scholarly journals Regulatory and Study Conditions for the Determination of Bioequivalence of Highly Variable Drugs

2009 ◽  
Vol 12 (1) ◽  
pp. 138 ◽  
Author(s):  
Laszlo Endrenyi ◽  
Laszlo Tothfalusi
Keyword(s):  
Point Estimate ◽  
Highly Variable Drugs ◽  
Geometric Means ◽  
Drug Products ◽  
Consumer Risk ◽  
Alternative Settings ◽  
Power Curves ◽  
Undesirable Outcome ◽  
Regulatory Criterion

Purpose. The FDA Working Group on Highly Variable (HV) Drugs recently presented interim procedures and conditions for determining the bioequivalence (BE) of HV drug products. They included analysis by the method of scaled average BE (SABE), a switching coefficient of variation of CVS = 30% and a regulatory standardized variation of CV0 = 25% for applying SABE, and the use of a secondary regulatory criterion restricting to 0.80-1.25 the point estimate for the ratio of estimated geometric means (GMR) of the two formulations. These conditions are scrutinized in the present communication. Methods. 3-period BE studies were simulated with various statistical and regulatory assumptions. Power curves, obtained by gradually increasing the true GMR, compared performances of the methods of SABE, a constrained point estimate of GMR (PE/GMR), and the composite of these two approaches. The consumer risk of each procedure was evaluated. Results. With CV0 = 30% and PE/GMR = 0.80-1.25, the composite criterion of BE relied on the confidence limits of SABE. In contrast, with CV0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion approached almost completely the features of the GMR point estimate, especially at high within-subject variation. The consumer risk was near 5% with CV0 = 30% but much higher when CV0 = 25%. Conclusions. The condition of CVS = CV0 = 30% and PE/GMR = 0.80-1.25 is recommended as a composite regulatory criterion. With alternative settings of the conditions, such as the recommended CV0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion would reflect almost entirely the GMR point estimate. This would be an undesirable outcome.

scholarly journals Sample Sizes for Designing Bioequivalence Studies for Highly Variable Drugs

2011 ◽  
Vol 15 (1) ◽  
pp. 73 ◽  
Author(s):  
Laszlo Endrenyi ◽  
Laszlo Tothfalusi
Keyword(s):  
Sample Size ◽  
European Medicines Agency ◽  
Point Estimate ◽  
Sample Sizes ◽  
Regulatory Requirement ◽  
Highly Variable Drugs ◽  
Geometric Means ◽  
The Relationship ◽  
Additional Constraints ◽  
Regulatory Constraint

Purpose. To provide tables of sample sizes which are required, by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), for the design of bioequivalence (BE) studies involving highly variable drugs. To elucidate the complicated features of the relationship between sample size and within-subject variation. Methods. 3- and 4-period studies were simulated with various sample sizes. They were evaluated, at various variations and various true ratios of the two geometric means (GMR), by the approaches of scaled average BE and by average BE with expanding limits. The sample sizes required for yielding 80% and 90% statistical powers were determined. Results. Because of the complicated regulatory expectations, the features of the required sample sizes are also complicated. When the true GMR = 1.0 then, without additional constraints, the sample size is independent of the intrasubject variation. When the true GMR is increased or decreased from 1.0 then the required sample sizes rise at above but close to 30% variation. An additional regulatory constraint on the point estimate of GMR and a cap on the use of expanding limits further increase the required sample size at high variations. Fewer subjects are required by the FDA than by the EMA procedures. Conclusions. The methods proposed by EMA and FDA lower the required sample sizes in comparison with unscaled average BE. However, each additional regulatory requirement (applying the mixed procedure, imposing a constraint on the point estimate of GMR, and using a cap on the application of expanding limits) raises the required number of subjects. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Quantitative Analysis of 5-Hydroxymethylfurfural in Linezolid Injection by High Performance Liquid Chromatography

2020 ◽  
Vol 16 (8) ◽  
pp. 1059-1067
Author(s):  
Jéssica Maurício Batista ◽  
Christian Fernandes
Keyword(s):  
High Performance ◽  
Potassium Phosphate ◽  
Gradient Elution ◽  
High Performance Liquid Chromatographic ◽  
Official Method ◽  
Ph Variation ◽  
Drug Products ◽  
Liquid Chromatographic Method ◽  
Liquid Chromatographic

Background: Linezolid is a synthetic broad-spectrum antibacterial belonging to the class of oxazolidinones. Linezolid for intravenous infusion is isotonized with dextrose. In acidic environment, the dehydration of dextrose produces furan derivatives, 5-hydroxymethylfurfural (5-HMF) being the main one. The determination of this degradation product is of fundamental importance, since there is evidence it is cytotoxic, genotoxic, mutagenic and carcinogenic. However, there is no official method for the determination of 5-HMF in drug products. Objective: The aim of this study was to develop and validate a high performance liquid chromatographic method to quantify 5-HMF in injection of linezolid. Methods: The chromatographic separation, after optimization, was performed on C18 (150 x 4.6 mm, 5 μm) column. Mobile phase was composed of 14 mM potassium phosphate buffer pH 3.0 ([H+] = 1.0 x 10-3) and methanol in gradient elution at 1.0 mL min-1. The injection volume was 10 μL and detection was performed at 285 nm. Results: The method was optimized and validated, showing selectivity, linearity in the range from 0.075 to 9.0 μg mL-1, precision (RSD ≤ 2.0%), accuracy (mean recovery of 100.07%) and robustness for temperature and pH variation. Conclusion: The method was shown to be adequate to determine 5-HMF in injection containing linezolid in routine analysis.

Real-time performance of filtering facepiece respirators at the workplace/Echtzeit-Performance partikelfiltrierender Halbmasken am Arbeitsplatz

Gefahrstoffe ◽  
2019 ◽  
Vol 79 (10) ◽  
pp. 378-384
Author(s):  
C. Sun ◽  
C. Thelen ◽  
I. Sancho Sanz ◽  
A. Wittmann
Keyword(s):  
Field Measurements ◽  
Paper Mill ◽  
Measuring System ◽  
Pilot Test ◽  
Protection Factor ◽  
Workplace Performance ◽  
Geometric Means ◽  
Training Facility ◽  
Workplace Conditions

The efficacy of a respirator under real workplace conditions is presented by its workplace protection factor (WPF). The aim of this study was to assess a portable measuring system for the determination of WPF for particulate filtering facepiece respirators. WPFs of CE-marked FFP2 and FFP3 filtering facepiece respirators were measured as a pilot test conducted at two workplaces: an inter-company training facility and a paper mill, with a total of seven test subjects. Each subject was quantitatively fit tested prior to the field measurements. Two TSI PortaCount instruments measured the particle concentrations simultaneously and continuously inside and outside the respirator for 15 min, with three repetitions. The results of the fit test (overall fit factor) ranged from 22 to 199. Individual WPF results ranged from 16 to 568 for FFP2 respirators, and from 13 to 232 for FFP3 respirators. The geometric means (GM) of the WPF were 135 with a 5th percentile value of 37 (FFP2), and 47 with a 5th percentile value of 12 (FFP3). This pilot test provides a new method of evaluating the workplace performance of filtering facepiece respirators.

Determination of pesticide residues in wine by SPME and GC/MS for consumer risk assessment

1998 ◽  
Vol 15 (3) ◽  
pp. 280-287 ◽  
Author(s):  
Matteo Vitalif ◽  
Maurizio Guidotti ◽  
Raffaella Giovinazzo ◽  
Ovidio Cedronet
Keyword(s):  
Risk Assessment ◽  
Pesticide Residues ◽  
Consumer Risk

scholarly journals Lack of Effect of Simultaneously Administered Didanosine Encapsulated Enteric Bead Formulation (Videx EC) on Oral Absorption of Indinavir, Ketoconazole, or Ciprofloxacin

2002 ◽  
Vol 46 (2) ◽  
pp. 385-391 ◽  
Author(s):  
Bharat D. Damle ◽  
Vanaja Mummaneni ◽  
Sanjeev Kaul ◽  
Catherine Knupp
Keyword(s):  
Oral Absorption ◽  
Historical Data ◽  
Point Estimate ◽  
Open Label ◽  
Time Curve ◽  
Geometric Means ◽  
Point Estimates ◽  
Concentration Time ◽  
Crossover Studies ◽  
Post Hoc

ABSTRACT Didanosine formulation that contains a buffer to prevent it from acid-mediated degradation can result in a significant decrease in the oral absorption of certain drugs because of interactions with antacids. An enteric formulation of didanosine is unlikely to cause such drug interactions because it lacks antacids. This study was undertaken to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, three drugs that are representative of a broader class of drugs affected by interaction with antacids. Healthy subjects of either gender were enrolled in three separate open-label, single-dose, two-way crossover studies. Subjects were randomized to treatment A (800 mg of indinavir, 200 mg of ketoconazole, or 750 mg of ciprofloxacin) or treatment B (same dose of indinavir, ketoconazole, or ciprofloxacin, but with 400 mg of didanosine as an encapsulated enteric bead formulation). A lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed C max and AUC0-∞ values (i.e., values for the area under the concentration-time curve from time zero to infinity) of indinavir, ketoconazole, and ciprofloxacin were contained entirely between 0.75 and 1.33. For indinavir (n = 23), the point estimate (90% CI; minimum, maximum) of the ratios of C max and AUC0-∞ values were 0.99 (0.91, 1.06) and 0.96 (0.91, 1.02), respectively. In the ketoconazole study, 3 of 24 subjects showed anomalous absorption of ketoconazole (i.e., an ∼8-fold-lower AUC compared to historical data), which was the reference treatment. A post hoc analysis performed after these three subjects were excluded indicated that the point estimates (90% CI) of the ratios of Cmax and AUC0-∞ values were 0.99 (0.86, 1.14) and 0.97 (0.85, 1.10), respectively. For ciprofloxacin (n = 16), the point estimate (90% CI) of the ratios of C max and AUC0-∞ values were 0.92 (0.79, 1.07) and 0.91 (0.76, 1.08), respectively. All three studies clearly indicated a lack of interaction. The T max and t 1/2 for indinavir, ketoconazole, and ciprofloxacin were similar between treatments. Our results showed that the lack of interaction of didanosine encapsulated enteric bead formulation with indinavir, ketoconazole, and ciprofloxacin indicates that this enteric formulation of didanosine can be concomitantly administered with drugs whose bioavailability is known to be reduced by interaction with antacids.

scholarly journals A Simple Method for Quantitative Determination of Active Drug Polymorphs and Amorphous in Drug Products by Fourier Transform-Raman Spectroscopy

2005 ◽  
Vol 125 (10) ◽  
pp. 807-814 ◽  
Author(s):  
Takahiro UENO ◽  
Koji URAKAMI ◽  
Atsuya HIGASHI ◽  
Kazuichi UMEMOTO ◽  
Masayuki GODO ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Fourier Transform ◽  
Quantitative Determination ◽  
Active Drug ◽  
Simple Method ◽  
Drug Products ◽  
Fourier Transform Raman Spectroscopy ◽  
Fourier Transform Raman

Bioequivalence and safety of a novel fentanyl transdermal matrix system compared with a transdermal reservoir system

2018 ◽  
Vol 7 (2) ◽  
pp. 99-107 ◽  
Author(s):  
Kenneth Todd Moore, MS ◽  
Holly D. Adams, MS ◽  
Jaya Natarajan, PhD ◽  
Jay Ariyawansa, MS ◽  
Henry M. Richards, MD
Keyword(s):  
Matrix System ◽  
Transdermal Fentanyl ◽  
Open Label ◽  
Time Curve ◽  
Geometric Means ◽  
Reservoir System ◽  
Fentanyl Concentration ◽  
The Matrix ◽  
To Receive

Objectives: Fentanyl is a potent synthetic opioid used for the management of chronic pain. A newer transdermal matrix system was developed and compared with a reservoir system used in the United States.Setting: An open-label, single-center, randomized, two-period crossover study was conducted to evaluate the bioequivalence of the transdermal matrix system to the transdermal reservoir system. Seventy-four subjects completed treatment with both the reservoir system (100 μg/h) and the matrix system (100 μg/h), each applied for 72 hours. After application of the first system, subjects completed a 9-day washout and then crossed over to receive the other system for another 72 hours.Main outcome measure: Blood samples for the determination of serum fentanyl concentrations were taken in each treatment period for up to 120 hours following application.Results: The ratios of geometric means for maximum fentanyl concentration (Cmax) and area under the concentration-time curve (AUClast and AUC∞ ) were 106 percent, 110 percent, and 110 percent, respectively. The 90% confidence intervals for the ratios of the geometric means were contained within the bioequivalence criteria of 80-125 percent. The matrix system adhered well to skin. Systemic and topical safety profiles were comparable between treatments.Conclusions: The transdermal fentanyl matrix system adhered well, was well tolerated, and produced systemic exposures of fentanyl that were bioequivalent to the reservoir system.

Higher Yield and Quality through Particle Identification

2008 ◽  
Vol 51 (2) ◽  
pp. 55-65
Author(s):  
O. Valet ◽  
M. Lankers
Keyword(s):  
Rapid Determination ◽  
Particle Identification ◽  
Manufacturing Processes ◽  
Data Sets ◽  
Drug Products ◽  
Particulate Contamination ◽  
Yield And Quality ◽  
Analytical Result ◽  
Nasal Drug Products

The sources of particulate contamination are often not easy to identify. To control manufacturing processes, the measurement of particle concentration and size is necessary and has been routinely performed for many years. Technology has been developed to increase the information available for the immediate evaluation of particles. The method analyzes airborne particles or particles isolated from liquids automatically according to their number, size, and chemical composition.1,2 The analysis of thousands of particles enables users to locate the major sources of contamination in various manufacturing processes. The analytical tool provides rapid determination of particulate contamination, thus allowing for a quick, efficient response. Over time, the ability to compare analytical result data sets assists in detecting trends and implementing the appropriate quality management. Routine use of the technology contributes to ongoing supervision and optimization of production processes. This study reports on the use of the technology to analyze foreign particles associated with oral, inhalable, and nasal drug products (OINDP), parenterals, and coronary stents. Applications for troubleshooting and identifying latent contamination sources are discussed through several examples.

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