Concentrations of (-)-zopiclone and (+)-zopiclone were determined in plasma and brain after oral administration, to investigate the stereoselectivity of distribution in rats. Zopiclone enantiomers were administered separately to rats and concentrations were determined by chiral HPLC in plasma and brain. In initial experiments, rats were treated with urethane before cannulation for blood sampling but as this drug modified zopiclone pharmacokinetics, it was not used in subsequent studies. This study showed that zopiclone pharmacokinetics after oral gavage in rats are stereoselective. After oral administration of (+)-zopiclone, no stereoconversion was observed in plasma. Conversely, after administration of (-)-zopiclone, both enantiomers were found in plasma and brain with (+)-zopiclone/(-)-zopiclone ratios of 1 and 8.4 in plasma and brain, respectively. Our findings suggest that zopiclone undergoes stereoconversion and that it is stereospecifically distributed to the brain.

No abstract

OBJECTIVE: To study the pharmacokinetic parameters of a once-daily regimen of amikacin (15 mg/kg) in association with other antimicrobial agents in 35 children with severe Gram-negative infections. METHODS: A Bayesian approach was developed to optimize the amikacin regimen. The predictive performance was assessed by computing bias and precision. Each patient was evaluated for toxicity after 5 days of treatment. RESULTS: Peak amikacin concentrations on days 2 and 5 of therapy averaged 31.3 plus minus 9.0 mg/L and 32.4 plus minus 7.4 mg/L, respectively. To achieve peak serum concentrations between 30 and 40 mg/L, individualized dosage was necessary in 19 of 35 children. The pharmacokinetic parameters showed large interindividual variations, with a mean half-life of 2 h and a mean volume of distribution of 0.36 L/kg. No nephrotoxicity was observed in any of the children. After individualization of dosage on the basis of one measurement of peak concentration, no significant differences were observed between predicted and subsequently measured amikacin concentrations. CONCLUSIONS: Once-daily dosage of amikacin (15 mg/kg) is well tolerated in pediatric patients; however, a loading dose of 20 mg/kg is recommended to achieve a therapeutic peak value between 30 and 40 mg/L. Initial serum monitoring is essential in a population such as children, with wide interpatient variability. Using the Bayesian approach, the amikacin regimen in children can then be predicted with minimal bias and good precision.

Objective:To study the elimination of teicoplanin during plasma exchange, a procedure currently used to treat a variety of disorders involving immune complexes. Teicoplanin is a glycopeptide antibiotic that exhibits a long terminal half-life (100-150 h) and is highly bound t o plasma proteins (unbound fraction (f,)=0.2).Methods: Twelve adults with systemic polyarteritis nodosa, cryoglobulinemia-induced vasculitis or dysglobulinemic neuropathy undergoing plasma exchange were studied. Each patient received intravenous teicoplanin, 6 mg/kg body weight, immediately before plasma exchange. Plasma was assayed for teicoplanin by high-pressure liquid chromatography.Results: A high level of protein binding of teicoplanin was measured within this patient population (98%). The mean quantity of teicoplanin eliminated (2SD) was 74.6234.6 mg. The mean drug fraction eliminated by plasma exchange (?SD) was 19.5?5.6%. Mean fu value as determined by ultrafiltration (2SD) was 2.221.7%. Conclusions:These results show that plasma exchange influences teicoplanin pharmacokinetics, with a clinically significant quantity being eliminated. If trough teicoplanin concentrations of around 10 mg/L are desired, it is recommended that teicoplanin dosage be supplemented or given after plasma exchange.level of 20-25 mg/L is recommended [6]. When teicoplanin levels are measured by microbial assay, the optimal range is 25% higher (manufacturer's recom-213

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.