Biomedical subjects

Stéphane Corvaisier

Publications and source records attributed to Stéphane Corvaisier.

5 recordsLinked to original sources

PubMed2004

Population pharmacokinetics of pyrimethamine and sulfadoxine in children treated for congenital toxoplasmosis.

The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis. A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling. PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months. Drug concentrations were measured by high-performance liquid chromatography. A total of 101 measurements in serum were available for both drugs. Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h(-1), 4.379 liters/kg, 0.00839 h(-1), and 5.5 days for PYR and 1.659 h(-1), 0.392 liters/kg, 0.00526 h(-1), and 6.6 days for SDX, respectively. Wide interindividual variability was observed. The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively. Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children. Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight. The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established. A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children.

Antiprotozoal Agents↗

PubMed2003

Aminoglycoside nephrotoxicity: modeling, simulation, and control.

The main constraints on the administration of aminoglycosides are the risks of nephrotoxicity and ototoxicity, which can lead to acute, renal, vestibular, and auditory toxicities. In the present study we focused on nephrotoxicity. No reliable predictor of nephrotoxicity has been found to date. We have developed a deterministic model which describes the pharmacokinetic behavior of aminoglycosides (with a two-compartment model), the kinetics of aminoglycoside accumulation in the renal cortex, the effects of aminoglycosides on renal cells, the resulting effects on renal function by tubuloglomerular feedback, and the resulting effects on serum creatinine concentrations. The pharmacokinetic parameter values were estimated by use of the NPEM program. The estimated pharmacodynamic parameter values were obtained after minimization of the least-squares objective function between the measured and the calculated serum creatinine concentrations. A simulation program assessed the influences of the dosage regimens on the occurrence of nephrotoxicity. We have also demonstrated the relevancy of modeling of the circadian rhythm of the renal function. We have shown the ability of the model to fit with 49 observed serum creatinine concentrations for a group of eight patients treated for endocarditis by comparison with 49 calculated serum creatinine concentrations (r(2) = 0.988; P < 0.001). We have found that for the same daily dose, the nephrotoxicity observed with a thrice-daily administration schedule appears more rapidly, induces a greater decrease in renal function, and is more prolonged than those that occur with less frequent administration schedules (for example, once-daily administration). Moreover, for once-daily administration, we have demonstrated that the time of day of administration can influence the incidence of aminoglycoside nephrotoxicity. The lowest level of nephrotoxicity was observed when aminoglycosides were administered at 1:30 p.m. Clinical application of this model might make it possible to adjust aminoglycoside dosage regimens by taking into account both the efficacies and toxicities of the drugs.

Adult↗

PubMed2003

Aminoglycoside dosages and nephrotoxicity: quantitative relationships.

OBJECTIVE: To develop a model that relates the probability of occurrence of nephrotoxicity to the cumulative area under the curve (AUC) of amikacin serum concentration. DESIGN AND PATIENTS: This was a retrospective study of two groups of patients in whom nephrotoxicity was observed after administration of amikacin. The first group consisted of patients treated with once-daily administration (ODA) [n = 13]. The second group consisted of patients treated with twice-daily administration (TDA) [n = 22]. MAIN OUTCOME MEASURES: The probability of nephrotoxicity occurrence. RESULTS: The model is a powerful tool to represent and describe the influence of the dosage regimen on aminoglycoside nephrotoxicity. The onset of nephrotoxicity is delayed in the ODA group (p = 0.01) for the same total daily dose among the two groups. The cumulative serum AUC values at onset of nephrotoxicity were greater for the ODA group (p = 0.029). In addition, for the same probability of nephrotoxicity occurrence (50%), the cumulative AUC for the ODA dosage regimen is 2 613 mg. h/L versus only 1 521 mg. h/L for the TDA dosage regimen. The difference in nephrotoxicity between ODA and TDA is greatest for a cumulative AUC of 2 495 mg. h/L, which corresponds to standard therapy with amikacin 900 mg/day during a 7-day period, i.e. 15 mg/kg/day for a 60kg patient with normal renal function (initial creatinine clearance >80 mL/min). For an AUC above 2 495 mg. h/L, the difference in nephrotoxicity decreases slowly to zero. This result means that ODA is especially justified when the treatment is administered over a short duration, i.e. less than 7 days. CONCLUSIONS: The utility of selecting ODA in order to obtain less nephrotoxicity in comparison with TDA is therefore not established when the treatment is prolonged. In clinical use, the choice of the dosage regimen is not clear-cut, and both expected efficacy and expected toxicity must be taken into account in order to obtain an overall optimisation of each patient's therapy.

Amikacin↗

PubMed2003

[Clinical trials and outpatient dispensation: the pharmaceutical counseling place].

Drug dispensations in clinical trials essentially concern outpatients (90%), and several mistakes and bad uses have been noted. The aim of this work is to set up a pharmaceutical counselling for outpatients in clinical trials. The bibliographic research on this subject did not learn us about similar experiences, but several references helped us to select the support of information: personal meeting between patient and pharmacist to introduce a written leaflet. Pharmaceutical information mentioned in the leaflet has to be validated and has to respect the clinical trials regulations. In the same way, information does not interfere with the inclusion-exclusion criteria or with the physician's observations. Then, information has been deliberately limited to the practical aspects of medications. Anonymous questionnaires have been delivered to the thirty first patients concerned to value their satisfaction with our services. The need of a clear and practical pharmaceutical counselling in clinical trials has been clearly established. Such a pharmaceutical counselling in clinical trials is one component of the overall drug-use process and potentially increases drug compliance. This pharmaceutical counselling on drug management has been well accepted by patients and has been supported by physicians and clinical trial sponsors.

Clinical Trials as Topic↗

PubMedDate not supplied

[Evaluation of drug cost reduction resulting from the free supply of investigational drugs].

Excluding all other costs or benefits of participation in clinical trials, the objective of this study was to evaluate and analyse the cost avoidance represented by the free supply of the investigational drug in place of paying for a marketed drug. The cost avoided was defined as money that would most likely have been spent, but not because of inclusion of the patient in the clinical study. Only studies for which a marketed alternative drug was available with a standard dosage have been analysed. The numbers of delivered doses or the treatment durations were tabulated from pharmacy dispensing records for each study, and were used to calculate the medication cost avoided. No marketed alternative drug was available for 10 of 56 clinical studies. In total, in 2000, the cost avoidance was estimated between [symbol: see text] 585,492 and [symbol: see text] 603,674, with a wide variability between studies or between patients (CV: 120-520%). The two disease categories associated with the largest cost avoidance were multiple sclerosis and growth hormone deficiency. The cost avoidance was essentially of benefit to the medical insurance or the patient (98%) and was lower than [symbol: see text] 10,000 for the hospital, because 91% of patients are not hospitalised. So, why are clinical studies involving ambulatory patients performed in hospital? Of the 56 studies analysed, 46 could be shown to be non-innovative, because a marketed alternative drug was available. Few studies appeared to permit free access to treatment with non-reimbursable marketed drugs.

Adult↗