Zypitamag^® vs. Livalo^®

Zypitamag (pitavastatin magnesium) is a pharmaceutical alternative to Livalo (pitavastatin calcium) that was approved through the 505(b)(2) regulatory pathway. According to U.S. FDA definitions, drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, but a different salt.² Therefore, these therapeutics are not classified as pharmaceutical equivalents; rather, they are classified as a pharmaceutical alternative.

Bioequivalence Studies

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The approval of Zypitamag was based on unpublished studies demonstrating the bioequivalence of Zypitamag and Livalo (described below), as well as the clinical and safety data currently available for Livalo.³ For this reason, the prescribing information for Zypitamag and Livalo contain the same recommendations.^1,4

The FDA requested that two studies be performed to evaluate the bioequivalence of Zypitamag and Livalo:

1. A single-dose, fasting bioequivalence study, comparing Zypitamag 4 mg tablets against Livalo 4 mg tablets.
2. A single-dose, food-effect study, comparing Zypitamag 4 mg tablets under fasting and fed conditions.

1. Single-Dose, Fasting Bioequivalence Study

A single-dose, fasting bioequivalence study was performed to assess serum concentrations of pitavastatin after administration of Zypitamag 4 mg tablets in comparison to Livalo 4 mg tablets. This study was unpublished, but was provided to the FDA as part of the 505(b)(2) application.⁵ The study design is illustrated below. Blood samples were collected pre-dose and at intervals over 48 hours post-product administration. Safety parameters were assessed throughout the duration of the study (vitals, laboratory safety tests etc.).

Bioequivalence was determined by a statistical comparison of total area under the curve (AUC_t; from time 0 - 48 hrs), infinite area under the curve (AUC_i; from time 0 - ∞) and maximum concentration (C_max) for both treatments. The 90% confidence interval conformed to the limits for AUC_t, AUC_i and C_max set by the FDA in Guidance for Industry. Based on these results, the Zypitamag 4 mg tablet and Livalo 4 mg tablet were considered to be bioequivalent under fasting conditions.

Figure 1: Mean Plasma Concentration of Zypitamag (pitavastatin magnesium) 4 mg tablet and Livalo (pitavastatin calcium) 4 mg tablet vs. Time (hr) Under Fasting Conditions.⁵

2. Single-Dose, Food Effect Bioavailability Study

A single-dose, food-effect study was performed to compare serum concentrations of pitavastatin after administration of Zypitamag 4 mg tablets under fasting and fed conditions. This study was unpublished, but was provided to the FDA as part of the 505(b)(2) application.⁵ The study design is illustrated below. Blood samples were collected pre-dose and at intervals over 48 hours post-product administration. Safety parameters were assessed throughout study (vitals, laboratory safety tests etc).

Food effect bioavailability was determined by a statistical comparison of AUC_t, AUC_i and C_max for the test product in fasting and fed conditions. The 90% confidence intervals were within the limits for AUC_t and AUC_i but not for C_max as set by the FDA, Guidance for Industry, meaning that Zypitamag exhibits a food effect observed in C_max but not in AUC_t and AUC_i. This was found to be consistent with the following statement made in the Livalo PI. "Administration of LIVALO with a high fat meal (50% fat content) decreases pitavastatin C_max by 43% but does not significantly reduce pitavastatin AUC." From the above studies it is evident that Zypitamag 4 mg tablets are bioequivalent to and exhibit the same behavior as that of Livalo 4 mg tablets.

Figure 2: Mean Plasma Concentration of Zypitamag (pitavastatin magnesium) 4 mg tablets vs. Time (hr) Under Fasting and Fed Conditions.⁵

Based on the results obtained in the bioequivalence study under fasting conditions and the single dose food effect study, Zypitamag 4 mg tablets and Livalo 4 mg tablets are considered bioequivalent by the FDA.⁵

The FDA also required data on the dissolution profile of Zypitamag in comparison to Livalo.⁶ Dissolution studies were performed for the following strengths of Zypitamag (2 mg and 4 mg) in comparison to the corresponding strengths of Livalo (2 mg and 4 mg, respectively). Studies were performed at 37 °C ± 0.5 °C in a variety of acidic, basic and neutral buffers. Comparative dissolution profiles were found between Livalo and Zypitamag in all experimental settings tested. One representative dissolution curve is included for reference.

Figure 3: Representative In Vitro Dissolution Curve for Zypitamag (pitavastatin magnesium) and Livalo (pitavastatin calcium) in 900 mL of 0.05 M phosphate buffer; pH 6.8. (n = 12 for each treatment).⁶

Overall, based on the review of the clinical and laboratory safety data, both the study products were found to have an acceptable risk-benefit profile by the FDA.⁵

For further details on indications and dosing, please refer to the Zypitamag Prescribing Information and the Important Safety Information below.

References

¹ Zypitamag Prescribing Information. Cadila Healthcare Ltd. 2020(September).
² Approved Drug Products with Therapeutic Equivalence Evaluations - 38th Edition. U.S. Department of Health and Human Services. Food and Drug Administration, Office of Medical Products and Tobacco, Center for Drug Evaluation and Research, Office of Generic Drugs, Office of Generic Drug Policy;2018.
³ Zypitamag FDA Approval Documents - Clinical Review. Center for Drug Evaluation And Research;2017.
⁴ Livalo Prescribing Information. Kowa Pharmaceuticals America, Inc. 2020(September).
⁵ Zypitamag FDA Approval Documents - Clinical Pharmacology and Biopharmaceutics Review. Center for Drug Evaluation and Research;2017.
⁶ Zydus Pharmaceuticals (USA) Inc. Pitavastatin Tablets, 1 mg, 2 mg and 4 mg (Magnesium Salt) Module 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods - Original 505(b)(2) Application.