A sparse sampling strategy (3 samples per patient, 521 patients) was implemented in 22 Phase 2 studies of docetaxel (Taxotere) at the first treatment cycle for a prospective population pharmacokinetic evaluation. In addition to the 521 Phase 2 patients, 26 (data rich) patients from Phase I studies were included in the analysis. NONMEM analysis of an index set of 280 patients demonstrated that docetaxel clearance (CL) is related to alpha 1-acid glycoprotein (AAG) level, hepatic function (HEP), age (AGE), and body surface area (BSA). The index set population model prediction of CL was compared to that of a naive predictor (NP) using a validation set of 267 patients. Qualitatively, the dependence of CL on AAG, AGE, BSA, and HEP seen in the index set population model was supported in the validation set. Quantitatively, for the validation set patients overall, the performance (bias, precision) of the model was good (7 and 21%, respectively), although not better than that of the NP. However, in all the subpopulations with decreased CL, the model performed better than the NP; the more the CL differed from the population average, the better the performance. For example, in the subpopulation of patients with AAG levels > 2.27 g/L (n = 26), bias and precision of model predictions were 24 and 32% vs. 53 and 53%, respectively, for the NP. The prediction of CL using the model was better (than that of the NP) in 73% of the patients. The population model was redetermined using the whole population of 547 patients and a new covariate, albumin plasma level, was found to be a significant predictor in addition to those found previously. In the final model, HEP, AAG, and BSA are the main predictors of docetaxel CL.

Enoxaparin was well tolerated when administered subcutaneously or intravenously, and there appears to be no need to modify the currently recommended dose for obese volunteers.

Pefloxacin mesylate is well absorbed by the oral route. The antimicrobial activity in dog, cynomolgus monkey, and human plasma was essentially due to unchanged drug which respectively accounted for 64, 94, and 84% of the total activity (ratios derived from relative area under the curve [AUC] values). Half-lives ranged from 1.9 h in mice to 8.6 h in humans. Protein binding was weak, about 20% in plasma. Except in brain, concentrations in most of the organs and tissues tested in rats and dogs were higher than the plasma levels. Microbiological activity in urine was mainly due to pefloxacin and norfloxacin, the N-desmethyl metabolite. The norfloxacin/pefloxacin ratios were 0 in mice, ca. 1 in rats and dogs, 1.6 in cynomolgus monkeys, and 2.3 in humans. The principal urinary compounds were unchanged drug in mice, pefloxacin glucuronide and pefloxacin N-oxide in rats and dogs, norfloxacin and pefloxacin in monkeys, and pefloxacin N-oxide and norfloxacin in humans. The urinary recovery of identified metabolites was 29.5% of the dose in mice, 37.8% in rats, 36.3% in dogs, 26.5% in monkeys, and 58.9% in humans. Biliary excretion occurred and was extensive in rats and dogs, mainly as a glucuronide conjugate of the drug. In rat and human bile, the main active compound was unchanged pefloxacin.Pefloxacin [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid (1589 RB)] has a high order of in vitro activity against gram-positive and gram-negative bacteria (2, 6, 7) and when administered as a single dose has significant activity against infections with Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens in mice (unpublished data). This paper concerns the absorption, distribution, metabolism, and elimination of pefloxacin dihydrate mesylate in mice, rats, dogs, cynomolgus monkeys, and humans.(These results were presented in part at the 13th International Congress of Chemotherapy, Vienna, Austria, 1983.) MATERIALS AND METHODS Drug and reagents. Pefloxacin dihydrate mesylate ( Fig. 1) and possible metabolites were synthesized in our laboratories; the structures are shown in Fig. 2. All reagents were of analytical grade. Doses and concentrations are expressed with reference to the anhydrous substance except for doses administered to rats and dogs, which are expressed in terms of the dihydrate (the degree of hydration of the salt was unknown when the early experiments were performed); hence, the quoted doses of 10, 25, and 50 mg/kg in these animals correspond to 9.2, 23.1, and 46.2 mg of anhydrous pefloxacin per kg.In vivo experiments. Male Swiss mice (24 to 28 g), male Wistar rats (200 to 300 g), male and female beagle dogs (13 to 16 kg), and male Macacafascicularis monkeys (3.2 to 4.4 kg) were treated after a 17-h fast. All animal experiments were carried out in our laboratory except for the monkey assays, which were performed at IFM Center (Evreux, France). Pefloxacin mesylate was dissolved in saline for intravenous administration. Oral or intraduodenal doses were given t...

The binding of docetaxel to human plasma proteins was studied by ultrafiltration at 37 degrees C and pH 7.4. Docetaxel was extensively (> 98%) plasma protein bound. At clinically relevant concentrations (1-5 micrograms/ml), the plasma binding was concentration-independent. Lipoproteins, alpha1-acid glycoprotein and albumin were the main carriers of docetaxel in plasma, and owing to the high interindividual variability of alpha1-acid glycoprotein plasma concentration, particularly in cancer, it was concluded that alpha1-acid glycoprotein should be the main determinant of docetaxel plasma binding variability. Drugs potentially coadministered with docetaxel (cisplatin, dexamethasone, doxorubicin, etoposide, vinblastine) did not modify the plasma binding of docetaxel. In blood, docetaxel was found to be mainly located in the plasma compartment (less than 15% associated to erythrocytes).

Riluzole is a novel neuroprotective agent that has been developed for the treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to establish its pharmacokinetics on single- and multiple-dose administration in young white male volunteers. The mean absolute oral bioavailability of riluzole (50-mg tablet) was approximately 60%. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) values were linearly related to dose for the range studied. Cmax occurred at 1.0 hour to 1.5 hours after administration. Plasma elimination half-life appeared to be independent of dose. After repeated administration of 100 mg riluzole for 10 days, some intraindividual variability in bioavailability was seen. A high-fat meal significantly reduced the rate (tmax = 2 hours compared with 0.8 hours; Cmax = 216 ng.mL-1 compared to 387 ng.mL-1) and extent of absorption (AUC = 1,047 ng.hr.mL-1 versus 1,269 ng.hr.mL-1). With multiple-dose administration, riluzole showed dose-related absorption, although the terminal plasma half-life was prolonged slightly. Steady-state plasma concentrations were achieved within 5 days. Steady-state trough plasma concentrations were significantly higher with a 75-mg dose twice daily than with a 50-mg dose three times daily, although AUC values did not differ.