Biomedical subjects

M Tod

Publications and source records attributed to M Tod.

77 records · Page 5Linked to original sources

PubMedDate not supplied

Pharmacokinetics of cyclophosphamide (CP) and 4-OH-CP/aldophosphamide in systemic vasculitis.

Cyclophosphamide given in association with corticosteroids has markedly improved the prognosis of systemic vasculitis. Little information has been reported on cyclophosphamide pharmacokinetics in these diseases and data evaluating its metabolite, 4-hydroxycyclophosphamide/aldophosphamide, pharmacokinetics and concentrations are lacking. Cyclophosphamide was administered as a 1-h intravenous infusion every 3 weeks for six cycles to ten vasculitis patients. Serum cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide concentrations were assayed on the first cycle of the treatment by reversed-phase high-pressure liquid chromatography with ultraviolet detection. The mean (+/- SD) 4-hydroxycyclophosphamide/aldophosphamide and cyclophosphamide areas under the serum concentration-time curves were, respectively, 1.86 +/- 1.12 and 154.1 +/- 62.7 mg/L x h with a ratio of 1.30 +/- 0.76%. The mean maximum serum 4-hydroxycyclophosphamide/aldophosphamide was reached 2.3 h after cyclophosphamide administration. The mean (+/- SD) cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide half-lives were, respectively, 5.5 +/- 3.1 and 7.6 +/- 2.3 h. The results are consistent with those obtained for cancer patients, in spite of a wide interpatient variability of concentrations and pharmacokinetic parameters.

Adult↗

PubMedDate not supplied

Clinical pharmacokinetics during plasma exchange.

Drug removal during plasma exchange (PE) is a complex phenomenon that is defined by the molecule pharmacokinetic characteristics. Plasma-protein binding and the volume of distribution (Vd) are two kinetic parameters that strongly affect the efficiency of drug removal by PE. The effect of PE on drug kinetics has been specifically studied with antivirals, cardiotonic agents, antibiotics, corticosteroids, antalgics, anti-epileptic agents and non-steroidal anti-inflammatory drugs. This effect can be evaluated using different parameters: extracorporeal clearance, half-life, amount eliminated, and fraction of the drug removed. The estimated fraction eliminated (Fe) from the body by PE is the best parameter to evaluate the effectiveness of the exchange procedure; it can account for 0.5-30 per cent. Results reported in the literature showed that PE most influences drugs with a low Vd, regardless of the extent of protein binding. We established that, during PE, there is a linear relationship between Fe and the fraction of the drug in extracellular fluids. The fraction eliminated during PE is approximately one-seventh of the fraction of the drug in extracellular fluids. We propose to use this extracellular fraction as a predictive index: when < 20, extraction is low; the amount eliminated becomes consequential only when the index > 20. Dosage supplementation may be needed to maintain an adequate drug concentration in the body. Practically, for drugs with a low Vd (< 0.3 l/kg), it seems necessary to adjust the dosage.

Algorithms↗

PubMedDate not supplied

[Extraction of drugs in plasma exchange].

Plasma exchange has been proposed for treating diseases mediated by circulating immune complexes. Removal of drugs during plasma exchange is a complex function of pharmacokinetic characteristics and specifications of the plasma exchange procedure: the time of plasma exchange, the filtered volume of plasma, the number of procedure. The effect of plasma exchange on the kinetics of drugs can be evaluated by different parameters: amount eliminated, extracorporeal clearance, fractional drug removal, extracorporeal elimination rate constant. Knowledge of the impact of plasma on the elimination of drugs is essential to the design of the dosage regimen in patients treated with plasma exchange. The fraction of the estimated amount in body removed by plasma exchange is the best parameter to evaluate the effectiveness of the exchange procedure, but it is necessary to know the proportion of body pool of drug at the start of the plasma exchange. Drug recovery by each exchange may account for 0.5%-30% of the dose. Controlled studies are needed to quantify the effects of plasma exchange on drug therapy. Dosage adjustment is sometimes required.

Humans↗

PubMedDate not supplied

[Review and use of decision rules for bioequivalence trials].

To declare bioequivalent two different formulations of one active drug, bioavailability studies are conducted, usually based on area under the plasma concentration-time curves and peak concentrations. The decision follows a statistical basis with right statement of the hypotheses of bioequivalence that are described. This procedure allows to control the consumer risk of falsely accepting bioequivalence while minimizing the new formulation risk of erroneously rejecting bioequivalence. Six decision rules meeting these criteria are reviewed and compared with numerical data: classic confidence interval; symmetric confidence interval; Hauck-Anderson method; two one-sided tests procedure; bayesian method; non parametric confidence interval. The six rules all have very similar performance. However, the bayesian procedure which gives a probability of the location of the true relative bioavailability could likely complete the two one-sided tests procedure and/or the classic confidence interval method that are recommended in regulatory guidelines. Some other statistical points that have received different interpretation in the international regulations are finally evoked and discussed.

Biological Availability↗

PubMedDate not supplied

[Value of the theory of the optimal sampling scheme for bioequivalence studies].

Use of optimal sampling theory (OST) in pharmacokinetic studies allows a large reduction of the number of sampling times without loss in parameter estimation precision. OST has been applied to the determination of bioavailability parameters [area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration, (Tmax)]. Three different Monte-Carlo simulations in twelve subjects have been performed, corresponding to different pharmacokinetic models: one-compartment with or without a lag time, two-compartment. Bioavailability parameters were estimated using a non-compartmental method (with 12 to 16 sampling times) and OST method (6 to 7 sampling times). Estimates were compared with true values. Bias and RMSE were similar with both methods for AUC and Cmax, while Tmax was better estimated using OST method. However, when a posteriori identifiability of the model was poor, use of a maximum a posteriori Bayesian estimator improved considerably the efficacy of OST method. Potential interest of OST for increasing statistical power of bioequivalence studies at the same cost is discussed, as well as possible limitations.

Biological Availability↗