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.

Bioequivalence study of two Ibuprofen formulations administered intravenously in healthy male volunteers.

OBJECTIVE: To compare the systemic bioavailability of two ibuprofen formulations, Pedea((R)) (ibuprofen intravenous [IV] formulation) and Imbun((R)) (ibuprofen intramuscular [IM] formulation) in 18 healthy male volunteers. METHODS: Each subject received a 5 mg/kg dose of ibuprofen base as a short 15-minute IV infusion as the Pedea((R)) ibuprofen IV formulation or as the reference Imbun((R)) IM formulation. Concentrations of R- and S-ibuprofen were measured by a validated HPLC method with a lower limit of quantification of 0.100 microg/mL. RESULTS: A single 5 mg/kg injection of Pedea((R)) was well tolerated. The most frequent adverse event was a mild to moderate burning sensation along the injection vein probably related to the study treatments.The maximum serum concentration (C(max)) of R- and S-ibuprofen ranged from 20 to 35 microg/mL with both formulations. No statistical differences were observed for either C(max) or area under the plasma concentration-time curve (AUC). 90% CIs calculated for C(max) and AUC from time zero to infinity (AUC(infinity)) of R-ibuprofen and S-ibuprofen were included in the bioequivalence range 0.80-1.25. Based on AUC(infinity), the mean (SD) relative bioavailability of Pedea((R)) (ibuprofen IV formulation) versus the Imbun((R)) IM reference formulation was 1.06 (0.17) for R-ibuprofen and 1.05 (0.08) for S-ibuprofen. CONCLUSION: This study showed that Pedea((R)) (test formulation) is bioequivalent to Imbun((R)) IM (reference formulation) for both R-ibuprofen and S-ibuprofen. The Imbun((R)) IM formulation (lyophilisate) could be replaced by the Pedea((R)) ready-to-use IV solution. Moreover, these results allow a comparison of safety and efficacy data previously generated with either formulation. Consequently, neonatologists, who previously used the IM formulation intravenously for the treatment of patent ductus arteriosus in preterm infants, will now be able to administer the new ready-to-use IV solution of ibuprofen directly.

Bioavailability and pharmacokinetic profile of glyceryl trinitrate and of glyceryl dinitrates during application of a new glyceryl trinitrate transdermal patch.

The pharmacokinetics and bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolites, i.e. 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0), were compared during a single 24-h application of a new GTN transdermal patch (Epinitril 10, hereinafter called EPI-10) or a reference patch (hereinafter called ND-10) releasing 10 mg GTN in 24 h. The study was an open, randomized balanced cross-over study on 24 healthy male volunteers to whom the patches were applied to the antero-lateral part of the thorax in two periods separated by a 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and at 0.5, 2 and 3 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope-labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). The ratios of the AUCs of GTN, 1,2-GDN and 1,3-GDN measured during application of EPI-10 or of ND-10 were within the 0.85-1.25 limits required to assess equivalence of the extent of bioavailability. The ratios of the Cmax were within said limits for the signal metabolite 1,2-GDN and only slightly below (0.78-1.16) for the parent GTN. EPI-10 can therefore be considered equivalent to ND-10 also with regard to the rate of bioavailability. Under both patches GTN reached steady-state levels after 3-6 h of patch application and remained on sustained levels during the whole 24-h application. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h. Both patches were well tolerated at the application site. For its small size, thinness and transparency, EPI-10 is very patient friendly, a quality that improves compliance with the therapeutic regimen.

Plasma levels of glyceryl trinitrate and dinitrates during application of three strengths of a new glyceryl trinitrate transdermal patch.

The pharmacokinetic characteristics and the bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolities 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0) during a single 24-h application of three strengths of a newly developed GTN transdermal patch (Epinitril) were investigated. The three strengths coded in this paper EPI-5, EPI-10 and EPI-15 have a nominal release rate of GTN of 5, 10 and 15 mg, respectively, in 24 h. The study was an open, randomized balanced cross-over study on 18 healthy male volunteers, to whom the patches were applied for 24 h to the antero-lateral part of the thorax in three periods, separated by an at least 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and 1, 3 and 6 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). GTN and its two metabolites reached the plateau already 3 h after application of the patches and remained on extended and fairly constant levels during the whole 24-h application. The plasma levels of the three nitrates were proportional to the strengths of the patches. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h, an important property when an intermittent GTN therapy is needed in order to avoid tolerance to the drug. The patches were well tolerated at the application site. For their good tolerability, small size and transparency, the new GTN patches are very patient friendly, a quality that improves compliance with the therapeutic regimen.

Pharmacokinetics of estradiol valerate 2mg + dienogest 2mg (climodien® 2/2) after single and repeated oral administration in healthy postmenopausal women.

OBJECTIVE: To evaluate the pharmacokinetics and tolerability of estradiol valerate 2.0mg plus dienogest 2.0mg (Climodien® 2/2). DESIGN AND SETTING: This was an open single-and multiple-dose study. STUDY PARTICIPANTS: 16 healthy postmenopausal women. INTERVENTIONS: Pharmacokinetic parameters were determined in plasma after single and multiple daily intake of Climodien® 2/2 for 12 weeks. Accumulation during multiple administration was calculated from the area under the plasma concentration-time curve (AUC). Changes in plasma levels of other hormones and sex hormone-binding globulin (SHBG) were also measured. RESULTS: The observed accumulation of estradiol (accumulation ratio R(1) = 3.3) and free estrone (R(1) = 2.4) was higher than that predicted from single-dose data (R(theor) = 1.7 and 2.0 for estradiol and free estrone, respectively). This was thought to be due to high interindividual variability in estrogen parameters, or the degree of extrapolation required when calculating the half-life (t1/2). The observed accumulation of total estrone after multiple-drug administration was as predicted from single-dose results (R(1) and R(theor) = 1.5). The pharmacokinetics of dienogest were not time dependent, the observed accumulation (AUC(0-24h) 627 vs 483 µg/L · h) was as predicted from single-dose results (R(1) and R(theor) = 1.3). Reduced total plasma testosterone levels confirmed the antiandrogenic effect of dienogest.The main adverse events with Climodien® 2/2 (breast tension in five participants and irregular vaginal bleeding in four) reflected its hormonal content, and laboratory screening tests revealed no tolerability concerns. CONCLUSIONS: Estradiol may accumulate in plasma during multiple-drug administration with Climodien® 2/2 more than predicted from single-dose results. However, dienogest kinetics after multiple-drug administration were as predicted from single-dose results. Climodien® 2/2 demonstrated antiandrogenic effects and was well tolerated.

Estradiol and estrone plasma levels during application of three strengths of a 7-day estradiol transdermal patch.

BACKGROUND: A new estradiol transdermal patch was developed for a once weekly application, with the aim to achieve an optimum practicability and to improve long-term compliance with estrogen replacement therapy. The pharmacokinetics of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) during a 7-day application of the new patch is reported in this publication. METHODS: Unconjugated estradiol and estrone were assayed in plasma in a three-way crossover study on 18 postmenopausal women during and after a 7-day application of 3 strengths of the new patch, with daily release rates of 25, 50 and 75 micrograms of estradiol. RESULTS: During the 7-day application of the transdermal patches the concentration in plasma of unconjugated estradiol increased from less than 5 pg/ml, typical of postmenopause, to average concentrations of 26, 49 and 66 pg/ml under the patches with the release rates of 25, 50 and 75 micrograms/day of estradiol, respectively. The increases were linearly related and proportional to the strength of the patches. Upon removal of the patches, the estradiol concentrations returned to the basal postmenopausal values in 8-24 h. Retarded with regard to estradiol, there was also an increase of unconjugated estrone, from basal concentrations of 24 pg/ml to average concentrations of 39, 54 and 62 pg/ml, respectively. Estrone returned to its basal concentrations 24-48 h after removal of the patches. The estradiol/estrone ratio from the low pre-treatment values of 0.15-0.21 typical of postmenopause increased to average values of 0.51, 0.92 and respectively 1.09 during the application of the patches with the three strengths. The ratios are in the range of those of unconjugated hormones during the fertile age of women. The patches were well tolerated by the skin, with rare mild and transient reactions that disappeared spontaneously and did not cause interruption of treatment. Also the systemic tolerability was good, with occasional mild or moderate side effects typical of estradiol found especially under the application of the two higher strengths, i.e. with release of 50 and 75 micrograms/day of estradiol. CONCLUSIONS: The effective pharmacokinetic performance over the 7-day application, combined with the good general and local tolerability and the need to apply the patches only once weekly confer to the new patches a favorable practicability for the long-term estrogen replacement therapy needed to control the most severe postmenopausal disorders.

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.

Pharmacokinetics of estradiol and of estrone during application of three strengths of an estradiol transdermal patch with active matrix.

The pharmacokinetic pattern of estradiol (CAS 50-28-2) and of estrone (CAS 53-16-7) during and after application of three strengths of a new transdermal estradiol patch (Dermestril) with active matrix was investigated in a cross-over study in 24 women in natural or surgical menopause. Free estradiol and estrone were assayed by GC-MS on plasma samples obtained during a 4-day application on the upper buttocks of the patches with 3 strengths and release rates of 25, 50 and 100 micrograms/day estradiol. The estradiol concentrations in plasma increased from 0-10 pg/ml typical of menopause to average concentrations of 23, 40 and 79 pg/ml during the application of the new estradiol transdermal patches with the three strengths. The concentrations of estradiol are in the range of those during the early follicular phase in women in fertile age. The increases were linearly related with the strength of the patches. Upon removal of the patches the estradiol concentrations returned to the basal low values in 8-24 h. Retarded with regard to estradiol, there was also an increase of estrone, from basal average concentrations of 22-32 pg/ml up to 31, 39 and 60 pg/ml. The increase of estrone was less pronounced than that of estradiol. Also estrone returned to its basal concentrations 24 h after removal of the patches. The estradiol/ estrone ratio from very low values typical of postmenopause increased to values of about 1, i.e. in the range of those found during the fertile age of woman. The adhesion of the patches was satisfying, provided that direct rough frictions were avoided. The patches were locally well tolerated, with rare mild and transient irritating effects on the skin. Also the systemic tolerability was good, with occasional mild or moderate side effects typical of estradiol (headache, mastodynia and pelvic heaviness) which in the practical use can be easily avoided by the application of patches of lower strength.

High-performance liquid chromatographic determination of baclofen in human plasma.

A reversed-phase isocratic HPLC method is described for the determination of baclofen in human plasma. Solid-phase extraction using a SCX Bond Elut column is used followed by derivatization with o-phthalaldehyde-tert.-butanethiol and electrochemical detection. Both the within- and between-day R.S.D. and inaccuracy are less than 10% and 7%, respectively, even at the limit of quantification of the method, i.e., 10 ng/ml. The method was shown to give optimum performance in terms of sensitivity, precision and accuracy for the pharmacokinetic study of baclofen after a single oral administration to volunteers.

Pharmacokinetics of carboplatin in a patient suffering from advanced ovarian carcinoma with hemodialysis-dependent renal insufficiency.

Pharmacokinetics of carboplatin were determined in a patient suffering from advanced ovarian cancer with total hemodialysis-dependent chronic renal failure undergoing 3 consecutive cycles of chemotherapy. Dosage was adjusted to reach active AUC (area under the plasma concentration versus time curve) of ultrafilterable carboplatin. A hemodialysis, performed 24 h after administration results in a decrease of 20% of ultrafilterable carboplatin AUC. The relative dialysis efficacy of ultrafilterable carboplatin was great: 84 +/- 3%. The chemotherapy regimen consisted of carboplatin-cyclophosphamide combination for 6 cycles every 4 weeks. After treatment completion, the patient showed a complete response and remains disease free 16 months after the end of the treatment. Carboplatin-based chemotherapy can be given to patients undergoing chronic hemodialysis without life-threatening toxicity with a dialysis performed 24 h after the administration and with a dose adjustment of carboplatin to reach a AUC of 6 mg/ml.min for untreated patients. In these conditions, response in platinum-sensitive tumors can be obtained.

[Continuous double administration of 5 fluorouracil (intravenous and intraperitoneal) modulated by folinic acid: phase I clinical study and pharmacokinetics in patients with intra-abdominal developing cancers]. / 5-fluorouracile en perfusion continue double voie (intraveineuse et intrapéritonéale) modulé par l'acide folinique: étude clinique de phase I et pharmacocinétique chez des patients porteurs de cancers à évolution intra-abdominale.

Thirteen patients with intra-abdominal malignancies entered a phase I study of fluorouracil (5-FU) given by continuous infusion (96 h) iv and ip, simultaneously, and modulated by high-dose folinic acid-iv. Severe but reversible stomatitis was the only dose-limiting toxicity at a dose of 5-FU of 550 mg/m2/day. Local toxicity (5-FU-induced abdominal pain) was a significant side effect in patients receiving more than 1 cycle. The pharmacokinetic advantage of 5-FU-ip was confirmed in our study (ratio AUC peritoneum/plasma between 160 and 328). The systemic exposure to 5-FU (plasmatic AUC ranging from 73.4 to 173.21 microM) and to AF were found in efficacious ranges. The recommended dose of 5-FU iv and ip is 500 mg/m2/day. This regimen is feasible and may potentially have application for adjuvant chemotherapeutic programs after surgery for colorectal cancer.

Cellular pharmacokinetics of doxorubicin in patients with chronic lymphocytic leukemia: comparison of bolus administration and continuous infusion.

The purpose of this study was to determine whether administration of doxorubicin (DOX) as a continuous infusion or a bolus injection resulted in similar leukemic cell drug concentration in patients with refractory chronic lymphocytic leukemia (CLL). This study was carried out on five patients with refractory CLL, with DOX administered either as a bolus injection (35 mg/m2; CHOP protocol) or as a constant-rate infusion for a period of 96 h (9 mg/m2 per day; VAD protocol). The two types of drug administration were used alternatively with the same patient. Plasma and cellular DOX concentration were determined using high-performance liquid chromatography. Peak plasma DOX levels were higher after the bolus injection than after continuous administration (1509 +/- 80 ng/ml vs 11.6 +/- 1.8 ng/ml, respectively), whereas the plasma area under the curve (AUC) levels were similar. Maximum DOX cellular concentrations were 8629 +/- 2902 ng/10(9) cells (bolus injection) and 2745 +/- 673 ng/10(9) cells (96 h infusion). The cellular AUC after the bolus injection was 2.85 times greater than that observed after continuous administration. This difference was due to a higher cellular peak level followed by a relatively prolonged retention of the drug, with a loss of only 25% in the first 24 h following. These findings demonstrated that in CLL the cellular DOX exposure can be notably modified by the method of drug administration, with higher drug intracellular concentrations being achieved after bolus administration than with the infusion schedule.

Sublingual apomorphine in Parkinson's disease: a clinical and pharmacokinetic study.

The clinical response and the pharmacokinetic parameters of 3 mg subcutaneous (SC) and 30 mg sublingual (SL) apomorphine were compared in nine patients with Parkinson's disease. The magnitude of the motor responses (evaluated by tapping and walking tests and the Webster scale) was similar for SC and SL apomorphine. However, the onset to action was delayed after SL when compared with SC apomorphine. No significant difference was found in bioavailability (area under the curve: AUC) or peak plasma concentration (Cmax) between SC and SL apomorphine, whereas time to peak plasma concentration (Tmax) was shorter after SC apomorphine. Eight other patients were treated for a mean time of 4 months with SL apomorphine with a significant reduction in daily "off" hours. However, four of these eight patients developed stomatitis after some weeks of treatment. These results indicated that (a) pharmacokinetics parallel the clinical response to SL apomorphine, (b) SL apomorphine can reduce severe off periods in parkinsonian patients when used chronically, and (c) its long-term use is limited by a severe side effect (stomatitis).