This single-center, randomized, open, two-preparation, single-dose, two-period, self-crossover trial aimed to assess the bioequivalence and safety of the test (T) preparation compared to the reference (R) preparation following intravenous injection in healthy subjects under fasting conditions. Twenty-four healthy subjects were enrolled in the study and subjects were randomly divided into two groups at a 1:1 ratio and were administered once per period, with an 8-day washout period. During each period, serum drug concentrations were detected for pharmacokinetic analysis and adverse events were recorded for safety analysis. The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration-time curve from time zero to the last measurable concentration, and area under the serum concentration-time curve from time zero to infinite time fell within the predefined bioequivalence range of 80%-125%, indicating bioequivalence between the T and R preparation under fasting conditions. Additionally, four subjects (16.7%) experienced five instances of adverse events in the T group, while five subjects (21.7%) experienced five instances of adverse events in the R group. This trial indicated the potential bioequivalence between the T and R products under fasting conditions, based on pharmacokinetic and safety profile.

Parallel artificial membrane permeability analysis (PAMPA) is used to determine the permeability of compounds through concentrated negatively charged phospholipid bilayer barriers. We employed MacroFlux (a scaled-up version of PAMPA) to test the permeation rate of terazosin hydrochloride (TH) tablets and predict in vivo bioequivalence. The dissolution profiles and permeability of one reference formulation, and seven generic TH tablets, were compared. The dissolution profiles of these generic tablets were equivalent to that of the reference drug in four different media. However, the flux and the total permeated amount of some generic TH tablets were below the lower limit of the confidence interval of the original acceptance range in MacroFlux, which implied risk in the bioequivalence test in vivo. We further evaluated potential factors responsible for this discrepancy by µFlux, including active pharmaceutical ingredient (API) permeability and excipient prescriptions. The analysis showed that different properties of API were a main factor leading to biological inequivalence in the MacroFlux assay, while excipient prescriptions did not have an impact on bioequivalence risk. These data indicated that the flux assay may be a helpful as an auxiliary method for predicting bioequivalence of generic drugs and analyze the factors responsible for bioequivalence risk.

Granulation is the critical process for the pharmaceutical development of poorly water-soluble drug products. Poorly formulated products have challenges in dissolution and bioequivalence studies. Rivaroxaban (RXB) is a poorly soluble drug and has 66% fasting bioavailability at a high strength of 20 mg. Establishing the bioequivalence between test and reference products for high strength requires comparative dissolution profiles and bioequivalence. Improper granulation products and the rest of the batches failed in virtual bioequivalence. The present study provided insight into the optimization of the wet granulation process for manufacturing RXB generic immediate-release tablets using PBPK modeling and simulations. Furthermore, PBPK models are not only useful for formulation optimization but also for process optimization during pharmaceutical product development.
UNASSIGNED:
UNASSIGNED: The online version contains supplementary material available at 10.1007/s40203-024-00249-6.

UNASSIGNED: To assess the bioequivalence between Gan & Lee (GL) glargine U300 and Toujeo® regarding pharmacokinetics (PK), pharmacodynamics (PD), and safety in Chinese healthy male participants.
UNASSIGNED: A single-center, randomized, double-blind, single-dose, two-preparation, two-sequence, four-cycle repeated crossover design study was performed to compare GL glargine U300 and Toujeo® in 40 healthy participants. The primary PK endpoints were the area under the curve of glargine metabolites, M1 concentration from 0 to 24 hours (AUC0-24h), and the maximum glargine concentration within 24 hours post-dose (Cmax). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 hours (AUCGIR.0-24h) and the maximum GIR within 24 hours post-dose (GIRmax).
UNASSIGNED: GL Glargine U300 demonstrated comparable PK parameters (AUC0-24h, Cmax, AUC0-12h, and AUC12-24h of M1) and PD responses [AUCGIR.0-24h, GIRmax, AUCGIR.0-12h, and AUCGIR.12-24h] to those of Toujeo®, as indicated by 90% confidence intervals ranging from 80% to 125%. No significant disparities in safety profiles were observed between the two treatment groups, and there were no reported instances of serious adverse events.
UNASSIGNED: The PK, PD, and safety of GL glargine U300 were bioequivalent to that of Toujeo®.
UNASSIGNED: https://www.chinadrugtrials.org.cn/, identifier CTR20212419.

This study aimed to evaluate the pharmacokinetics (PKs) and safety of a generic drug, linezolid, compared to those of a reference drug in healthy Chinese subjects under both fasting and fed conditions. This was a randomized, open-label, 2-period, 2-sequence crossover study. The subjects received a single dose of the test or reference drug, linezolid (600 mg), in each period. The PK parameters were calculated using a non-compartmental method and compared between the 2 drugs. Bioequivalence was analyzed using geometric mean ratios (GMRs) of the 2 formulations and their corresponding 90% confidence intervals (CIs). The safety of the 2 formulations was assessed under both fasting and fed conditions. Forty-eight subjects completed the study, 24 each in the fasting and feeding groups. The average plasma concentration-time patterns of linezolid were similar for both medications under both conditions. The GMR and 90% CIs of the maximum plasma concentration and the area under the plasma concentration-time curve of linezolid were ranged from 0.80 to 1.25. Both drugs were well tolerated with a similar incidence of adverse drug reactions. In conclusion, the PK and safety profiles of the 2 formulations were comparable. Food intake did not influence the PK profiles of linezolid. These results suggest that the test drug can be used as an alternative to reference drugs.

The present monograph discusses the possibility of BCS-based biowaivers for immediate release pharmaceutical products containing raltegravir potassium, which is used to treat human immunodeficiency virus (HIV) infections. Raltegravir potassium can be assigned to BCS class II or IV since this compound has low solubility and uncertain permeability. Therefore, according to the ICH M9 guideline, it is not recommended to apply BCS-based biowaiver to approval of immediate release solid dosage forms of raltegravir potassium, either for new generic versions or when moderate to major changes in composition and/or the manufacturing method of the product are made.

Conventional dissolution tests only assess the aqueous release of drugs to ensure quality and performance, without indicating whether absorption occurs through the portal or the lymphatic circulation. To address this issue, this study aimed to develop novel first-generation dissolution models that could investigate the release and uptake of oral lymphotropic drugs and examine relevant formulation issues. Dissolution of three commercial lymphotropic drug products (Terbinafina, Apo-terbinafine, and Lamisil) was done using modified versions of USP Apparatus II and IV. The developed models contained a lymphatic compartment filled with artificial chylomicrons to account for absorption through intestinal lymphatic pathway. The various products exhibited different release profiles into the aqueous media and the lymphatic media across the two tested models. The modified USP IV apparatus demonstrated greater distinction in aqueous release patterns. However, the release pattern into the lymphatic media remained similar in both models. This work represents a progress in meeting the challenges posed by the increasing complexity of pharmaceutical products containing lipophilic drugs or formulations, and has the potential to contribute towards the development of in-vitro bioequivalence standards for formulations targeting intestinal lymphatics.

This was an open-label, randomized, single-dose, 2-period, crossover clinical trial with an adaptive design to evaluate the bioequivalence and comparative pharmacokinetics of generic glecaprevir/pibrentasvir versus the brand name product in healthy White male and female volunteers under fed conditions. Safety profiles were also assessed. A total of 56 healthy adult volunteers were enrolled and randomly assigned in a 1:1 ratio to receive a single dose of either the generic or reference formulation. After a 7-day washout period, subjects received the alternate product. Blood samples were collected at pre-specified time points up to 48 hours post-dosing. Plasma concentrations of glecaprevir and pibrentasvir were determined using a validated high-performance liquid chromatography-tandem mass spectrometry method. The geometric mean ratios of the test to the reference formulation for maximum plasma concentration (Cmax) and area under the concentration-time curve from drug administration to the last measurable concentration (AUC0-t) fell within the predefined bioequivalence range of 80%-125%. Both formulations demonstrated comparable pharmacokinetic profiles for glecaprevir and pibrentasvir, and can be considered bioequivalent. No adverse events were reported, and both formulations were well tolerated by all participants.

Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA\'s \"weight of evidence\" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.

The advanced in silico simulation tools, such as physiologically based biopharmaceutics models (PBBM) or physiologically based pharmacokinetic models (PBPK), play critical role in model informed formulation development. This approach has been successfully implemented in the present case for development of novel omeprazole delayed-release orally disintegrating tablets (ODT) formulation, aimed to enhance patient compliance.PBBM was developed using physicochemical, biopharmaceutical, and dissolution data. The dissolution studies for pilot formulations were conducted in biopredictive media in fasting (0.1 N HCl followed by pH 6.8) and fed (pH 5 followed by pH 6.8) conditions. The model was extensively validated in three stages: pilot fasted, pilot fed virtual bioequivalence and food effect assessments. Impressively, the model was able to predict both passed and failed batches appropriately.Based on insights from the pilot study, a higher scale pivotal formulation was optimised. Prospective predictions were made for pivotal formulations using validated model and bio results were found to be in line with model predictions in fasting condition.Overall, a rationale and patient compliant formulation was developed using innovative modelling approach and filed to regulatory agency. The novel omeprazole formulation enhanced patient compliance through ease of administration thereby circumventing challenges of conventional formulation.