Biomedical subjects

Florent Rougier

Publications and source records attributed to Florent Rougier.

2 recordsLinked to original sources

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↗