Safety and pharmacokinetics of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose.

Intravenous (i.v.) paracetamol is used as 1-g infusions with a maximal daily dose of 4 g/day. However, a higher initial analgesic dose could be of interest in the immediate postoperative period when the pain is maximal. The purpose of the present study was to determine in healthy subjects the safety and the pharmacokinetics of i.v. paracetamol, starting with a 2-g dose, followed by 1-g doses every 6 h, leading to a total of 5 g the first 24 h. This was an open-label, single-sequence study. The paracetamol pharmacokinetic profile was assessed in 26 subjects after both the 2-g starting dose and the 1-g doses. Safety, especially hepatotoxicity, was evaluated up to 72 h after the initial 2-g dose. Following the first 15-min i.v. administration of paracetamol 2 g, plasma concentrations ranged from 67.9+/-21.8 mug/ml (peak plasma concentration (C(max)) at the end of infusion) to 6.2+/-2.3 mug/ml (trough plasma concentration (C(min)) measured just before the next infusion) without any C(max) in the toxic range for any subject. After the repeated 1-g infusions, the plasma concentrations were approximately 35% lower than that measured after 2 g, showing the absence of accumulation. No clinical adverse events related to the drug administration nor clinically relevant changes in laboratory parameters, including biochemical signs of hepatotoxicity, were reported. After i.v. administration of paracetamol 2-g starting dose and 5 g during the first 24 h, the pharmacokinetics of paracetamol remain unchanged, with concentrations far below the toxic threshold. Overall, these results demonstrate that the i.v. administration of a 2-g starting dose of paracetamol, followed by three i.v. administrations of 1 g during the first 24 h is safe in healthy subjects.

Pharmacokinetics of repaglinide in healthy caucasian and Japanese subjects.

The objective of this study was to investigate the pharmacokinetics of three different single doses (0.5, 1.0, and 2.0 mg) of repaglinide in healthy Caucasian and Japanese subjects. In this single-center, open-label, randomized, three-period crossover study, 27 healthy male subjects (15 Caucasian and 12 Japanese) each received three different single doses of repaglinide (0.5, 1.0, and 2.0 mg) at consecutive 24-hour intervals. Pharmacokinetic profiles, including area under the curve (AUC0-t), maximum serum concentration (Cmax), time to Cmax (tmax), and half-life (t1/2), were determined for each dose of repaglinide. The relative change in blood glucose level (RC1h) and area under the blood glucose curve (AUGC0-1) at 1 hour after dose were also measured. After oral dosing, both Cmax and AUC0-t increased linearly with dose within the 0.5- to 2.0-mg dose range, regardless of ethnic group. Both Cmax and AUC0-t were significantly higher in Japanese subjects than in Caucasian subjects. At each dose of repaglinide, Cmax and AUC were statistically significantly higher in Japanese than in Caucasian subjects (p = 0.0038 and 0.023, respectively). Discrepancies in body weight and body mass index (BMI) between Caucasian and Japanese subjects could not explain the between-group differences in Cmax or AUC0-t. Statistically significant differences in pharmacodynamic parameters (RC1h and AUGC0-1) were found between ethnic groups (p < 0.0001), the difference being more pronounced for RC1h than AUGC0-1. At a dose of 2.0 mg, the mean decrease in RC1h was 41% for Japanese subjects and 24% for Caucasian subjects. Hypoglycemic reactions were more common at the highest dose (2.0 mg), where they were observed more frequently in Japanese (7 cases) than in Caucasian subjects (4 cases). It was concluded that higher serum levels of repaglinide and greater reductions in blood glucose levels are found in Japanese than in Caucasian subjects following a single oral dose of repaglinide within the 0.5- to 2.0-mg dose range. Repaglinide is well tolerated in both ethnic groups. The results indicate that glycemic control targets may be achieved at lower doses within the recommended range (0.5-4.0 mg/meal) when repaglinide is used to treat Japanese patients in comparison to Caucasian patients.

Phase I pharmacokinetics study of high-dose fotemustine and its metabolite 2-chloroethanol in patients with high-grade gliomas.

The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I-II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III-IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2 x 300 to 2 x 500 mg/m2. Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination half-lives of 4.15 +/- 2.57 and 28.8 +/- 12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96 +/- 2.89 to 12.22 +/- 3.95 mg l-1 h. Drug clearance was independent of the dose given and equal to 109 +/- 65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r = 0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.

Phase I clinical and pharmacokinetic study of S9788, a new multidrug-resistance reversal agent given alone and in combination with doxorubicin to patients with advanced solid tumors.

PURPOSE: The objectives of this phase I study were to evaluate the toxic effects and the maximum tolerated dose (MTD) of S9788, a new modifier of multidrug resistance (MDR), when given alone and in combination with doxorubicin to patients with advanced solid tumors; to achieve a potentially active plasma concentration of S9788; and to study the pharmacokinetics of both drugs. METHODS: A total of 26 patients (median age 58 years) entered the study. S9788 was given alone as a 30-min infusion at day 1 and in combination with a 50-mg/m2 bolus of doxorubicin at days 8 and 29. Dose levels of S9788 were escalated from 8 to 96 mg/m2 according to the modified Fibonacci scheme. Plasma samples were taken predose as well as during and up to 48 h after the beginning of infusion for S9788 and doxorubicin quantitation. Fractionated urine samples were also collected for up to 24 h for S9788 determination. RESULTS: The dose-limiting side effects of S9788 consisted of bradycardia, sometimes associated with faintness or dizziness. The MTD of S9788 was 96 mg/m2. No enhancement of doxorubicin toxicity was observed. One partial response (duration 140 days) was observed at 96 mg/m2 in a patient with multiple lung metastases from a refractory urothelial carcinoma. Pharmacokinetic studies were performed in 24 patients. Since the mean apparent elimination half-life of S9788 was 46 +/- 23 h and the last plasma sampling time was 48 h, only model-independent parameters were considered. Plasma levels of S9788 were below the limit of quantitation (4 x 10[-3] microM) before each drug administration. S9788 plasma levels of up to 3.7 microM could be obtained with this administration schedule. The urinary elimination of the unchanged drug was negligible, whatever the collection period. In spite of the large inter- and intraindividual variability, plasma pharmacokinetics of S9788 given as a 30-min i.v. infusion were linear up to 96 mg/m2 and were not modified by doxorubicin administration. Doxorubicin pharmacokinetic parameters did not seem to be influenced by S9788 coadministration. CONCLUSION: The dose-limiting toxicity of S9788 consisted of bradycardia or clinical symptoms suggesting a vasovagal impact such as faintness or dizziness. The MTD of S9788 was 96 mg/m2. The pharmacokinetic parameters of doxorubicin in this study were close to those usually described and were not influenced by escalation of the S9788 dose. No pharmacokinetic interaction was observed between S9788 and doxorubicin. The clinical tolerability of the combined treatment is in good agreement with the pharmacokinetic findings, since no enhancement of doxorubicin toxicity was observed.

[Bayesian estimation of pharmacokinetic parameters of etoposide]. / Estimation bayésienne des paramètres pharmacocinétiques de l'étoposide.

Studies of the relationships between the pharmacokinetics of a drug and its pharmacodynamics could significantly improve chemotherapy efficacy. However, despite their proven value, pharmacokinetic studies sometimes appear as cumbersome and difficult procedures. The bayesian approach associated with an optimal sampling time strategy (OST) allows the determination of the pharmacokinetic parameters of a drug with a smaller number of blood samples compared with that required by the classic maximum likelihood estimation (MLE). Therefore, the bayesian approach may lead to a less discomfort to the patients and less work for the medical staff. Such a method was developed to determine the individual pharmacokinetic parameters of etoposide (VP16). First, the statistical characteristics of the pharmacokinetic parameters were evaluated in 14 courses from 14 patients. Then, based on these results, a three-sample strategy was developed. Validation of this methodology was performed in 7 new patients and evaluated by computing bias and precision. The performance of the developed methodology shows that it could successfully be applied for the determination of VP16 pharmacokinetic parameters.

Comparative bioavailability study of two oral omeprazole formulations after single and repeated administrations in healthy volunteers.

OBJECTIVE: Two oral enteric-coated pellet formulations of omeprazole, Pepticum((R)) (test formulation) and Mopral((R)) (reference), were administered to 24 healthy volunteers for 5 days at a daily dose of 20mg omeprazole in order to investigate the comparative bioavailability of the two formulations. RESULTS: The data obtained in this study demonstrated the bioequivalence of the two formulations. No statistical differences were observed for the area under the plasma concentration-time curve (AUC(0-t)), the parameter to which the inhibition of acid secretion induced by omeprazole is directly related. Differences observed in maximum plasma drug concentration (C(max)) at day 1 for both formulations were not statistically significant. At steady-state, the differences found in C(max) were associated with a p-value <0.05 with the 90% confidence interval lying between the acceptance range (70 to 140%). Regarding time to reach C(max) (t(max)), p < 0.01 was found both after single and repeated doses. In both cases, Pepticum((R)) showed a delay in reaching C(max) compared with Mopral((R)): 2.15 +/- 1.11 vs 1.48 +/- 0.52h (day 1) and 1.94 +/- 0.66 vs 1.31 +/- 0.75h (day 5). CONCLUSION: This study confirmed the reported increases in AUC and C(max) after repeated administrations, the important intersubject variability and the excellent biological and clinical tolerability of both formulations.

Phase I and pharmacokinetic study of a novel mitomycin C analog KW-2149.

KW-2149 is a new, semisynthetic, C-7-N-substituted, mitomycin C (MMC) analog showing equal or superior antitumor activity in both in vitro and in vivo assays. The preclinical activity profile combined with the hematological toxicity data in rodents and the water solubility of the compound compare favorably with MMC. The aim of this phase I study was to determine the toxicity profile and the optimal dosage of KW-2149. In this phase I study 37 patients received 97 courses of KW-2149 administered as an i.v. bolus injection every 21 days at sequential dose levels: 5, 10, 17, 25, 35, 47, 60, 75, 90 and 100 mg/m2. Hematological toxicity was moderate even at the 100 mg/m2 dose level. Grade IV leucopenia and thrombocytopenia were observed in one of three patients at the 100 mg/m2 dose level. There was some evidence of a delayed-type bone marrow toxicity. Pulmonary toxicity was dose limiting, with grade III toxicity occurring in all three patients treated at a dose of 100 mg/m2. The type of lung toxicity was similar to the one observed with other antitumor antibiotics. No renal or cardiac toxicity was observed. Other toxicities were generally mild. Antitumor activity was observed in four patients. Data of drug monitoring demonstrated rapid metabolism and/or distribution of KW-2149 with a short half-life and the emergence of the cytotoxic metabolites M-16 and M-18. The dose-limiting toxicity of KW-2149 is pulmonary toxicity.