An Overview of Adalimumab Therapy for Ankylosing Spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory disease known for causing pain, stiffness, and reduced mobility in the axial skeleton. Adalimumab, a tumor necrosis factor (TNF) inhibitor, has emerged as a promising therapeutic option for AS. METHODS: This systematic review involved a comprehensive search of randomized controlled trials related to AS treatment, conducted in major databases such as MEDLINE, Google Scholar, and PubMed. The search terms encompassed ankylosing spondylitis, adalimumab, methotrexate, other non-biologic DMARDs, glucocorticoids, NSAIDs, and analgesics. A total of 14 randomized controlled trials with 4,500 participants were included in the review. RESULTS: The review's results revealed that adalimumab demonstrated notable superiority when compared to a placebo. It effectively reduced disease activity, improved physical function, and lowered inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate. Adalimumab demonstrated a favorable safety profile, with adverse events comparable to those observed with placebo. CONCLUSION: Based on the results, adalimumab is deemed an effective treatment for AS, showcasing its potential as a first-line therapeutic option. Notably, no significant increase in adverse events was observed compared to placebo. However, the conclusion emphasizes the need for further studies with extended follow-up durations to ascertain the long-term efficacy and safety of adalimumab in AS management. This systematic review provides valuable insights supporting the use of adalimumab in the treatment of AS and underscores the importance of ongoing investigations into its long-term effects to optimize its clinical utilization in AS patients.

Methylene blue in anticancer photodynamic therapy: systematic review of preclinical studies.

Background: Methylene blue has a long history of clinical application. Thanks to phenothiazine chromophore, it has potential in photodynamic anticancer therapy. In spite of the growing body of literature that has evaluated the action of this dye on different types of cancer, the systematic understanding of this problem is still lacking. Therefore, this systematic review was performed to study the efficacy of methylene blue in photodynamic anticancer therapy. Methods: This systematic review was carried out in accordance with the PRISMA guidelines, and the study protocol was registered in PROSPERO (CRD42022368738). Articles for the systematic review were identified through the PubMed database. SYRCLE's risk of bias tool was used to assess the studies. The results of systematic analysis are presented as narrative synthesis. Results: Ten studies met the inclusion criteria and these full texts were reviewed. In the selected articles, the dosage of dye infusion ranged from 0.04 to 24.12 mg/kg. The effectiveness of photodynamic therapy with methylene blue against different types of cancer was confirmed by a decrease in tumor sizes in seven articles. Conclusion: The results of the systematic review support the suggestions that photodynamic therapy with methylene blue helps against different types of cancer, including colorectal tumor, carcinoma, and melanoma. In cases of nanopharmaceutics use, a considerable increase of anticancer therapy effectiveness was observed. The further research into methylene blue in photodynamic anticancer therapy is needed. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=368738), identifier (CRD42022368738).

Investigation of Polyphenolic Compounds in Different Varieties of Black Chokeberry Aronia melanocarpa.

The purpose of this work was to study the qualitative and quantitative composition of the main groups of biologically active substances in the fresh fruits of five different varieties of black chokeberry (Aronia melanocarpa (Michx.) Elliot), carried out within the framework of the search for available and cost-effective raw materials for food product fortification. Samples of aronia chokeberry were grown at the Federal Scientific Center named after I.V. Michurin in the Tambov region of Russia. Using a modern chemical-analytical methodology, the contents and profiles of anthocyanin pigments, proanthocyanidins, flavonoids, hydroxycinnamic acids, organic acids (malic, quinic, succinic, and citric), monosaccharides, disaccharides, and sorbitol were determined in detail. Based on the results of the study, the most promising varieties were determined in terms of the content of the main biologically active substances.

Development and Validation of an LC-MS/MS Method for Simultaneous Determination of Short Peptide-Based Drugs in Human Blood Plasma.

A novel HPLC-ESI-MS/MS method for simultaneous gonadotropin-releasing hormone (GnRH) analogs and somatostatin analog quantitation was developed and validated. The developed method was successfully applied to pharmacokinetic studies. The sample preparation process included solid-phase extraction (SPE). Effective chromatographic separation of the analytes and internal standard (dalargin) was achieved with a C18 column, using a gradient elution with two mobile phases: 0.1% v/v formic acid (aqueous solution) and 0.1% v/v formic acid (acetonitrile solution). The linearity of the method was demonstrated within a concentration range of 0.5-20 ng/mL, with correlation coefficients between 0.998-0.999 for goserelin, buserelin, triptorelin, and octreotide, respectively. The relative standard deviation (RSD, %) values for method accuracy and precision did not exceed 20% at the lower level of quantitation (LLOQ) or 15% at other concentration levels.

Cooling down with Entresto. Can sacubitril/valsartan combination enhance browning more than coldness?

BACKGROUND: It is a growing importance to induce a new treatment approach to encourage weight loss but also to improve maintenance of lost weight. It has been shown that promotion of brown adipose tissue (BAT) function or acquisition of BAT characteristics in white adipose tissue (terms referred as "browning") can be protective against obesity. MAIN TEXT: Amongst numerous established environmental influences on BAT activity, cold exposure is the best interested technique due to its not only effects on of BAT depots in proliferation process but also de novo differentiation of precursor cells via ß-adrenergic receptor activation. A novel combination drug, sacubitril/valsartan, has been shown to be more efficient in reducing cardiovascular events and heart failure readmission compared to conventional therapy. Also, this combination of drugs increases the postprandial lipid oxidation contributing to energy expenditure, promotes lipolysis in adipocytes and reduces body weight. To date, there is no research examining potential of combined sacubitril/valsartan use to promote browning or mechanisms in the basis of this thermogenic process. CONCLUSION: Due to the pronounced effects of cold and sacubitril/valsartan treatment on function and metabolism of BAT, the primary goal of further research should focused on investigation of the synergistic effects of the sacubitril/valsartan treatment at low temperature environmental conditions.

Affinity Capture Elution (ACE) ELISA Method Development and Validation for Novel RPH-104 Drug Immunogenicity Evaluation.

As the number of therapeutic protein products is growing rapidly, there is a strong need for the development of bioanalytical methods that are easy to perform, specific, sensitive, robust, and affordable. Methods for immunogenicity evaluation of therapeutic proteins take an important place in this field of bioanalytics. The aim of the study was to develop a method for immunogenicity testing of the novel RPH-104 drug using the Affinity Capture Elution (ACE) ELISA technique. RPH-104 is a promising Interleukin-1 (IL-1) inhibitor that is currently undergoing a series of clinical studies, including those on socially significant and orphan diseases. The developed method was validated for assay cut-point, sensitivity, selectivity, drug tolerance, hook effect, specificity, precision, and stability. Method sensitivity was established at 114.9 ng/mL, while low and high positive controls were equal to anti-RPH-104 antibody concentrations of 155 ng/mL and 2500 ng/mL, respectively. Method specificity was confirmed in the presence of the interfering compounds, namely IL-1α, IL-1ß, and IL1-Ra. The developed and validated ELISA method was successfully applied to subject samples.

Insights into the Cardiotoxic Effects of Veratrum Lobelianum Alkaloids: Pilot Study.

Jervine, protoveratrine A (proA), and protoveratrine B (proB) are Veratrum alkaloids that are presented in some remedies obtained from Veratrum lobelianum, such as Veratrum aqua. This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel NaV1.5, and machine learning-based structure-activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze Veratrum alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (-10.8 kcal/mol), logP value (4.188), and pKa value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC50. In general, all three analyzed alkaloids show the affinity to NaV1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by Veratrum aqua confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by NaV1.5 inhibition.

Veratrum Alkaloid Determination in Four Cases of Veratrum Aqua Poisonings.

Veratrum poisonings are described in the toxicology literature as multiple Veratrum species grow in different parts of the Northern Hemisphere and are occasionally ingested by mistake. Veratrum toxicity is attributed to the steroidal alkaloids contained in all parts of the plant. In Russia, Veratrum poisonings are more common since there is an over-the-counter Veratrum lobelianum-based tincture, Veratrum Aqua (VA), which is topically used for the treatment of lice infestation. Despite its toxicity, VA is misused in traditional medicine as a remedy for alcohol use disorder. We describe four cases of VA poisoning that occurred in Moscow, Russia. Three main V. lobelianum alkaloids (jervine, protoveratrine A (proA) and protoveratrine B) were determined in patient plasma and urine samples using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Here, we describe a novel validated LC-MS-MS method for jervine and proA quantification. A simple and rapid liquid-liquid extraction with methyl tert-butyl ether was utilized for analyte extraction. Chromatographic separation was achieved using a Poroshell 120 EC-C18 column, and the total run time was 14 min. The lower limit of quantification was 0.1 ng/mL for jervine and proA in both plasma and urine. Biological samples were obtained upon hospital admission and during treatment, thus enabling to get a better understanding of the alkaloid elimination profile. Upon admission, plasma concentrations of jervine (concentration range: 0.10-5.01 ng/mL) prevailed over proA (concentration range: 0-0.67 ng/mL). At this time, proA already reached maximum concentrations in urine (concentration range: 0.15-37.70 ng/mL). Maximum concentrations of jervine in urine were observed 24 h after admission (concentration range: 0.10-9.55 ng/mL). In all cases, plasma concentrations of Veratrum alkaloids correlated with condition severity. Since none of the patients confirmed VA intake, instrumental analysis was the basis for the definitive diagnosis of VA poisoning.

Development and Validation of four Nitrosamine Impurities Determination Method in Medicines of Valsartan, Losartan, and Irbesartan with HPLC-MS/MS (APCI).

Since 2018, regulation and control of genotoxic nitrosamine impurities levels have been a mandatory quality and safety characteristic for various drugs. The main issue of nitrosamine determination in drugs is a low sensitivity of the existing methods and a continuously extending list of controlled compounds. The reason is the low safe daily dose of these impurities and chromophores' absence within their structure. Development and validation of a method for nitrosamine impurities (regulated by the regulatory authorities) determination in Valsartan, Losartan, and Irbesartan using high-performance liquid chromatography with mass spectrometry detection. An Agilent Infinity II chromatographic system with a mass spectrometric detector (MSD 6460 Triple Quad) and atmospheric pressure chemical ionization was used in this study. During the development of a method, the optimal conditions for chromatographic separation (composition of mobile phases, gradient parameters) were selected, as well as the parameters of mass spectrometric detection were optimized. The usage of chemical ionization made it possible to achieve the method's maximum sensitivity concerning the studied nitrosamines, and the optimized parameters of mass spectrometric detection made it possible to get rid of the matrix effect. The absence of additional stages of purification and concentration can significantly reduce the total time of the analysis, which is a significant advantage of nitrosamine's advanced determination method. The resulting method was validated for specificity, linearity, LOQ, LOD, accuracy, and precision. Resulting method met all acceptance criteria and can be used for routine quality control of Valsartan, Losartan, and Irbesartan pharmaceutical substances.

Characterisation of α-amylase inhibitors in marigold plants via bioassay-guided high-performance thin-layer chromatography and attenuated total reflectance-Fourier transform infrared spectroscopy.

A high-performance thin-layer chromatography with microchemical derivatization and bioassay guided detection was used for bioanalytical profiling of selected marigold plant extracts. Anisaldehyde/sulfuric acid reagent and thymol/sulfuric acid reagent were used to visualize separated components on the chromatograms. Antioxidant activity and α-amylase inhibition were assessed with 2 bioassays, DPPH assay to detect free radical scavengers and starch-iodineassay method to detect compounds that inhibit α-amylase. The highest antioxidant activity of 10.12 µg of gallic acid equivalents (GAE) per 20 µL of extract was measured in extract from Tagetes flowers and the lowest in the extract from Calendula leaves with 5.10 µg of GAE. Multiple zones of α-amylase inhibition were detected. A detailed analysis of the ATR-FTIR spectra from the bands at RF = 0.24 suggest that faradiol esters and saturated fatty acids esters, palmitic acid, myristic acid, and lauric acid are responsible for α-amylase inhibition, unsaturated fatty acids for the band at RF = 0.51 and phytoecdysteroids for the band at RF = 0.53.

A new integrated HPTLC - ATR/FTIR approach in marine algae bioprofiling.

The aim of this study was to evaluate marine algae extracts in terms of their anti-inflammatory activity using a combination of chromatographic separation and chemical detection with subsequent infrared vibrational spectroscopy identification. Extraction parameters, chemical fingerprint, and the activity levels were considered for the method optimization. High-performance thin-layer chromatography (HPTLC) combined with microchemical derivatization, was used to separate and detect bioactive compounds with antioxidant activity and anti-inflammatory activities, and to detect different classes of terpenoids. Infrared attenuated total reflectance (ATR) spectral analysis of the bands with bioactive compounds, identified sulfated polysaccharides to be responsible for the anti-inflammatory activity in extracts of brown algae Carpoglossum confluens and Phyllospora comosa. Steroids as unique antioxidants with significant free radical scavenging activities were observed in extracts of brown algae Cystophora platylobium, Cystophora retorta, Carpoglossum confluens and Phyllospora comosa. HPTLC combined with biochemical assays and FTIR-ATR spectrometry was demonstrated to be a straightforward strategy for bioprofiling marine algae extracts.

Analytical Strategies in Lipidomics for Discovery of Functional Biomarkers from Human Saliva.

Human saliva is increasingly being used and validated as a biofluid for diagnosing, monitoring systemic disease status, and predicting disease progression. The discovery of biomarkers in saliva biofluid offers unique opportunities to bypass the invasive procedure of blood sampling by using oral fluids to evaluate the health condition of a patient. Saliva biofluid is clinically relevant since its components can be found in plasma. As salivary lipids are among the most essential cellular components of human saliva, there is great potential for their use as biomarkers. Lipid composition in cells and tissues change in response to physiological changes and normal tissues have a different lipid composition than tissues affected by diseases. Lipid imbalance is closely associated with a number of human lifestyle-related diseases, such as atherosclerosis, diabetes, metabolic syndromes, systemic cancers, neurodegenerative diseases, and infectious diseases. Thus, identification of lipidomic biomarkers or key lipids in different diseases can be used to diagnose diseases and disease state and evaluate response to treatments. However, further research is needed to determine if saliva can be used as a surrogate to serum lipid profiles, given that highly sensitive methods with low limits of detection are needed to discover salivary biomarkers in order to develop reliable diagnostic and disease monitoring salivary tests. Lipidomic methods have greatly advanced in recent years with a constant advance in mass spectrometry (MS) and development of MS detectors with high accuracy and high resolution that are able to determine the elemental composition of many lipids.

An improved extraction protocol for therapeutic dabigatran monitoring using HPLC-MS/MS.

A new sample extraction protocol was developed for pharmacokinetic studies of dabigatran with high-performance liquid chromatography separation - electrospray ionization time-of-flight mass spectrometry analysis. After protein precipitation with acetonitrile, free dabigatran and its metabolites are separated into water phase by water-dichloromethane liquid-liquid extraction to purify the sample from proteins and endogenous lipophilic compounds. Chromatographic separation was achieved on an Agilent Zorbax SB-CN column (150 × 4.6 mm, 5 µm)) using 0.1% aqueous solution of formic acid and acetonitrile (80:20) as the mobile phase. Agilent Zorbax SB-CN column was selected to improve sample resolution and to avoided early elution of dabigatran previously seen when using a C18 column. The extended calibration curve was constructed from 5 to 1000 ng/L while precision and accuracy were assessed at four levels across the linear dynamic ranges. Within-run precision was <5.6% and the between-run precision was <3.9%. The method accuracy ranged from 89.8% to 104.4%. The developed method was successfully applied to 30 patient samples to evaluate antithrombotic efficacy and anticoagulant activity of dabigatran following knee endoprosthesis surgery.

Lipidomic analysis as a tool for identifying susceptibility to various skin diseases.

This review is about the significance of the use of lipidomic analysis for identifying susceptibility to skin diseases. Exactly this article describes the use of lipidomic analysis in different studies to detect abnormalities in the lipid composition of the skin to diagnose and prevent various dermatological diseases.

Peptide-Based Therapeutics for Oncology.

The development of peptide-based drugs, which are usually synthetic analogues of endogenous peptides, is currently one of the most topical directions in drug development. Among them, antitumor peptide-based drugs are of great interest. Anticancer peptides can be classified into three main groups based on their mechanism of action: inhibitory, necrosis-inducing and pro-apoptotic peptides. As an antitumor therapy, peptides are considered to have at least the same efficacy as chemotherapy or surgical treatment, but offer advantages in terms of safety and tolerability, given that chemotherapy is usually characterized by severe adverse effects, and surgery carries additional risks for patients. Short peptides have a number of benefits over other molecules. First, compared with full-length proteins and antibodies, short peptides are less immunogenic, more stable ex-vivo (prolonged storage at room temperature), and have better tumor or organ permeability. Moreover, the production of such short peptide-based drugs is more cost effective. Second, in comparison with small organic molecules, peptides have higher efficacy and specificity. Finally, due to the fact that the main products of peptide metabolism are amino acids, these drugs are usually characterized by lower toxicity. Short peptides have a highly selective mechanism of action, thereby demonstrating low toxicity. Furthermore, with the addition of different stabilizing structural modifications, as well as novel drug delivery systems, the peptide-based drugs are proving to be promising therapeutics for cancer mono- or polytherapy. However, challenges remain including that endogenous and synthetic peptide molecules can be oncogenic. Therefore, it is important to investigate whether peptides contribute to tumor growth. In order to answer such questions, numerous preclinical and clinical studies of peptide-based therapeutics are currently being conducted.

Validated HPLC-MS/MS method for quantification of ethylmethylhydroxypyridine succinate in rat brain and its application to a pharmacokinetic study.

2-ethyl-6-methyl-3-hydroxypyridine (EMHP) succinate is the original antioxidant and antihypoxic drug commonly prescribed in Russia. The objective of this study was to develop a rapid, simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for EMHP quantitation in rat brain tissue with the use of a bead beating homogenizer. The comparison between two approaches to brain tissue preparation was performed, when spiking the blank brain tissue with EMHP reference standard and internal standard (IS) before and after homogenization step. Chromatographic separation was achieved using Zorbax Eclipse Plus C18 column (1.8 µm, 2.1 × 50 mm) and elution was performed with the mobile phase, consisting of 10 mM of ammonium formate aqueous solution with 0.1% formic acid as solvent A and 0.1% formic acid in methanol as solvent B [44%(А):56%(В), v/v]. Flow rate was 0.4 mL/min and the total run time for each sample analysis was 2.0 min. EMHP and amantadine, IS of this study, were analyzed in positive ionization mode. Ion transitions of m/z 138.0 → 123.0 for EMHP and m/z 152.0 → 135.0 for amantadine were selected in multiple reaction monitoring mode. The developed method for EMHP determination in rat brain samples was validated for selectivity, linearity, accuracy, precision, matrix effects, and stability. The lower and upper limits of quantification were determined to be 1 and 1500 ng/g, respectively. The developed and validated HPLC-MS/MS method was successfully applied to determine EMHP concentrations in rat brain tissue following the intraperitoneal administration at a dose of 3.4 mg/kg.

The impact of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran equilibrium peak concentration in patients after total knee arthroplasty.

BACKGROUND: Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. PATIENTS AND METHODS: A total of 60 patients, aged 37-81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). RESULTS: Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p<0.008). There was no statistically significant genotype-dependent difference in the trough concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene. CONCLUSION: Our findings indicate that the polymorphisms of ABCB1 rs1045642 may have a prominent contribution to the safety of dabigatran in patients after knee surgery. Moreover, TT genotype may be associated with the higher risk of hemorrhagic complications in this population. There were no influence of polymorphism of ABCB1 rs4148738 and CES1 rs2244613 on dabigatran peak and through concentrations. Larger studies are needed to confirm our observations.

Biowaiver monographs for immediate release solid oral dosage forms: piroxicam.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bioinequivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of Cmax ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of Cmax for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo.

Biowaiver monographs for immediate-release solid oral dosage forms: ketoprofen.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing ketoprofen are reviewed. Ketoprofen's solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA)/dissolution data were taken into consideration. The available data suggest that according to the current Biopharmaceutics Classification System (BCS) and all current guidances, ketoprofen is a weak acid that would be assigned to BCS Class II. The extent of ketoprofen absorption seems not to depend on formulation or excipients, so the risk of bioinequivalence in terms of area under the curve is very low, but the rate of absorption (i.e., BE in terms of peak plasma concentration, C(max) ) can be altered by formulation. Current in vitro dissolution methods may not always reflect differences in terms of C(max) for BCS Class II weak acids; however, such differences in absorption rate are acceptable for ketoprofen with respect to patient risks. As ketoprofen products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR ketoprofen solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients present also in IR solid oral drug products containing ketoprofen, which are approved in International Conference on Harmonisation or associated countries, for instance, as presented in this paper; (b) both the test drug product and the comparator dissolve 85% in 30 min or less in pH 6.8 buffer; and (c) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When one or more of these conditions are not fulfilled, BE should be established in vivo.