Robert Lionberger

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters—OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using ³H-estrone sulfate, ³H-N-methyl quinidine, and ³H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC₅₀ values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC₅₀ values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC₅₀ values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC₅₀ values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants.

One of the potential essential factors that restricts generic industry from applying the Biopharmaceutics Classification System (BCS) Class III biowaiver is adherence to the stringent formulation criteria for formulation qualitative (Q1) sameness and quantitative (Q2) similarity. The present study has investigated formulations and excipients from 16 putative BCS Class III drug substances in a total of 19 drug products via 133 approved abbreviated new drug applications (ANDAs) containing in vivo bioequivalence (BE) studies in human subjects during the time period from 2006 to 2022. We included the BCS Class III drugs in this study by referring to published literature, the World Health Organization (WHO) BCS Class I-IV list, FDA internal assessments, and physicochemical properties (high solubility and low permeability) of specific drug substances. Based upon all 133 approved generic formulations in this study, the highest amount of each different compendial excipient with a total of 40 is defined as its corresponding typical amount that has not shown any potential impact on in vivo drug absorption. In the present study, although only 30.08% of the investigated generic formulations met Q1 the same/Q2 similar formulation criteria for the BCS Class III biowaiver, and while approximately 69.92% failed to meet those criteria with non-Q1/Q2 similar formulations, all test/reference ratios (T/R) and 90% confidence intervals for all instrumental PK parameters (AUC_0-t, AUC_0-inf, and Cmax) met the bioequivalence (BE) criteria (80–125%). The results of formulation assessment suggest that the commonly used excipients without atypical amounts did not impact absorption of 16 putative BCS Class III drug substances. The rate and extent of absorption of drugs appears to be more dependent upon the biopharmaceutic and physiochemical properties of BCS Class III drug substance and less, or not dependent upon their formulations, excipients, and the excipients class. Our findings may lead to a more flexible formulation design space regarding the stringent BCS Class III formulation criteria.

Regulatory science is science and research intended to improve decision making in a regulatory framework. Improvements in decision making can be in both accuracy (making better decisions) and in efficiency (making faster decisions). Science and research supported by the Generic Drug User Fee Amendments of 2012 (GDUFA) have focused on two innovative methodologies that work together to enable new approaches to development and review of generic drugs: quantitative models and advanced in vitro product characterization. Quantitative models faithfully represent current scientific understanding. They are tools pharmaceutical scientists and clinical pharmacologists use for making better and faster product development decisions. Advances in the in vitro product comparisons provide the measurements of product differences that are the critical input into the models. This paper outlines four areas where science and research funded by GDUFA support synergistic use of models and characterization at critical decision points during generic drug product development and review.

Excipients are ubiquitous in drug formulation, ensuring that active ingredient drugs are properly released on dosing, retain their properties over time, and are palatable, among other roles. Despite their crucial roles, surprisingly little is known about their systemic availability and activities on molecular targets. Here we review key excipient properties, introduce a public‐accessible database that enumerates and categorizes them, and sketch a strategy for exploring their possible direct actions on molecular targets.

Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00–125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD’s within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.

Patients should have confidence that the generic drugs they are prescribed in the United States can be effectively substituted for the brand product or another generic product. Through new bioequivalence study designs for narrow therapeutic index (NTI) drugs and postapproval studies of generic substitution, the US Food and Drug Administration's (FDA's) ongoing generic drug regulatory science activities are designed to ensure successful generic substitution for all drug products. Clinical Pharmacology & Therapeutics (2013); 94 4, 438–440. doi:10.1038/clpt.2013.104