Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) Formulation and Paclitaxel in Polyethoxylated Castor Oil: A Randomized,Two-Period Crossover Study in Patients With Advanced Cancer

Background

Preclinical studies comparing paclitaxel formulated with polyethoxylated castor oil with the sonicated formulation of liposome-entrapped paclitaxel (LEP) have demonstrated that LEP was associated with reduced toxicity while maintaining similar efficacy. Preliminary studies on the pharmacokinetics in patients support earlier preclinical data, which suggested that the LEP Easy-to-Use (LEP-ETU) formulation and paclitaxel formulated with castor oil may have comparable pharmacokinetic properties.

Objectives

Our objectives were: (1) to determine bioequivalence of paclitaxel pharmaceutically formulated as LEP-ETU (test) and paclitaxel formulated with castor oil (reference); and (2) to assess the tolerability of LEP-ETU following intravenous administration.

Methods

Patients with advanced cancer were studied in a randomized, 2-period crossover bioequivalence study. Patients received paclitaxel 175 mg/m² administered as an intravenous infusion over 180 minutes, either as a single-treatment cycle of the test formulation followed by a single-treatment cycle of the reference formulation, or vice versa.

Results

Thirty-two of 58 patients were evaluable and were included in the analysis for bioequivalence. Mean total paclitaxel C_max values for the test and reference formulations were 4955.0 and 5108.8 ng/mL, respectively. Corresponding AUC_0-∞ values were 15,853.8 and 18,550.8 ng·h/mL, respectively. Treatment ratios of the geometric means were 97% (90% CI, 91%–103%) for C_max and 84% (90% CI, 80%–90%) for AUC_0-∞. These results met the required 80% to 125% bioequivalence criteria. The most frequently reported adverse events after LEP-ETU administration were fatigue, alopecia, and myalgia.

Conclusion

At the studied dose regimen, LEP-ETU showed bioequivalence with paclitaxel formulated with polyethoxylated castor oil.     

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer.

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m(-2) d(-1) on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m(-2) d(-1), experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m(-2) d(-1)) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m(-2) d(-1)). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m(-2)d(-1) in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.     

Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1, in rats.

A semi-purified corn-based diet containing 50 mg/kg of pure (not less than 90%) fumonisin B1 (FB1), isolated from culture material of Fusarium moniliforme strain MRC 826, was fed to a group of 25 rats over a period of 26 months. A control group of 25 rats received the same diet without FB1. Five rats from each group were killed at 6, 12, 20 and 26 months. The liver was the main target organ in the FB1-treated rats and the hepatic pathological changes were identical to those previously reported in rats fed culture material of F.moniliforme MRC 826. All FB1-treated rats that died or were killed from 18 months onwards suffered from a micro- and macronodular cirrhosis and had large expansile nodules of cholangiofibrosis at the hilus of the liver. Ten out of 15 FB1-treated rats (66%) that were killed and/or died between 18 and 26 months developed primary hepatocellular carcinoma. Metastases to the heart, lungs or kidneys were present in four of the rats with hepatocellular carcinoma. No neoplastic changes were observed in any of the control rats. Chronic interstitial nephritis was present in the kidneys of FB1-treated rats killed after 26 months. No lesions were observed in the esophagus, heart or forestomach of FB1-treated rats and this is contrary to previous findings when culture material of the fungus was fed to rats. It is concluded that FB1 is responsible for the hepatocarcinogenic and the hepatotoxic but not all the other toxic effects of culture material of F.moniliforme MRC 826 in rats.     

Spinal cord compression–do we miss it?

Four children with spinal cord compression due to malignant tumours are presented. The severity of the condition was not initially recognized by parents, or the nature of the likely cause by the initial physicians. Lower limb asymmetrical weakness, clear-cut sensory levels, and marked pain indicate need for urgent imaging and exclusion of a space occupying lesion. In 1997 diagnosis of Guillain-Barré syndrome should not be made without careful prior spinal imaging.     

Outpatient lumbar myelography. Initial results in 79 examinations using a low-dose metrizamide technique

Seventy-nine patients underwent lumbar myelography on an outpatient basis, with a low (3.75 g) dose of metrizamide as the radiocontrast agent and a 25-gauge spinal needle used for lumbar puncture. No patient experienced significant neurotoxicity following the examination; 70.8% (56 of 79) experienced minimal (23%) or no (48%) side effects. Three patients (3.8%) were admitted to the hospital for management of common side effects (headache, nausea/vomiting, back pain). We obtained postmyelographic computed tomographic scans on 96% (76 of 79) of the patients. Our initial results suggest that outpatient lumbar myelography is safe and can be performed with a very acceptable incidence of side effects.