Evaluation of MPA and MPAG removal by continuous venovenous hemodiafiltration and continuous venovenous hemofiltration.

The study assessed the removal of mycophenolic acid (MPA) and its major glucuronide metabolite (MPAG) during continuous venovenous hemofiltration (CVVHF) and continuous venovenous hemodiafiltration (CVVHDF) in 4 heart transplant recipients treated for at least 6 days with mycophenolate mofetil (MMF) in addition to cyclosporine and corticosteroids. The sieving coefficient ranged from 0.02 to 0.04 for MPA and from 0.15 to 0.33 for MPAG. The clearance of MPAG by CVVHDF or CVVHF ranged from 7.52 mL/min to 19.45 mL/min, and that of MPA was lower than 2.28 mL/min, with no significant difference between the two continuous replacement therapies. Whereas MPA percentage recovered by hour following CVVHDF or CVVHF was negligible, the percentage of MPAG represents up to 12.9% of the administered dose. A relevant decrease in the free fraction of MPA and MPAG was observed after continuous renal replacement therapy (CRRT). These preliminary results demonstrate that MPAG is able to permeate the filter. In light of the alteration in protein binding following CRRT and the competition between MPA and MPAG to albumin site, drug monitoring of MPA and MPAG in patients undergoing CVVHDF or CVVHF may be suggested. Moreover, monitoring of free MPA may be of interest for these patients.

Relationship between MPA free fraction and free MPAG concentrations in heart transplant recipients based on simultaneous HPLC quantification of the target compounds in human plasma.

A simple and sensitive HPLC method for the simultaneous analysis of free MPA and free MPAG was developed. Separation was achieved on a X-Terra RP18 column with acetonitrile-40 mM orthophosphoric acid as eluents using a gradient elution mode over 35 min at a flow rate of 1.5 ml/min. The assay was linear in the range 0.005 mg/L (LOQ) to 5mg/L for free MPA and 0.05 mg/L (LOQ) to 200 mg/L for free MPAG. Isolation of free MPA and free MPAG was done by ultrafiltration and the ultrafiltrate was directly injected. A positive correlation between MPA free fractions and free MPAG concentrations was found. Likewise, free MPAG was related to total MPAG concentrations in the seven heart transplant patients.

A limited sampling strategy for estimating individual pharmacokinetic parameters of coagulation factor VIII in patients with hemophilia A.

Therapeutic drug monitoring of factor VIII is well established in the treatment of patients with hemophilia attributable to important interindividual variability. The individual initial factor VIII dosage is usually calculated according to individual pharmacokinetic parameters obtained after a dose test administered before the surgery, using at least five-concentration data. The authors proposed a limited sampling strategy to estimate individual pharmacokinetic parameters from one- or two-concentration data in patients with hemophilia A before surgery. The mean population pharmacokinetic parameters and the interindividual variability (CV) were obtained from a group of 33 patients according to a two-compartment model using NONMEM. Eighteen additional patients were used to estimate the predictive performances of the population parameters and to evaluate the limited sampling strategies. Population parameters were clearance 2.6 mL/h per kilogram (CV 45.4%), initial volume of distribution 2.8 L (CV 21.1%). From two sampling times (0.5 and 6 hours or 0.5 and 8 hours after the end of infusion), the estimation of pharmacokinetic parameters was precise and not biased. Until now, in the hemophilic center of Lyon, the factor VIII dosage before surgery was based on the determination of the clearance, estimated from five- to nine-concentration data and on the target concentration (infusion rate = clearance x target). Ruffo et al proposed a limited sampling strategy (two-stage method) to estimate pharmacokinetic parameters from two concentration measurements drawn 3 and 9 hours after the dose. No information was given on the bias and precision of the estimation. This paper reports a one-stage method for a population pharmacokinetic study of factor VIII. The Bayesian estimation of individual pharmacokinetic parameters based on only two sampling times (0.5 and 6 hours or 0.5 and 8 hours after the end of infusion) is useful to define the best factor VIII dosage in hemophilic patients before surgery.

A rapid and simple HPLC method for the analysis of propofol in biological fluids.

A selective and sensitive high-performance liquid chromatographic method for the analysis of propofol in biological samples was developed. Propofol and thymol (internal standard) were analysed on a Purospher RP-18 endcapped (75 mmx4 mm, 3 microm) stationary phase using acetonitrile and water (65:35, v/v) as eluents at a flow rate of 0.6 mL/min. The excitation and emission wavelengths were 276 and 310 nm, respectively. Sample treatment consisted of deproteinization by acetonitrile containing the internal standard and direct injection of the supernatant. Mean analytical recovery were 105% (CV 2.0%) at concentrations ranging from 0.05 to 10 mg/L. The quantification limit was 3 ng/mL for a 500 microL sample plasma volume and 5 ng/mL for a 500 microL blood sample. The intra-day and inter-day precisions were lower than 5.5% for three concentrations assessed (0.05, 1.0 and 10.0 mg/L). Considering the column size and the flow rate, the separation was achieved with an analysis time less than 6 min with a reduced consumption of solvent. This rapid HPLC method using a simple treatment procedure is sensitive enough for monitoring propofol in human biological samples.