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Wosulin N. ATC code: A10A C01. Wosulin N is an intermediate acting insulin preparation.
Wosulin 30/70. ATC code: A10A D01. Wosulin 30/70 is an intermediate acting insulin preparation.
Pharmacology: Pharmacodynamics: The prime activity of insulin is the regulation of glucose metabolism.
In addition, insulin has several anabolic and anti-catabolic actions on a variety of different tissues. Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and protein synthesis and amino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid output.
The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated as follows by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient. (See figure.)
Click on icon to see table/diagram/imageA Study to Compare Pharmacokinetics and Pharmacodynamics of Proposed Biosimilar Product with Reference Medicinal Product (Humulin R) in Healthy Subjects was Conducted: A Randomised, Single Centre, Double Blind, Three Treatment, Three-Period, Crossover, Glucose Clamp Study was conducted to test for Bioequivalence between Recombinant Human Insulins, Wockhardt's Regular Insulin Injection Soluble (E. coli) with Wockhardt's Regular Insulin Injection Soluble (Yeast) and Bioequivalence between Wockhardt's Regular Insulin Injection Soluble (E. coli) with Humulin R in Healthy Subjects.
The primary objective was to test for bioequivalence (BE) based on the pharmacokinetic (PK) parameters (Cmax and AUC0-12h) and pharmacodynamics (PD) parameters (AUC-GIR0-12h, and GIRmax) between recombinant human insulin formulations. Comparative safety and local tolerability of the three insulin preparations was also assessed. During the clamp procedure, blood was collected over 12 hours at pre-specified intervals for determination of blood glucose, plasma insulin and C-peptide. There was an interval of 5 to 28 days between the treatments. Concentration-time profile of plasma insulin was determined in the time interval of 0 to 12 hours post-dose, and the PK endpoints for Wockhardt's Regular Insulin Injection Soluble (E. coli), Wockhardt's Regular Insulin Injection Soluble (Yeast) and Humulin R derived from the individual profile and used for PK analysis. Glucose infusion rate (GIR) was recorded during the clamp period of 0 to 12 hour post dose, and the PD endpoint for plasma insulin was derived from the individual GIR profile. C-peptide was assessed during the glucose clamp as a measure of endogenous insulin secretion. A total of 60 subjects were included in the study and were randomised into 3 arms to receive single subcutaneous (SC) injections of Wockhardt's Regular Insulin Injection Soluble (E. coli)/Test drug (A), Humulin R/Reference-1 (C) and Wockhardt's Regular Insulin Injection Soluble (Yeast)/Reference-2 (B) as crossover. Plasma data from all 59 subjects with complete data in all the dosing visits were available and utilized for PK and PD analyses. The PD data from one of the subjects was identified as an outlier and was excluded from the PD analysis. (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageThe CI 90% for the geometric LS mean ratio for both PK endpoints, Cmax and AUC0-12h was entirely contained within the bioequivalence interval of 80% to 125%. Bioequivalence was also demonstrated for primary Pharmacodynamic endpoints as CI 95% of the geometric LS mean ratios for AUC-GIR0-12h and GIRmax were entirely contained within the bioequivalence interval of 80% to 125%.
Conclusion: Wockhardt's Regular Insulin Injection Soluble (E. coli) demonstrated average bioequivalence to Wockhardt's Regular Insulin Injection Soluble (Yeast) and to Humulin R respectively in all PK and PD endpoints. The AEs experienced by subjects were similar in all three arms. Hence, it can be concluded that all the both formulations were comparably safe and well tolerated when compared to Humulin R.
A Study to Compare Pharmacokinetics of Proposed Biosimilar Product with Reference Medicinal Product (Humulin N) in Healthy Subjects was Conducted: A Randomised, Single Centre, Double Blind, Two Treatment, Two-sequence, Two Period, Crossover Glucose Clamp Study to Test for Bioequivalence between Wockhardt's Wosulin N (Brand name used in the Clinical Trial) (100 IU/mL) {Insulin Injection Isophane, r-DNA Origin} and Humulin N (100 U/mL) {Insulin Injection Isophane (r-DNA Origin)}, in Healthy subjects.
The primary objective is to test for bioequivalence based on the pharmacokinetic parameters (Cmax and AUC0-24h) of Insulin Injection Isophane, r-DNA origin formulations, Wockhardt's Wosulin N (E. coli) and Humulin N in healthy subjects.
Analysis of the PK parameter showed that the 90% CI of the geometric LS mean ratio for AUC0-24h was entirely contained within the bioequivalence interval of 80% to 125%; similarly, the 90% CI of the geometric LS (least squares) mean ratio for Cmax was entirely contained within the bioequivalence interval of 80% to 125%. Therefore, Wockhardt's Wosulin N and Humulin N (Eli Lilly) formulations are bioequivalent because the 90 % CI of geometric LS mean ratios for both parameters were entirely contained within the bioequivalence interval. (See Table 3.)
Click on icon to see table/diagram/imageConclusion: In conclusion, a single dose of test formulation Insulin Injection Isophane (Brand name: Wosulin N used in the Clinical Trial) was found to be safe and bioequivalent to the reference formulation Insulin Injection Isophane 10 mL 100 units/mL Humulin N as 90% confidence interval for the geometric least square mean ratios of test to reference formulations, based on ln-transformed PK parameters of Cmax and AUC0-24h, were within the bioequivalence acceptance range of 80% to 125%. From the adverse event profile and local tolerability of the subjects, it appeared that the test product was equally safe as that of reference product.
A Study to Compare Pharmacokinetics of Proposed Biosimilar Product with Reference Medicinal Product (Humuline 30/70) in Healthy Subjects was Conducted: A Randomised, Single Centre, Double Blind, Two Treatment, Two-Period, Crossover Glucose Clamp Study to Test for Bioequivalence between Wockhardt's Wosulin 30/70 (100 IU/mL) {Insulin Injection Biphasic Isophane in ration of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (r-DNA origin)} and Humuline 30/70 (100 U/mL) {70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (rDNA origin)} in Healthy Subjects.
The objective is to test for bioequivalence based on the pharmacokinetic parameters (Cmax and AUC0-24h) of Wockhardt's WosulinTM 30/70 (100 IU/mL) {Biphasic Isophane Insulin Injection/ 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (r-DNA origin)} and Humuline 30/70 (100 U/mL) {70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (rDNA origin)} in healthy subjects.
Analysis of the PK parameter showed that the 90% CI of the geometric LS mean ratio for AUC0-24h was entirely contained within the bioequivalence interval of 80% to 125%; similarly, the 90% CI of the geometric LS (least squares) mean ratio for Cmax was entirely contained within the bioequivalence interval of 80% to 125%. Therefore, Wockhardt's Wosulin 30/70 and Humuline 30/70 (Eli Lilly) formulations are bioequivalent because the 90% CI of geometric LS mean ratios for both parameters were entirely contained within the bioequivalence interval. (See Table 4.)
Click on icon to see table/diagram/imageWosulin 30/70 and Humuline 30/70 are bioequivalent based on the results for the primary PK endpoints. The 90% CI for the geometric LS mean ratio was entirely contained within the bioequivalence interval of 80% to 125% for AUC0-24h and Cmax - the primary PK end points. These results indicate similar rate and extent of absorption for the two formulations. Based on analysis of AEs, clinical laboratory evaluation, local tolerability test and vital signs examination it is demonstrated that Wockhardt's Wosulin 30/70 is well tolerated and has a comparable safety profile to Humuline 30/70.
In conclusion, this study demonstrated the PK bioequivalence of Wosulin 30/70 and Humuline 30/70 and both the formulations were comparably safe and well tolerated after administration of 0.4 IU/kg dose in healthy volunteers.
Pharmacokinetics: The pharmacokinetics of insulin do not reflect the metabolic action of that hormone. Therefore, it is more appropriate to examine glucose utilisation curves (as previously discussed) when considering the activity of insulin.
Toxicology: Preclinical Safety Data: Wosulin is human insulin produced by recombinant technology. No serious events have been reported in sub chronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.
