Sampling intervals verification in pharmacokinetics studies.

Regulatory agencies do not specify how to plan the sampling intervals in pharmacokinetics (PK) studies. Every interval between each sampling point forms one of the fractions of the area under the curve (AUC). The aim of this study is to propose a method of qualitative evaluation of PK studies, on the basis of the analysis of the partial AUC fields' values. For the pharmacokinetic analysis, average concentrations of high variability drug-itraconazole were used before (BO) and after sampling intervals optimization (AO). PK calculations were performed using Phoenix(TM) WinNonlin 6.3(®) (Certara L.P.) and in house software Biokinetica 4.0. Arithmetic formula and acceptance limit (AL%) was established, below which the mean of partial fields (MAF) value in PK study can be considered optimal. In case of MAF the CV% value before optimization was 125.35 and after the optimization 46.51. In the cases of AUC fractions for several partial fields BO data, the AL% value was exceeded. The values of AUC fractions did not exceed AL% established for AO data. The paper proposes an empirical method of quality assessment, made on the basis of the percentage of the AUC fractions. This method can be used in the quality assessment of PK studies.

Leave-one-out procedure in the validation of elimination rate constant analysis.

Many registration agencies and other organizations define how to calculate the elimination rate constant (kel) value. No validation procedures have been introduced to verify the correct selection of the concentration-time (C-T) points used for the kel calculation. The purpose of this paper is to discover whether kel analysis can be subjected to the condensed validation procedure and what acceptance criteria should be adopted for such a procedure. For the analysis, data collected during bioequivalence studies of 4 drugs were selected, including 2 highly lipophilic drugs (itraconazole, atorvastatin) and 2 weakly lipophilic drugs (trimetazidine, perindopril). Pharmacokinetic calculations were performed with the use of WinNonlin Professional v 5.3. Internal validation of the kel analysis using leave-one-out cross-validation was performed. The present analysis proves that the C-T selection process for the kel calculations cannot be automated. In each of the analysed data series there were such C-T sequences that did not meet even one of the validation criteria. This paper proposes 3 validation criteria which need to be met in order to confirm the optimal selection of C-T data to calculate kel: Q 2≥0.6, R2≥ 0.85, Q 2-R2<0.3, were Q 2 - squared cross-validated correlation coefficient, R2 - coefficient of determination). Application of the validation procedure for the kel analysis under discussion proves the accuracy of the calculations, even if repeated kel analysis is based on a different sequence of points in the elimination phase.

The bioavailability of injectable, amorphous form of aztreonam.

Amorphos injectable form of aztreonam (BIOKTAM) was prepared. It was shown that after intramuscular or intravenous administration there are not any considerable differences in the bioavailability of aztreonam from BIOKTAM and of the drug from AZACTAM.

Esters of cephalosporins. Part I. Permeability of cefuroxime liberated from its 1-acetoxyethyl ester through biological membranes; influence of the form and size of the ester particles.

Concentrations of cefuroxime [II] in blood of rats were measured 30 and 60 min. after administration of amorphous form possessing various particles size (ranging from 0.09 to 0.4 nm) and crystal form of 1-acethoxyethyl ester of cefuroxime [I]. In vitro the concentrations of [II] were measured 15 and 45 min. after application of [I]. HPLC method was used for cefuroxime estimation. Close correlation between the particles size of the amorphous [I] and the concentrations of [II] in vivo as well as in vitro was found, the particles with lover size possessed higher bioavailability. The cefuroxime front the crystal form of ester is poorly absorbed and the concentrations of [II] after its application were similar to those observed after of the bigest particles of amorphous form both in vivo and in vitro.

Effect of simultaneous administration of ibuprofen and ethanol on the alkaline phosphatase activity in the small intestine.

Using the interferometric technique the authors studied the effect of simultaneous administration of ibuprofen (Polfa) and ethanol on the activity of alkaline phosphatase in the proximal jejunum. Both ibuprofen and ethanol cause in the digestive tract functional and morphological changes. The used technique of quantitative determination of alkaline phosphatase activity at the site of its primary location made possible an assessment of changes in the activity of the enzyme caused by the administered agents. It was found that after 60 days of the experiment both agents caused a statistically greater changes were observed in the rats receiving both these agents simultaneously. The obtained results suggest the conclusion that simultaneous administration of ibuprofen and ethanol causes in the mucosal gland in the proximal small intestine development of an interaction of the additive.