LB-001 - A GENERIC TACROLIMUS CAPSULE SHOWN NOT TO BE BIOEQUIVALENT TO THE BRAND TACROLIMUS CAPSULE IN A POST-APPROVAL PHARMACOKINETIC BIOEQUIVALENCE STUDY IN HEALTHY SUBJECTS

W. Sun¹, S. Mahjabeen², M. Kinjo², S. Thomas³, Z. Ni², M. Frost², A. Markollari⁴, R. Best⁴, S. Le⁴, M. Kim¹, L. Zhao⁵; ¹Division Of Therapeutic Performance II, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA, ²FDA, , , ³U.S. Food and Drug Administration, U.S. Food and Drug Administration, Silver Spring, MD, United States, ⁴BioPharma Services Inc., , , ⁵Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.

Background: Tacrolimus, a narrow therapeutic index (NTI) immunosuppressant, is a poorly water-soluble drug. Converting tacrolimus from crystalline to amorphous form can improve its aqueous solubility and drug release rate. The reference listed drug (RLD), PROGRAF® and its generic products including Accord Healthcare’s (AH) tacrolimus capsules contain amorphous tacrolimus. However, a previous FDA-funded research study found AH’s product to be unstable as it crystallized under accelerated storage conditions while the RLD maintained its amorphous form. Therefore, a post-approval in vivo pharmacokinetic (PK) bioequivalence (BE) study was conducted to evaluate BE of AH’s product (Test) to its RLD.

Methods: A single-dose, randomized, open-label, two-treatment, two-sequence, four-period, fully replicated crossover BE study was conducted under fasting conditions. Sixty-seven healthy subjects received fresh (i.e., no crystalline was detected) RLD 1 mg and Test 1 mg. Tacrolimus concentrations in whole blood were determined using the LC-MS/MS method. The BE assessment was based on FDA’s NTI criteria.

Results: Sixty-two of 67 subjects were included in the PK and statistical analyses. Using the unscaled average BE procedure, the 90% CI for AUC0-72 and Cmax were 106.04% – 124.76% and 157.38% – 188.17%, respectively. Using the reference-scaled average BE procedure, the 95% upper confidence bounds were less than 0 for AUC0-72 (i.e., -0.043) but greater than 0 for Cmax (i.e., 0.365). The upper limit of the 90% CI for the ratios of within-subject standard deviation (SD) of Test and RLD was less than 2.5 for both AUC0-72 (i.e., 0.2997) and Cmax (i.e., 0.2080).

Conclusion: The Test exhibited higher Cmax than the RLD, and Test and RLD were not bioequivalent. It is expected that Cmax of Test decreases when amorphous tacrolimus crystallizes over time resulting in variable BE conclusions. Based on the findings from this BE study and other information including the aforementioned FDA-funded research study, FDA concluded that data are insufficient to conclude that AH’s tacrolimus capsule provides the same therapeutic effect as PROGRAF®. In Sept 2023, FDA changed the therapeutic equivalence rating for AH’s product from AB (drug products are therapeutically equivalent) to BX (not automatically substitutable at the pharmacy).