blood, about 90% partitioned in plasma. Following ultracentrifugal fractionation of the serum, it was found that less than 5% distributed in the d greater than 1.20 protein fraction (albumin-rich fraction) and more than 95% in the lipoprotein fractions. The distribution of probucol in the lipoprotein fractions correlated with the lipoprotein total lipid volume under saturation conditions (incubation of isolated lipoprotein fractions) as well as nonsaturation conditions (fractionation of serum exposed to [14C]probucol). Incubation of the albumin-rich fraction and of apolipoproteins originating from the isolated lipoprotein fractions showed that they account for a negligible part in the interaction of probucol with blood components. The probucol uptake of individual sera was shown to be correlated to the lipid content of the serum. When probucol was incubated in erythrocyte suspensions containing variable amounts of lipoproteins, probucol partitioned less in erythrocytes as the lipoprotein concentration increased in the suspension.
Nouvelle revue française d'hématologie
International journal of clinical pharmacology, therapy, and toxicology
The binding parameters of valproic acid (VPA) to human serum albumin (HSA) were determined by equ... more The binding parameters of valproic acid (VPA) to human serum albumin (HSA) were determined by equilibrium dialysis and computed using non-linear regression. However unclassic, it was observed that the binding parameters of VPA varied according to the concentration of the HSA solutions used. At 580 microM HSA, VPA is bound to two classes of binding sites with the association constants K1 = 56000 M(-1) and K2 = 750 M(-1), and their respective numbers of binding sites n1 = 2 and n2 = 5. Free serum fraction of VPA is significantly increased by 500, 1000 and 1500 microM palmitate, 250 microM clofibrate, 320 microM phenylbutazone, or 360 microM salicylate. In any case, the increase of the VPA serum free fraction is highly correlated with the inhibitor concentration. On the other hand, the free serum fraction of warfarin is increased by 600 microM VPA (100 micrograms/ml). In patients with liver disease, the variations of the free serum fraction of VPA are correlated to the albumin and to the bilirubin concentrations. Serum binding of VPA is significantly decreased in the two groups of patients as compared with the control group.