Jayanta Kumar Mandal

Nanosomal Amphotericin B is an efficacious alternative to Ambisome® for fungal therapy.

Amphotericin B was formulated in lipids (Nanosomal Amphotericin B) without using any detergent or toxic organic solvents during the preparation. Electron microscopy and particle size determination of Nanosomal Amphotericin B showed a homogeneous population of nanosized particles below 100 nm. Hemolysis assay indicated that Nanosomal Amphotericin B causes significantly less lysis of red blood cells than Amphotericin B deoxycholate and was comparable to Ambisome. A maximum daily dose of Nanosomal Amphotericin B at 5 mg/kg in rabbits and 10 mg/kg in mice for 28 days showed no symptoms of toxicity, mortality or significant body weight reduction. Hematological and gross pathological analysis of tissues revealed no abnormalities attributable to the drug treatment. Nanosomal Amphotericin B and Ambisome were injected (iv) at 2 mg/kg consecutively for 5 days into mice infected with Aspergillus fumigatus. The treatment resulted in 90% survival with Nanosomal Amphotericin B and only 30% survival with Ambisome after 10 days of fungal infection. However, all of the 10 control mice which were not treated with Amphotericin B died within 5 days of fungal infection. Nanosomal Amphotericin B is safe, cost effective and provides an alternative option for treatment of fungal disease.

Bioequivalence of Two Tacrolimus Formulations Under Fasting Conditions in Healthy Male Subjects

BACKGROUND Tacrolimus is a macrolide immunosuppressant indicated for prophylaxis of transplant rejection. The European regulatory authorities require comparative bioavailability studies with an innovator product to grant marketing authorization of generic products. OBJECTIVE The purpose of this study was to test the bioequivalence of generic (test) and innovator (reference) tacrolimus capsules. METHODS Two open-label, 2-period, single-dose, crossover studies compared 0.5 mg and 5 mg capsule test formulations of tacrolimus with reference products in fasting, healthy male volunteers. The 2 study periods were separated by a 20-day (0.5 mg) or 21-day (5 mg) washout period. Blood samples were collected for up to 72 (0.5 mg) or 192 (5 mg) hours post-dose. Tacrolimus concentrations in whole blood were determined using a validated LC-MS/MS method. The primary evaluation criteria were C(max) and AUC(0-72) (0.5 mg) or AUC(0-t) (5 mg). Bioequivalence was assumed if the 90% CIs for the test/reference ratios of log-transformed C(max) and AUC values were within the limits specified by existing European guidelines. Data on safety and patient well-being were collected throughout the study. RESULTS The 90% CIs for 0.5 mg were 102.99%-120.80% for C(max) and 91.51%-105.92% for AUC(0-72); those for 5 mg were 110.61%-120.96% for C(max) and 96.17%-103.55% for AUC(0-t). These values meet the requirements for assuming bioequivalence as defined in the European Medicines Agency guidelines for narrow therapeutic index drugs (80%-125% for C(max) and 90%-111% for AUC). There were no relevant differences in the safety profiles of the test and reference formulations. CONCLUSIONS In these comparative bioavailability studies of fasting, healthy male volunteers, the test and reference formulations of tacrolimus 0.5 mg and 5 mg capsules were well tolerated and met the requirements of the European regulatory bioequivalence guidelines. Both studies have been submitted for registration with Clinical Trials Registry-India: CTRI application references REF/2011/05/002346 (0.5 mg) and REF/2011/05/002347 (5 mg).

Single-dose, Two-way Crossover, Bioequivalence Study of Mycophenolate Mofetil 500 mg Tablet Under Fasting Conditions in Healthy Male Subjects

BACKGROUND Mycophenolate mofetil (MMF) is an immunosuppressant indicated for prophylaxis of acute organ transplant rejection. Generic MMF is less costly than the branded product, but European regulatory authorities require bioequivalence studies for the marketing of generics. OBJECTIVES The aims of the 2 studies reported were to assess the dissolution and bioavailability of a generic (test) and branded (reference) formulation of MMF 500 mg. METHODS An in vitro analytical dissolution profile test was conducted comparing 500 mg MMF test drug with a reference drug. A separate single-dose, randomized, open-label, 2-way crossover study involving fasting, healthy, adult male volunteers was conducted. Two study periods-1 test drug period and 1 reference drug period-were separated by a 14-day washout period. Blood samples were collected for up to 60 hours after drug administration for the determination of MMF and mycophenolic acid (MPA) pharmacokinetics. Concentrations of the analytes were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method; pharmacokinetic parameters were calculated using noncompartmental analysis; C(max), AUC(0-t), and AUC(0-∞) were the primary evaluation criteria. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of natural logarithm transformed values (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored throughout the study. RESULTS The dissolution profiles of the test drug matched those of the reference drug at 4 pH levels. In the bioequivalence study, a total of 126 male subjects were dosed, and 117 subjects completed the study. The 90% CIs for MPA were C(max), 94.13% to 116.46%; AUC(0-t), 98.26% to 102.36%; and AUC(0-∞), 97.85% to 101.99%. These values met with the European regulatory definition of bioequivalence. Reported adverse events were similar in both the test and reference drugs. CONCLUSIONS This single-dose study found that the test and reference MMF 500 mg tablets met the European regulatory criteria for assuming bioequivalence in fasting, healthy, male subjects. Both formulations were well tolerated. (Clinical Trials Registry - India [CTRI]: 2011/03/002211).