There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended‐release (ER) tablets. We compared the pharmacokinetics (PKs) and pharmacodynamics of ...brand name versus two generic formulations (drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (Tmax) in adults with hypertension. Participants were randomized to equal drug doses (50–150 mg/day) administered in one of two sequences (brand‐drug1‐brand‐drug2 or brand‐drug2‐brand‐drug1) and completed 24‐h PK, digital heart rate (HR), ambulatory blood pressure (BP), and HR studies after taking each formulation for greater than or equal to 7 days. Metoprolol concentrations were determined by liquid chromatography tandem mass spectrometry, with noncompartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low‐to‐high frequency ratio was determined per quartile over the 24‐h period. Thirty‐six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50 mg dose, the primary PK end points of area under the concentration‐time curve and Cmax were similar between products; Tmax was 6.1 ± 3.6 for the brand versus 3.5 ± 4.9 for drug 1 (p = 0.019) and 9.6 ± 3.2 for drug 2 (p < 0.001). Among all 36 participants, 24‐h BPs and HRs were similar between products. Mean 24‐h HRV low‐to‐high ratio was also similar for drug 1 (2.04 ± 1.35), drug 2 (1.86 ± 1.35), and brand (2.04 ± 1.77), but was more sustained over time for the brand versus drug 1 (drug × quartile interaction p = 0.017). Differences in Tmax between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.
The exposure‐response relationship of direct acting oral anti‐coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to ...bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically‐based PK (PBPK) model for dabigatran etexilate (DABE) and its metabolites. The model was developed following a middle out approach leveraging available in vitro and in vivo data. External validity of the model was confirmed by overlapping predicted and observed PK profiles for DABE as well as free and total dabigatran for a dataset not used during model development. The verified model was applied to interrogate the impact of modulating the microenvironment pH on DABE systemic exposure. The PBPK exploratory analyses highlighted the high sensitivity of DABE exposure to supersaturation ratio and precipitation kinetics.
Immunogenicity assessment is important for biological products due to potential impacts of immunogenicity on safety and efficacy. We reviewed the prescribing information and the FDA’s clinical ...pharmacology review of 121 approved biological products for evaluating and reporting of immunogenicity data. Of the 121 products, 89% (
n
= 108) reported the incidence of immunogenicity and 49% (
n
= 59) reported immunogenicity impact on efficacy. However, only 26% (
n
= 31) reported whether the immunogenicity affected pharmacokinetics. A subset of 16 products reported effects of anti-drug antibodies (ADA) on both systemic clearance and efficacy; 8 of 16 products had increased systemic clearance coinciding with reduced efficacy, and 6 of 16 products had no changes in either clearance or efficacy. Factors contributing to infrequent reporting of the ADA effect on exposure and methods for determining the effect of ADA on exposure are summarized. Measuring ADA and drug concentrations concurrently over time enables the evaluation of ADA impact on pharmacokinetics. Within-subject comparison of concentration data (before
vs
. after ADA formation) is a useful alternative to between-subject (ADA+
vs
. ADA−) comparison when sample size is limited or when the majority of subjects developed ADA. The biological complexity of immune responses presents challenges to quantifying the ADA impact on pharmacokinetics using model-based methods. Our findings support that pharmacokinetic exposure is more sensitive than efficacy endpoints for evaluating ADA effects. A decrease in drug concentration due to formation of ADA during treatment can serve as an early indicator for potential reduced efficacy occurring at a later time.
To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug ...intestinal absorption and the differences in oral bioavailability between human and rat.
The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis.
No correlation (r(2) = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r(2) = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r(2) > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns.
The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.
According to the interviews the CRCG conducted with the generic drug industry, industry is strongly interested in applying MIE approaches as an alternative to conventional end point BE studies for ...inhalation and LAI products to their product development programs. The annual GDUFA science and research reports are another resource to check out the progress in MIE, which include a summary of research activities, research highlights, comprehensive lists of new, ongoing, and completed grants and contracts, and outcomes generated from the GDUFA-funded science and research program in each fiscal year. ...the value of artificial intelligence (AI) and machine learning (ML), potentially combined with real-world evidence/data, in advancing the development of complex generics has been well-recognized by industry, regulatory agency, and other stakeholders, thus the need for further research has been emphasized. Specifically, AI and ML may demonstrate their utility in optimizing the program design and reduce study duration; in utilizing public domain information (e.g., drug labeling) to facilitate unique study designs for complex generic drug product or exploratory studies on related compounds in support of generic development.
This workshop report summarizes the presentations and panel discussion related to the use of physiologically based pharmacokinetic (PBPK) modeling approaches for food effect assessment, collected ...from Session 2 of Day 2 of the workshop titled “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches.” The US Food and Drug Administration in collaboration with the Center for Research on Complex Generics organized this workshop where this particular session titled “Oral PBPK for Evaluating the Impact of Food on BE” presented successful cases of PBPK modeling approaches for food effect assessment. Recently, PBPK modeling has started to gain popularity among academia, industries, and regulatory agencies for its potential utility during bioavailability (BA) and/or bioequivalence (BE) studies of new and generic drug products to assess the impact of food on BA/BE. Considering the promises of PBPK modeling in generic drug development, the aim of this workshop session was to facilitate knowledge sharing among academia, industries, and regulatory agencies to understand the knowledge gap and guide the path forward. This report collects and summarizes the information presented and discussed during this session to disseminate the information into a broader audience for further advancement in this area.
A high-rate glycolysis is a fundamental property of solid tumors and is associated with an over-expression of glucose transporters and glycolytic enzymes. We hypothesize that over-expression of ...glucose transporters in tumors prevents apoptosis, promotes cancer cell survival, and confers drug resistance. Inhibition of glucose transporter will preferentially sensitize the anticancer effects of chemotherapeutic drugs to overcome drug resistance in hypoxia.
Glucose transporter expressions were detected in cancer tissues and NCI 60 cancer cells with immunostaining and DNA microarray. Glucose uptake was measured with 3H-2-deoxy-glucose. Cytotoxicity of daunorubicin (DNR) in combination of glucose inhibitor was detected by MTS assay under hypoxic condition. Early stage apoptosis was monitored with Annexin V-FITC staining.
Immunostaining showed that GLUT1 was significantly increased in hypoxic regions of the human colon and breast tumors. The expression profiles of all glucose transporters in NCI 60 cancer cells exhibited distinct expression patterns. Phloretin exhibited more than 60% glucose uptake inhibition. Hypoxia conferred two to fivefold higher drug resistance in SW620 and K562 to DNR. Inhibition of glucose uptake by phloretin sensitized cancer cells to DNR for its anticancer activity and apoptosis to overcome drug resistance only under hypoxia.
Cancer cells heavily rely on glucose transporters for glucose uptake to facilitate a high-rate glycolysis under hypoxia for their survival and drug resistance. Combination of glucose transporter inhibitors and chemotherapeutic drugs may provide a preferential novel therapeutic strategy to overcome drug resistance in hypoxia.
The net benefit of a treatment can be defined by the relationship between clinical improvement and risk of adverse events: the benefit‐risk ratio. The optimization of the benefit‐risk ratio can be ...achieved by identifying the most adequate dose (and/or dosage regimen) jointly with the best‐performing in vivo release properties of a drug. A general in silico tool is presented for identifying the dose, the in vitro and the in vivo release properties that maximize the benefit‐risk ratio using convolution‐based modeling, an exposure‐response model, and a surface response analysis. A case study is presented to illustrate how the benefit‐risk ratio of methylphenidate for the treatment of attention deficit hyperactivity disorder can be maximized using the proposed strategy. The results of the analysis identified the characteristics of an optimized dose and in vitro/in vivo release suitable to provide a sustained clinical response with respect to the conventional dosage regimen and formulations.
On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled “Regulatory Utility of ...Mechanistic Modeling to Support Alternative Bioequivalence Approaches.” The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop.
Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms in vivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug–drug interactions ...(DDIs) exist between a PPI, omeprazole, and nifedipine extended‐release formulations, where systemic exposure of nifedipine was increased in subjects after multiple‐dose pretreatment of omeprazole. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well‐understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically‐based pharmacokinetic (PBPK) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in in vitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to characterize the potential impact of pH. The PBPK models incorporated two‐stage in vitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple‐dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4‐mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH‐dependent formulation. The reported model‐based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations.
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