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O Petitjean

Publications and source records attributed to O Petitjean.

At least 37 records · Page 2Linked to original sources
PubMed1998

Clinical pharmacokinetics of diacerein.

Diacerein is a drug for the treatment of patients with osteoarthritis. This drug is administered orally as 50 mg twice daily. Diacerein is entirely converted into rhein before reaching the systemic circulation. Rhein itself is either eliminated by the renal route (20%) or conjugated in the liver to rhein glucuronide (60%) and rhein sulfate (20%); these metabolites are mainly eliminated by the kidney. The pharmacokinetics characteristics of diacerein are about the same in young healthy volunteers and elderly people with normal renal function, both after a single dose (50 mg) or repeated doses (25 to 75 mg twice daily). Rhein kinetics after single oral doses of diacerein are linear in the range 50 to 200 mg. However, rhein kinetics are time-dependent, since the nonrenal clearance decreases with repeated doses. This results in a moderate increase in maximum plasma concentration, area under the plasma concentration-time curve and elimination half-life. Nevertheless, the steady-state is reached by the third administration and the mean elimination half-life is then around 7 to 8 hours. Taking diacerein with a standard meal delays systemic absorption, but is associated with a 25% increase in the amount absorbed. Mild-to-severe (Child Pugh's grade B to C) liver cirrhosis does not change the kinetics of diacerein, whereas mild-to-severe renal insufficiency (creatinine clearance < 2.4 L/h) is followed by accumulation of rhein which justifies a 50% reduction of the standard daily dosage. Rhein is highly bound to plasma proteins (about 99%), but this binding is not saturable so that no drug interactions are likely to occur, in contrast to those widely reported with nonsteroidal anti-inflammatory drugs. Except for moderate and transient digestive disturbances (soft stools, diarrhoea), diacerein is well tolerated and seems neither responsible for gastrointestinal bleeding nor for renal, liver or haematological toxicity.

Aged↗
PubMed1997

Implementation and evaluation of a stochastic control strategy for individualizing teicoplanin dosage regimen.

A stochastic control strategy for individualizing teicoplanin dosing schedule in neutropenic patients is proposed and compared to the usual Bayesian approach based on the mode of the posterior density of the model parameters. Teicoplanin disposition is described by a bicompartmental model. Age, body weight, serum creatinine, white blood cell count, and sex can be included as covariates. Posterior density of model parameters is obtained by Bayes theorem under a discrete form from which the posterior density of teicoplanin trough concentrations are computed for any dosing schedule. Optimal maintenance dose is determined by minimizing the cost associated, through a logarithmic risk function, to the concentrations being outside the therapeutic range. In Monte Carlo simulation studies on 300 individuals, stochastic control was more accurate than, and equally precise as the usual Bayesian approach. Two-sample based predictions were not better than one-sample based ones. Inclusion of covariates in the model improved dramatically the performances of both strategies. A small retrospective study based on real data (n = 16 patients) shows that reasonable accuracy (bias of 0.7 mg/L) and precision (3 mg/L) in teicoplanin trough concentration prediction is obtained with both strategies provided that covariates are taken into account.

Age Factors↗
PubMed1997

Cefepime and amikacin synergy against a cefotaxime-susceptible strain of Enterobacter cloacae in vitro and in vivo.

We developed an experimental model of pneumonia to evaluate the efficacy of new antibiotic regimens against Enterobacter cloacae. Rats were infected by administering 8.5 log10 cfu E. cloacae intratracheally, and therapy was initiated 24 h later. At that time, animals' lungs showed bilateral pneumonia containing more than 7 log10 cfu/g of tissue. Because rats eliminate amikacin and cefepime much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters in humans. Using this model, we compared the bactericidal activities of cefepime and amikacin alone or in combination against the same cefotaxime-susceptible E. cloacae strain. The MICs of cefepime and amikacin for this strain were 0.5 and 2 mg/L, respectively. In-vitro killing studies showed that antibiotic combinations were synergic only at intermediate concentrations. At peak concentrations, the combination was only as effective as amikacin alone. At trough concentrations, a non-significant trend towards the superiority of the combination over cefepime alone was found. In-vivo studies showed that each antibiotic alone failed to decrease bacterial counts in the lungs except at 6 h, whereas the combination of both antibiotics induced a significant decrease in the lung bacterial count 6, 12 and 24 h after the onset of therapy when compared with tissue bacterial numbers in untreated animals or animals treated with either antibiotic alone. In-vivo synergy between cefepime and amikacin was observed at the three time points studied. No resistant clones emerged during treatment with any of the antibiotic regimens studied.

Amikacin↗
PubMed1996

Monitoring of 8-methoxypsoralen during extracorporeal photochemotherapy: evidence for a "first-dose" effect.

Therapeutic monitoring of 8-methoxypsoralen (8-MOP) was studied in 12 patients (age range 43-85 years, weight range 48-76 kg) treated for Sezary's syndrome by extracorporeal photochemotherapy (ECP) for 14-41 months. Before the beginning of each ECP cycle (2 sessions on consecutive days at about 4-week intervals), a blood sample was drawn to determine the 8-MOP plasma concentration 2 h after drug ingestion. Plasma 8-MOP levels were measured using a high-performance liquid chromatography method with spectrophotometric detection. Monitoring parameters (dose, 2-h plasma 8-MOP concentration) showed important interindividual and intraindividual variations. The 8-MOP dose ranged from 0.57 to 1.04 mg/kg. Intraindividual variations of 2-h 8-MOP levels ranged from 21% to 75%. Of the 652 measurements, 13% were < 100 ng/ml, the therapeutic threshold for effective ECP; in three of the seven patients, increasing the dose obtained levels exceeding the therapeutic threshold, i.e, the absorption was not saturable. Orthogonal regression analysis between plasma 8-MOP concentrations measured in two consecutive ECP sessions showed a first-dose effect: the 2-h plasma 8-MOP concentration was significantly lower after the first administration than after the second (approximately 1.26-fold). Because 8-MOP has been proven to be a potent suicide inhibitor of drug metabolism in rats and humans, it is possible that 8-MOP had an inhibitory effect on its own metabolism within the therapeutic dose range for ECP, which would explain in part the inter- and intraindividual variability in 8-MOP kinetics and first-dose effect.

Adult↗
PubMed1996

Influence of experimental rat model of multiple organ dysfunction on cefepime and amikacin pharmacokinetics.

We adapted an experimental model of multiple organ dysfunction to study the alterations it induces in the pharmacology of cefepime and amikacin. The half-lives of both antibiotics were significantly prolonged because of nonsignificant enhancement of the volume of distribution and reduced renal elimination. In the presence of multiple organ dysfunction, the concentration of each antibiotic in the lungs, compared with that in the lungs of healthy controls, was significantly decreased, despite similar concentrations in plasma, indicating that the application of a standard antibiotic concentration in plasma could lead to underdosage in tissues during the initial days of therapy.

Amikacin↗
PubMed1996

Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats.

The pharmacokinetic interaction between cefdinir and an angiotensin-converting enzyme inhibitor (captopril or quinapril) was investigated in rats. The linearity of cefdinir pharmacokinetics was demonstrated in three groups of rats receiving 10, 20, or 40 mg of cefdinir per kg of body weight intravenously. Then, three other groups of rats were established as follows: group 1 (n = 5) received cefdinir (10 mg/kg) intravenously, and 12 blood samples per rat were drawn between 0 and 8 h after injection of the dose; group 2 (n = 5) was treated in the same way as group 1, but captopril (0.8 mg/kg) was coadministered by intraintestinal injection into all animals; group 3 (n = 6) was treated in the same way as group 2, but quinapril (0.8 mg/kg) replaced captopril. Plasma cefdinir concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method. Finally, three groups of four or five rats each were set up as described above, but the cefdinir dose was 20 mg/kg and the animals were sacrificed 1 h after drug injection to collect blood to determine the unbound cefdinir fraction (fu) by ultrafiltration. The angiotensin-converting enzyme inhibitors increased the mean cefdinir area under the concentration-time curve up to 8 h by a factor of 1.8 (captopril; P < 0.05) and a factor of 3.5 (quinapril; P < 0.05). With captopril, mean cefdinir clearance was decreased by a factor of 2, and the volume of distribution increased by the same factor, while the fu increased from 15.4% +/- 3.0% (cefdinir alone) to 22.8% +/- 10.9% (cefdinir plus captopril). Captopril increased the cefdinir half-life from 0.62 +/- 0.17 to 2.92 +/- 0.95 h. With quinapril, the interaction was so strong that no elimination phase was detectable in four of the six rats, and therefore, no pharmacokinetic parameter values other than the cefdinir fu could be calculated; the cefdinir fu increased to 25.1% +/- 11.1%. It is concluded that captopril and quinapril (and/or their metabolites) have a major impact on the disposition of cefdinir in rats, probably by competition at the plasma protein-binding level and at the tubular anionic carrier level. This latter mechanism should also be relevant in humans.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Population pharmacokinetic study of isepamicin with intensive care unit patients.

The pharmacokinetics (PK) of isepamicin, a new aminoglycoside, were studied in 85 intensive care unit (ICU) patients and were compared with those observed in 10 healthy volunteers. A parametric method based on a nonlinear mixed-effect model was used to assess population PK. Isepamicin was given intravenously over 0.5 h at dosages of 15 mg/kg once daily or 7.5 mg/kg twice daily. The data were fitted to a bicompartmental open model. Compared with healthy volunteers, the mean values of the PK parameters were profoundly modified in ICU patients: elimination clearance was reduced by 48%, the volume of distribution in the central compartment (Vc) was increased by 50%, the peripheral volume of distribution was 70% higher, the distribution clearance was 146% lower, and the elimination half-life was ca. 3.4 times higher. The interindividual variability in PK parameters was about 50% in ICU patients. Five covariates (body weight [BW], simplified acute physiology score [SAPS], temperature, serum creatinine level, and creatinine clearance [CLCR]) were tentatively correlated with PK parameters by multivariate linear regression analysis with stepwise addition and deletion. The variability of isepamicin clearance was explained by three covariates (BW, SAPS, and CLCR), that of Vc was explained by BW and SAPS, and that of the elimination half-life was explained by CLCR and SAPS. Simulation of the concentration-versus-time profile for 500 individuals showed that the mean peak (0.75 h) concentration was 18% lower in ICU patients than in healthy volunteers and that the range in ICU patients was very broad (28.4 to 95.4 mg/liter). Therefore, monitoring of the isepamicin concentration is in ICU patients is mandatory.

Adult↗
PubMed1996

Population pharmacokinetic study of teicoplanin in severely neutropenic patients.

The teicoplanin pharmacokinetics (PK) of 30 febrile and severely neutropenic patients (polymorphonuclear count, < 500/mm3) with hematologic malignancies were compared with those determined for five healthy volunteers (HV). Neutropenic patients were given piperacillin combined with amikacin, and teicoplanin was added to the regimen the day fever developed in patients suspected of having a staphylococcal infection or 48 h later. Teicoplanin was given intravenously at a dosage of 6 mg/kg of body weight at 0, 12, and 24 h and once a day thereafter. Five to eleven blood samples per patient were collected. Teicoplanin concentrations were measured by liquid chromatography. A bicompartmental model was fitted to the data by a nonlinear mixed-effect-model approach. Multiple-linear regression analysis was applied in an attempt to correlate PK parameters to nine covariates. The mean trough concentrations of teicoplanin 48 h after the onset of treatment and 24 h after the last injection (last trough) +/- standard deviations were 8.8 +/- 4.1 and 17.5 +/- 13.5 mg/liter, respectively. A significant increase was noted in the mean rate of elimination clearance of teicoplanin in neutropenic patients compared with that of HV (0.86 versus 0.73 liter/h, P = 0.002), as was the case with rates of distribution clearance (5.89 versus 4.94 liter/h, P = 0.002); the mean half-life of distribution was significantly shorter in patients than in HV (0.43 versus 0.61 h, P = 0.002). In contrast, the volumes of the central compartment (ca. 5.8 liters for both groups), the volumes of distribution at steady state (HV, 37.6 liters; patients, 55.9 liters), and the elimination half-lives (HV, 39.6 h; patients, 52.7 h) were not significantly different between HV and neutropenic patients. Interindividual variabilities of rates of clearance (coefficient of variation [CV], 43%) and elimination half-lives (CV, 56%) were mainly explained by the variabilities among rates of creatinine clearance. Interindividual variabilities of the volumes of the central compartment (CV, 33%) and the volumes of distribution at steady state (CV = 51%) were correlated to interindividual variabilities among numbers of leukocytes and the ages of patients, respectively. On the basis of the population PK model of teicoplanin, simulations were made to optimize the dosing schedule. A supplemental 6 mg/kg dose of teicoplanin at 36 h resulted in a trough concentration at 48 h of 16.0 +/- 4.5 mg/liter, with only 7% of patients having a trough concentration of less than 10 mg/liter, compared with 46% of patients on the usual schedule.

Adult↗
PubMed1995

Determination of piracetam in human plasma and urine by liquid chromatography.

A method for the determination of piracetam in human plasma and urine by liquid chromatography with absorbance detection at 206 nm and isocratic elution is proposed. The assay involved a liquid-liquid extraction into hexane-2-propanol at pH 9.2. The calibration graphs were linear in the range 3-40 mg/l in plasma and 100-2000 mg/l in urine. Bias was negligible and coefficients of variation were less than 10% throughout the working range except at 100 mg/l in urine. The limits of quantification were 3 mg/l in plasma and 100 mg/l in urine. The assay was reliably used for pharmacokinetic studies in humans after administration of 800 mg of piracetam per os.

Chromatography, High Pressure Liquid↗
PubMed1995

Pharmacokinetics of amoxicillin coadministered with a saline-polyethylene glycol solution in healthy volunteers.

The pharmacokinetics of orally administered amoxicillin were investigated in 12 healthy volunteers in a crossover design. They received either a placebo or a saline-polyethylene glycol solution (SPG) for 4 d, the last dose being given simultaneously with 1 g amoxicillin; blood samples were drawn for the next 12 h. Amoxicillin kinetics were similar in the two treatments but small differences in some pharmacokinetic parameters reached significance. The mean +/- SD area under the curve was lower with SPG (43.8 +/- 6.8 against 47.8 +/- 8.2 mg h L-1, p < 0.05) but the treatments were equivalent according to Westlake's test (95% confidence interval = 14.95%). Analysis of SPG against placebo amoxicillin absorption kinetics after fitting the data to a Weibull model revealed a longer duration of the absorption, a slower rate of absorption, and a different shape of the curve. No clinical consequences are expected from these minor variations but possible mechanisms could be relevant to other drugs.

Adult↗
PubMed1995

A population pharmacokinetic study of alminoprofen penetration into synovial fluid.

The pharmacokinetics of alminoprofen in plasma and synovial fluid (SF) at steady state (300 mg t.i.d.) was studied in 45 patients with knee effusion. Plasma and SF samples, one each per patient, were obtained. Six groups were made according to the time of sampling after ingestion of the 13th dose: 1 h (n = 7), 2 h (n = 7), 4 h (n = 7), 6 h (n = 10), 8 h (n = 6), 12 h (n = 8). A three-compartment model was used to describe alminoprofen kinetics in plasma and SF, with two parameterizations, a 'classical' and a 'physiological' one. The non-linear mixed effect model approach was used to estimate the mean and variance of the pharmacokinetic parameters. The mean +/- SE of the estimates (coefficient of variation of interindividual variability as a percentage) were volume of distribution, 11.0 +/- 1.711 (12%); elimination rate constant, 0.236 +/- 0.025 h-1 (18%); absorption rate constant 2.80 +/- 0.31 h-1 (464%), clearance of influx into SF, 0.29 +/- 0.14 mL min-1; clearance of efflux into plasma, 0.56 +/- 0.25 mL min-1. These two clearances were not significantly different, which indicates that passive diffusion occurs in both directions. The mean +/- SD alminoprofen concentration versus time curve in plasma and SF at steady state was simulated and showed that the mean +/- SD maximal concentration in SF was 8.1 +/- 6.3 mg L-1 and was obtained 4 h after dose administration.

Absorption↗
PubMed1995

Influence of methodological aspects on tissue drug concentration estimation.

Fundamental studies in tissue drug extraction have been made using rokitamycin as a test probe. Radiolabelled rokitamycin was administered intravenously to 12 rats. Lungs and femurs were excised a few minutes later. Rokitamycin was extracted from lungs using six procedures (based either on ion-pairing, dissolution or deproteinization) whose performances (mean recovery and reproducibility) were compared. Three grinding procedures were also compared for the extraction of rokitamycin from bone: pulverization by a magnetic stirring bar in a liquid nitrogen bath, slicing into small pieces and crushing with pestle and mortar. The effect of binding proteins (albumin or alpha 1-acid glycoprotein) in the extraction mixture was also evaluated. Magnetic stirring bar grinding was the most efficient. Deproteinization was necessary to obtain the highest recovery, but the agent had to be chosen carefully. Binding proteins either had no effect or decreased the recovery of rokitamycin. Recovery from bone was lower than that from lung. Binding to cellular components in the post-extraction pellet was only 3% (lung) and 9% (bone). It is concluded that a careful optimization of the extraction procedure of a drug from a tissue allows quantitative and reproducible measurement of its concentration.

Animals↗
PubMed1995

Aminoglycosides.

Despite their nephrotoxic and ototoxic side effects, AG remain useful antibiotics because of their major, rapid, and dose-dependent bactericidal effects. Combination therapy with an AG appears particularly important in neutropenic and other high-risk patients to provide broad-spectrum bactericidal activity, synergism, and reduction of emergence of resistant pathogens. OD AG therapy is associated with high peak levels in serum that maintain efficacy and low-to-undetectable trough levels in serum that attenuate the risk of toxicity. Administration of short-term OD AG therapy to patients not at risk without renal impairment may not absolutely require dosing monitoring. This therapeutic strategy has been proved useful in clinical trials, now including febrile episodes in neutropenic patients, but it should be avoided during infections in which antimicrobial synergism is required, such as enterococcal endocarditis.

Aminoglycosides↗
PubMed1995

Fluconazole penetration in cerebral parenchyma in humans at steady state.

We studied fluconazole penetration in the brain in five patients who had a deep cerebral tumor whose removal required the excision of healthy brain tissue. Plasma and brain samples were simultaneously obtained after oral ingestion of 400 mg of fluconazole daily for 4 days (90% of steady state). Fluconazole penetration in healthy cerebral parenchyma was determined. Plasma and brain samples were assayed by high-pressure liquid chromatography. Concentrations in plasma and brain tissue were 13.5 +/- 5.5 micrograms/ml and 17.6 +/- 6.6 micrograms/g, respectively. The average ratio of concentrations in the brain and plasma (four patients) was 1.33 (range, 0.70 to 2.39). Despite the lack of data concerning the penetration of fluconazole in brain abscesses, these results should permit the use of a daily dose of 400 mg of fluconazole in prospective clinical studies that evaluate the effectiveness of this drug in the treatment of brain abscesses due to susceptible species of fungi.

Adult↗
PubMed1995

Time- and dose-dependent kinetics of all-trans-retinoic acid in rats after oral or intravenous administration(s).

The kinetics of all-trans-retinoic (RA) acid are known to be nonlinear. To clarify the mechanisms involved, RA kinetics were determined in four groups of rats: group 1 received a single 2-mg RA dose intravenously (N = 5); group 2 received the same treatment as group 1 after 12 days of oral RA (2 mg/day) (N = 6); group 3 received a single, oral 2-mg (N = 6) or 5-mg RA dose (N = 6); and group 4 (N = 5 + 3) received the same treatment as group 3 after 12 days of oral RA (2 mg/day). Blood samples, 10-12/animal, were taken during the 7 hr following the final dosage. Plasma RA concentrations were determined by liquid chromatography. Noncompartmental analysis showed that RA disposition after intravenous bolus dosing obeyed Michaelis-Menten (MM) kinetics in group 1 (no pretreatment) and linear kinetics in group 2 (pretreated), with a lower area under the concentration vs. time curve, which suggested time-dependent kinetics with autoinduction. The same autoinduction phenomenon was observed after oral dosing in groups 3 and 4. Moreover, the mean area under the concentration vs. time curve was not higher after 5 mg dosing than after 2 mg dosing, which indicated a saturable mechanism of absorption. Fitting the data to a three-compartment model with saturable absorption and elimination kinetics confirmed the autoinduction of RA elimination (maximal velocity of elimination = 3330 vs. 541 micrograms/hr, p = 0.006, MM constant KMe = 7.53 vs. 1.10 micrograms/ml, p = 0.006) after 12 days RA administration, and an MM absorption mechanism resulting in a saturable absorption (bioavailability F = 0.58 at 2 mg vs. 0.25 at 5 mg, group 3) that decreased after 12 days of RA treatment: the maximal velocity of absorption decreased from 1632 (group 3) to 631 micrograms/hr (group 4) (p = 0.02). The volume of distribution also decreased after pretreatment, which indicated a modification in tissular distribution (565 vs. 358 ml, p < 0.001, group 3 vs. 4).

Absorption↗
PubMed1994

The penetration of amphotericin B from an Intralipid formulation into fibrin loci in a rabbit model of candidiasis.

The kinetics of amphotericin B (AMB) concentrations in plasma and interstitial fluid were studied in an experimental model of Candida albicans infection in rabbits. Rabbits were infected by subcutaneously implanted fibrin clots containing the yeast. Three groups of five rabbits received a 4 mg kg-1 AMB infusion. AMB (Fungizone) was dissolved in 5% glucose (group I) or in 20% Intralipid at a final concentration of 1.5 (group II) or 3 mg mL-1 (group III). AMB was measured by liquid chromatography in plasma and in trypsin-dissolved fibrin clots up to 72 h after the infusion. No significant differences in AMB plasma and interstitial-fluid concentration kinetics between the three modes of administration were found. AMB penetration into fibrin clots was slow, with no significant differences between treatments. Thus, formulation of AMB in Intralipid does not modify either the drug's interstitial or plasma kinetics at equivalent doses.

Amphotericin B↗
PubMed1994

Application of optimal sampling theory to the determination of metacycline pharmacokinetic parameters: effect of model misspecification.

Use of optimal sampling theory (OST) in pharmacokinetic studies allows the number of sampling times to be greatly reduced without loss in parameter estimation precision. OST has been applied to the determination of the bioavailability parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (Tmax), elimination half-life (T1/2), of metacycline in 16 healthy volunteers. Five different models were used to fit the data and to define the optimal sampling times: one-compartment first-order, two-compartment first-order, two-compartment zero-order, two-compartment with Michaelis-Menten absorption kinetics, and a stochastic model. The adequacy of these models was first evaluated in a 6-subject pilot study. Only the stochastic model with zero-order absorption kinetics was adequate. Then, bioavailability parameters were estimated in a group of 16 subjects by means of noncompartmental analysis (with 19 samples per subject) using each optimal sampling schedule based procedure (with 6 to 9 samples depending on the model). Bias (PE) and precision (RMSE) of each bioavailability parameter estimation were calculated by reference to noncompartmental analysis, and were satisfactory for the 3 adequate models. The most relevant criteria for discrimination of the best model were the coefficient of determination, the standard deviation, and the mean residual error vs. time plot. Additional criteria were the number of required sampling times and the coefficient of variation of the estimates. In this context, the stochastic model was superior and yielded very good estimates of the bioavailability parameters with only 8 samples per subject.

Adult↗