Therapeutic Equivalence Research Articles

Analysis of Factors Related to Variation in Dissolution Profiles Estimated from Continuously Conducted Dissolution Tests of Generic Products.

The development of generic pharmaceuticals involves a bioequivalence study to ensure the therapeutic equivalence of the test formulation to the original innovative product. The formulation characteristics of generic products are expected to be maintained in the long term after approval. This study analyzed the factors contributing to the changes in the dissolution profiles of approved products during their life cycles. Cumulative data on the dissolution similarity of 1675 products of 127 ingredients tested by official laboratories in Japan were assessed according to Japanese bioequivalence guidelines with slight modifications. The products showing dissimilarities in dissolution profiles were analyzed for reporting year, therapeutic category, co-development, physical properties of the active pharmaceutical ingredient (API), and suspected reasons for dissolution change. The increase in the number of dissimilar products is related to the co-development of generic products. Although the solubility of the API was not associated with the dissolution change in the analysis of the total dissolution data, control of the API particle size is suggested to be important for drugs with poorly soluble APIs. Additionally, a risk factor for dissolution changes in the test solutions at a certain pH was the presence of acidic or basic residues. These results indicate the importance of proper development through a thorough evaluation of the formulation and process factors affecting the dissolution properties throughout the product lifecycle.

Home-based rehabilitation training with human key point detection for chronic low back pain patients: a randomized controlled trial protocol

BackgroundCore stability exercise (CSE) is a globally acknowledged intervention for managing chronic low back pain. However, the sustained adherence of patients with chronic low back pain to CSE can be challenging, mainly due to the absence of supervision and guidance from physical therapists during home-based exercise sessions. Consequently, exercise compliance tends to decline, resulting in suboptimal long-term effectiveness of the intervention. In this trial, our primary aim is to evaluate the potential therapeutic equivalence between home-based rehabilitation training employing key point identification technology and exercise guidance administered in a hospital setting.MethodsIn this trial, we will randomly assign 104 adults with chronic low back pain (CLBP) to either an intervention or control group, with 52 participants in each group. Both interventions will consist of three weekly 0.5-h sessions of core stability exercise (CSE). The intervention group will engage in home rehabilitation training utilizing key identification technology for movement, while the control group will perform supervised exercises in a hospital setting. Outcome assessments will be conducted at 4 weeks and 16 weeks after randomization. The primary outcome measure will be the change in pain intensity based on numeric rating scale (NRS scores) from baseline to 4 weeks. Secondary outcomes will include changes in physical function (measured by the Oswestry Disability Index (ODI)) and lumbar spine mobility as well as activity participation and treatment satisfaction.DiscussionIf home-based rehabilitation method is demonstrated to be non-inferior or even superior to traditional face-to-face exercise guidance, it could significantly advance the adoption of digital medical care and contribute to improving the overall health of the population.Trial registrationNCT05998434. Registered on 16 August 2023.

Patents and regulatory exclusivities on FDA-approved insulin products: A longitudinal database study, 1986-2019.

Insulin is the primary treatment for type 1 and some type 2 diabetes but remains costly in the United States, even though it was discovered more than a century ago. High prices can lead to nonadherence and are often sustained by patents and regulatory exclusivities that limit competition on brand-name products. We sought to examine how manufacturers have used patents and regulatory exclusivities on insulin products approved from 1986 to 2019 to extend periods of market exclusivity. We used the publicly available Food and Drug Administration (FDA) Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) to identify all approved biosynthetic insulin products. Individual products approved under the same New Drug Application (NDA)-e.g., a vial and pen-were considered as separate products for the purposes of analysis. We recorded all patents and regulatory exclusivities listed in the Orange Book on each product and used Google Patents to extract the timing of patent application and whether patents were obtained on delivery devices or others aspects of the product. The primary outcome was the duration of expected protection, which was determined by subtracting the FDA approval date for each product from its last-to-expire patent or regulatory exclusivity (whichever occurred later). We performed a secondary analysis that considered overall protection on insulin lines-defined as groups of products approved under the same NDA with the same active ingredients manufactured by the same company. We also examined competition from follow-on insulin products-defined as products approved with the same active ingredients as originators but manufactured by different companies (approved via a specific drug approval pathway under section 505(b)(2) of the Food, Drug, and Cosmetic Act). During the study period, the FDA approved 56 individual products across 25 different insulin lines and 5 follow-ons across 3 different insulin lines. Thirty-three (59%) of the 56 products were drug-device combinations. Manufacturers of 9 products approved during the study period obtained patents filed after FDA approval that extended their duration of expected protection (by a median of 6 years). Approximately 63% of all patents on drug-device combinations approved during the study period were related to delivery devices. The median duration of expected protection on insulin products was 16.0 years, and the median protection on insulin lines was 17.6 years. An important limitation of our analysis is that manufacturers may continue to add patents on existing insulin products while competitors may challenge patents; therefore, periods of protection may change over time. Among several strategies that insulin manufacturers have employed to extend periods of market exclusivity on brand-name insulin products are filing patents after FDA approval and obtaining a large number of patents on delivery devices. Policy reforms are needed to promote timely competition in the pharmaceutical market and ensure that patients have access to low-cost drugs.

Ledipasvir/Sofosbuvir in Hepatitis C Virus–Infected Children With Hematological Malignancies: A Pharmacokinetic Study

Children with hematological malignancies and chronic hepatitis C virus (HCV) infection are at a higher risk for rapid progression of liver disease and malignancy relapse due to multiple hepatitis flares and chemotherapy interruption. They are therefore potential candidates for microelimination of HCV infection. This study aimed to assess the effect of acute lymphoblastic leukemia (ALL) on the pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF) and the SOF major metabolite GS-331007. This was a 24-week, prospective, controlled, open-label, 2-arm PK study of patients receiving 45/200 mg once-daily LDV/SOF orally for 12 weeks. Eligible patients were HCV-RNA-positive, treatment-naive children aged 6 to <12 years and/or weighing 17 to <35 kg with genotype 4 chronic HCV infection without cirrhosis. The primary efficacy and safety end points were the achievement of sustained virologic response for all patients with absence of any adverse events leading to permanent discontinuation of the study drug. Steady-state noncompartmental analysis was performed to determine the PK parameters of SOF, GS-331007, and LDV as the primary PK outcome. Dose suitability was based on the 90% CI of exposure geometric mean ratio percentage within 50% to 200% compared with adults. Ten HCV-infected children with ALL (chemotherapy treatment group) and 12 eligible children with no malignancy (control group) were enrolled and completed the study period. All 22 patients achieved the sustained virologic response with no adverse events leading to interruption or permanent discontinuation of the study drug. Compared with the control group, the ALL group patients had similar SOF, GS-331007, and LDV exposure. Compared with adults, the AUCτ of GS-331007 was lower and the AUCτ and Cmax,ss of SOF and the Cmax,ss of LDV were modestly higher in the ALL group (acceptance limit, 50%-200%). However, the observed efficacy and favorable safety profile made these changes not clinically significant. Weight-based dosing of LDV/SOF (45/200 mg) is highly effective and safe among genotype 4 HCV-infected children weighing 17 to <35 kg and diagnosed with ALL undergoing maintenance chemotherapy. The similarity in the drug exposure, efficacy, and safety clinical end points between patients with and without hematological malignancy support their therapeutic equivalence. Further studies with a larger sample size may be required to confirm the safety of LDV/SOF in patients with ALL and to recommend appropriate dosing in children with hematological malignancies, if needed. gov identifier: NCT03903185.

Statistical Significance Versus Clinical Relevance: A Head-to-Head Comparison of the Fragility Index and Relative Risk Index.

Background In biostatistics, assessing the fragility of research findings is crucial for understanding their clinical significance. This study focuses on the fragility index, unit fragility index, and relative risk index as measures to evaluate statistical fragility. The fragility indices assess the susceptibility of p-values to change significance with minor alterations in outcomes within a 2x2 contingency table. In contrast, the relative risk index quantifies the deviation of observed findings from therapeutic equivalence, the point at which the relative risk equals 1. While the fragility indices have intuitive appeal and have been widely applied, their behavior across a wide range of contingency tables has not been rigorously evaluated. Methods Using a Python software program, a simulation approach was employed to generate random 2x2 contingency tables. All tables under consideration exhibited p-values < 0.05 according to Fisher's exact test. Subsequently, the fragility indices and the relative risk index were calculated. To account for sample size variations, the indices were divided by the sample size to give fragilityand risk quotients. A correlation matrix assessed the collinearity between each metric and the p-value. Results The analysis included 2,000 contingency tables with cell counts ranging from 20 to 480. Notably, the formulas for calculating the fragility indices encountered limitations when cell counts approached zero or duplicate cell counts hindered standardized application. The correlation coefficients with p-values were as follows: unit fragility index (-0.806), fragility index (-0.802), fragility quotient (-0.715), unit fragility quotient (-0.695), relative risk index (-0.403), and risk quotient (-0.261). Conclusion The fragility indicesand fragility quotients demonstrated a strong correlation with p-values below 0.05, while the relative risk index and relative risk quotient exhibited a weak association with p-values below this threshold. This implies that the fragility indices offer limited additional information beyond the p-value alone. In contrast, the relative risk index and risk quotient exhibitindependence from the p-value, indicating that theymay provide important additional information about statistical fragility by evaluating the divergence of observed results from therapeutic equivalence, irrespective of the p-value-based statistical significance.

Translated article] Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia

ObjectiveThe aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. MethodA literature search was conducted in Pubmed and Embase on November 10, 2022 for phase III clinical trials studying Bruton tyrosine kinase inhibitors in monotherapy in the first-line setting for chronic lymphocytic leukemia. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. ResultOf the 39 studies obtained in the review, 2 clinical trials were selected: 1 for zanubrutinib and 1 for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were atrial fibrillation, hypertension, and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the equivalent therapeutic alternatives guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. ConclusionsAssuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the 2 alternatives as equivalent therapeutic alternatives.

Are all JAK inhibitors for the treatment of rheumatoid arthritis equivalent? An adjusted indirect comparison of the efficacy of tofacitinib, baricitinib, upadacitinib, and filgotinib.

Comparisons of Janus kinase inhibitors (JAKi) for treatment of rheumatoid arthritis in patients with inadequate response to biologic disease-modifying anti-rheumatic drugs are lacking. We assessed the relative efficacy and safety of four JAKi (tofacitinib, baricitinib, upadacitinib, and filgotinib) in this context. We performed an adjusted indirect comparison (IC) of randomized clinical trials using Bucher's method with an IC and mixed calculator. Endpoints were Disease Activity Score C-reactive protein (DAS28-CRP) and American College of Rheumatology-20 (ACR20). Equivalence was assessed using the equivalent therapeutic alternatives (ETA) guidelines. We included four of 133 potentially relevant studies. IC showed no statistically significant differences between the four JAKi regarding DAS28-CRP < 3.2. Results were similar in terms of ACR20 except for tofacitinib showing lower efficacy than upadacitinib (RAR -18.4% [IC95% -33.4 to -3.5], p=0.0157). Statistically significant differences were related to the relevant difference for tofacitinib in both endpoints. Despite no statistical differences for baricitinib, we observed a probably clinically relevant difference regarding DAS28-CRP. Probably clinically relevant differences were found for tofacitinib vs. upadacitinib in both endpoints, and for baricitinib vs. upadacitinib in DAS28-CRP. Safety, drug-drug interactions, and convenience considerations did not modify the result of therapeutic equivalence assessment based on efficacy data. In conclusion, our results show that filgotinib and upadacitinib are ETA. Baricitinib and upadacitinib are also ETA due to a lack of clear differences and for showing superiority over placebo. The results for tofacitinib and upadacitinib show some inconsistency and more data are needed. Key Points • To date, neither a head-to-head comparison nor an indirect comparison between the Janus kinase inhibitors has been performed in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying anti-rheumatic drugs. • We performed an adjusted indirect comparison that included randomized clinical trials of tofacitinib, baricitinib, upadacitinib, and filgotinib to assess their equivalence in this scenario. • Our results show that baricitinib and filgotinib are equivalent therapeutic alternatives compared to upadacitinib. However, there is some inconsistency in the results of tofacitinib in front of upadacitinib.

A comprehensive review addressing the factors influencing generic drug substitution

Generic drug substitution is a common practice in healthcare systems worldwide to promote cost-saving treatments while maintaining therapeutic effectiveness. Several factors influence this substitution, including regulatory policies, safety and efficacy considerations, patient and physician preferences, and market dynamics. This review comprehensively analyzes how these factors interact and influence generic drug substitution in healthcare settings and across various therapeutic classes and highlight the importance of balancing cost-saving measures with maintaining patient safety and therapeutic efficacy. Policies and guidelines established by health authorities in each country influence the approval, interchangeability, and substitution of generic drugs. Bioequivalence and therapeutic equivalence are critical factors, particularly in drugs with narrow therapeutic indexes. Moreover, physicians’ acceptance and willingness to prescribe generic drugs, as well as patient acceptance and compliance with generic drug use, play a vital role in promoting generic substitution.

FDA changes therapeutic equivalence rating for Accord Healthcare's tacrolimus

FDA changes therapeutic equivalence rating for Accord Healthcare's tacrolimus

Lebanese pharmacists’ knowledge of generic drugs and factors affecting their use and selection following the pandemic and the economic crisis: A pilot cross-sectional study

Background Pharmacists are crucial in lowering pharmaceutical expenditures by substituting brand-name drugs for generic drugs. They are expected to understand the principles and practices of generic drug substitution for high-quality patient care. Some key areas of knowledge include bioequivalence and therapeutic equivalence, regulatory requirements, drug interchangeability, and adequate patient counseling. Objectives This study aims to assess the knowledge, perception, and practice of generic drug substitution among pharmacists in Lebanon following the crises and the factors affecting the prescription and selection of generic drugs. Methods A pilot descriptive cross-sectional study targeting 80 Lebanese pharmacists was conducted over 2 months (September-October 2022), in which data were collected using a uniform survey. Results Overall, pharmacists had a good knowledge of generic drugs in terms of active ingredients (97.5%), pharmaceutical form (85.0%), lower cost (88.7%), bioequivalence to the brand before (95.0%), and therapeutic equivalence. Nevertheless, 22.5% reported that generic drugs are less safe than brands, and 22.5% said they cause side effects or did not know. Among the possible factors that influence the prescription of generic drugs, 35.0% of pharmacists reported that the financial situation of the patient is among the least important factors, while the lack of possible alternatives (45.0%) and the difference in prices (40.0%) were the most important ones. The price of different generics on the market was among the most important factors (36.3%) affecting the selection of generic drugs, followed by the patient’s. preference (26.3%). Only 11.2% considered the information given by pharmaceutical firms could affect their choice, and 10.0% considered the presence or not of excipients with known effects in the formulation. Conclusion Most pharmacists in Lebanon were familiar with generic drugs and supported generic drug substitution. Factors affecting generic drug use and prescription should be further explored to clarify misconceptions and reduce possible adverse events.

Comparación indirecta ajustada de zanubrutinib e ibrutinib en el tratamiento de primera línea de la leucemia linfocítica crónica

ObjectiveThe aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. MethodA literature search was conducted in Pubmed and Embase on 10 November 2022 for phase III clinical trials studying Bruton's tyrosine kinase inhibitors in monotherapy in the first-line setting for CLL. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. ResultOf the 39 studies obtained in the review, two clinical trials were selected: one for zanubrutinib and one for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were auricular fibrillation, hypertension and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the ATE guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. ConclusionsAssuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the two alternatives as equivalent therapeutic alternatives.

Randomized, double-blind, multicenter study to evaluate efficacy, safety, tolerability, and immunogenicity between AVT04 and the reference product ustekinumab in patients with moderate-to-severe chronic plaque psoriasis

ABSTRACT Background This study compared efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity between AVT04 and reference product (RP) ustekinumab (Stelara®) in patients with moderate-to-severe chronic plaque psoriasis (PsO). Patients and methods This multicenter, double-blind, 52-week study randomized patients in 1:2 ratio to AVT04 or RP. At week 16, responsive patients (≥50% improvement in psoriasis area and severity index (PASI)) previously on AVT04 continued on AVT04, while those on RP were re-randomized 1:1 to switch to AVT04 or stay on RP. The primary endpoint was a percent improvement in PASI from baseline to week 12. Therapeutic equivalence was demonstrated if the confidence interval (CI) for the adjusted difference in means was contained within the equivalence margins; ±10% (90%CI). Results Of the 581 patients initially randomized (AVT04:RP, 194:387), 575 completed week 16 and 544 completed end of study visit. The percent PASI improvement for AVT04 vs RP was 87.3% vs 86.8% (CI: −2.14%, 3.01%); study met its primary endpoint. Efficacy, safety and PK profiles were comparable across treatment arms throughout the entire study duration, and the incidence of antibodies to ustekinumab had no clinically meaningful impact. Conclusion This study demonstrates the therapeutic equivalence between AVT04 and RP in patients with moderate-to-severe chronic PsO, with similar safety and tolerability. Trial registration NCT04930042; EudraCT Number: 2020-004,493-22

Isolation of alkaloidal and glycosidal fractions from leaves of Trigonella foenum-graecum L. cv. Desi indigenous to Pakistan for antiprostaglandin evaluation as substitute of nonsteroidal anti-inflammatory drugs

Ethnopharmacological relevanceTrigonella foenum graecum (fenugreek) has been in use for a long time as a traditional medicine and natural food additive. The reported gastro-protective property makes it unique among other herbs. Seeds and leaves have been shown to exert significant antiatherogenic, antidiabetic, antianorexic, antioxidant, anticarcinogenic, antihyperlipidemic, galactogogue and anti-inflammatory effects in several animal and human models. But its use as a substitute for ulcerative nonsteroidal anti-inflammatory drugs needs to be confirmed. Aim of the studyNonsteroidal anti-inflammatory drugs (NSAIDs) are in common use in treating inflammation associated with a variety of ailments, fever and pain such as menstrual cramps, back pain, arthritic pain and headaches. Their toxicity profile includes the risk of severe gastro-intestinal adverse events like increased bleeding tendency, ulceration, perforation, etc. Conventional NSAIDs have also been reported to reduce the glomerular filtration rate (GFR) by affecting afferent arterioles in nephrons. Exacerbated potassium levels were noted in patients using NSAIDs concomitantly with antihypertensive drugs belonging to the angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) classes. In this context, the need of the hour is to discover and isolate new compounds from the reported medicinal plants for evaluation of antiprostaglandin potential and safety profile in terms of the hepato-renal system. These compounds may be used as substitutes for NSAIDs in the future management of inflammation and pain with therapeutic equivalency and organ safety. In this scenario, the present study aimed to assess the antiprostaglandin potential of alkaloidal and glycosidal fractions from the leaves of Trigonella foenum-graecum L. cv. Desi variety, indigenous to Pakistan, in albino mice along with safety profile. The herb has been used as folk medicine since ancient times for treating inflammation and pain. Material and methodsAlkaloidal and glycosidal fractions were separated from a methanol extract of leaves of the fenugreek Desi variety. After separation of fractions, their subsiding effects on carrageenan-induced inflammation, air pouch exudate prostaglandin-E2 levels, Brewer's yeast induced pyrexia and acetic acid induced abdominal constrictions were assessed in adult male albino mice. The safety profile of fractions was assessed by measuring their effects on mice sera hepato-renal biomarkers. ResultAlkaloidal fraction of T. foenum Desi variety was found to be significantly effective in reducing inflammation, air pouch exudate PGE2 levels, fever (≤37 °C) and pain by inhibiting writhes (up to 96.58%) Gradual inhibition of paw edema was observed 1–6 h post-dose, with maximum reduction percentages of 62.82% and 62.57% for 100 mg and 200 mg, respectively. Both fractions did not disturb the normal physiology of the hepato-renal system by showing normal biomarker values. ConclusionIn summary, the results demonstrate the potent antiprostaglandin potential of the alkaloidal fraction of gastroprotective fenugreek “Desi” leaves with hepato-renal system safety and hence justify its use as a substitute for ulcerative nonsteroidal anti-inflammatory drugs.

A Comparative Study on Approval of Follow-on Version of Sevelamer Carbonate and Glatiramer Acetate (GA) in US, EU

Abstract: Many non-biological drugs, different in terms of their structure and mode of action, pharmacological classification, and therapeutic indication, have a common factor of structural complexity and are grouped as non-biological complex drugs (NBCDs). When an innovator drug nears the time of off-patent, different manufacturers attempt to produce its subsequent version, so the patients will have a cost-effective therapeutic equivalent. Since the innovator molecule is complex, its follow-on drug can be called its true generic version, if its bioavailability, bioequivalence and therapeutic equivalence to the innovator drug are demonstrated. However, it is observed that a case-to-case basis approach is implemented by European Medicines Agency (EMA) and Food and Drug Administration, US (USFDA) in the approval of such drugs and there is no uniformity observed between the two. : In this study, an attempt is made to study the complexity of molecules compare and understand the data requirements, and procedures adopted for the review and approval of such complex products. Therefore, drug sevelamer carbonate and glatiramer acetate are selected for the study. A methodical approach was followed. European assessment reports and drug approvals available in the orange book database of the former two regulatory agencies were studied. It is observed that the generic version of glatiramer acetate is approved as an abbreviated new drug application (ANDA) by Food and Drug Administration whereas the same was approved as the hybrid application by European Medicines Agency requiring the applicant to generate and submit more data. Thus, harmonization of the regulatory requirements for the approval of follow-on versions of such complex drugs is essential for better understanding, predictability of the regulatory process, and acceleration of the drug approval process, in the interest of patients. This will help the faster access of the drugs to the patients and allow interchangeability of the innovator drugs with its cost-effective generic version.

A novel abiraterone acetate oral suspension for patients with metastatic prostate cancer: An open-label, phase 3, randomized trial.

5052 Background: Abiraterone acetate (AA) is a first-line oral hormone therapy for metastatic prostate cancer (mPC), but the licensed formulation is limited by large tablet size, requirement to take on an empty stomach, and pharmacokinetic variability. TAVT-45, a novel formulation of AA granules for oral suspension, offers improved oral bioavailability (allowing dose reduction), decreased food effect, and may provide an option for the ~20-30% of patients with dysphagia. This Phase 3, open-label global study (NCT04887506) aimed to establish therapeutic equivalence between TAVT-45 granules and reference AA tablets (R-AA). Methods: Patients with castrate-resistant or castrate-sensitive mPC (mCRPC or mCSPC) were randomized 1:1 to receive TAVT-45 (1 sachet of AA granules [250 mg] in water or juice, twice daily) or R-AA tablets (2 x 500 mg once daily ≥1 h before or ≥2 h after food), plus prednisone (5 mg once [mCSPC] or twice [mCRPC] daily) for 84 days. Efficacy (serum testosterone and prostate-specific antigen [PSA]) and safety were assessed. Average serum testosterone concentrations on Days 9 &amp; 10 (primary endpoint, analyzed via analysis of covariance) were compared to show therapeutic equivalence. The key secondary endpoint was PSA-50 response (patients with ≥50% decrease in PSA from baseline at any time). mCRPC was the primary analysis population. Preliminary results are presented. Results: Of 107 randomized patients, 103 received TAVT-45 (n=54) or R-AA (n=49). The TAVT-45 and R-AA groups were well matched (mean [SD] age: 74.5 [8.45] and 74.9 [8.40] years; mCRPC: 61.1% and 61.2%). In mCRPC, serum testosterone concentrations fell rapidly from mean (SD) baseline of 9.7 (5.19) for TAVT-45 and 10.6 (7.32) ng/dL for R-AA, with all &lt;1 ng/dL by Day 9. Therapeutic equivalence between TAVT-45 and R-AA at Days 9 &amp; 10 was also shown in the full study population: Days 9 &amp; 10 average rounded-up least-squares mean serum testosterone levels were comparable (TAVT-45 [n=52]: 1.004 ng/dL; R-AA [n=47]: 1.015 ng/dL), and the geometric mean ratio between groups was 0.990 (90% CI: 0.978-1.002), with the 90% CI falling within 80.0–125.0% equivalence limits. No statistical difference between TAVT-45 vs R-AA was demonstrated for PSA-50 (mCRPC 85% vs 70%; mCSPC 90% vs 95%). The frequency of treatment-emergent adverse events (TEAEs) was similar between groups; most were mild or moderate. Serious TEAEs occurred in 5 TAVT-45 and 3 R-AA patients. There were two deaths in treated patients due to cardiorespiratory arrest (TAVT-45) and prostate cancer (R-AA); neither was considered related to study drug. Conclusions: This Phase 3 study demonstrates that TAVT-45, a novel AA formulation with improved bioavailability, yields similar testosterone/PSA responses and a comparable safety profile to R-AA, and as an oral solution, may be suitable for mPC patients with dysphagia. Clinical trial information: NCT04887506 .

Antibacterial therapy: questions posed by COVID-19 and real clinical practice

The COVID-19 pandemic was accompanied at different times by the prescription of various drugs. The prescription of antibacterial drugs was regarded differently, and even the term “pneumonia” was the subject of discussion. The frequency of antibiotic use during the pandemic varied widely across countries, with a general trend towards overprescribing. According to most studies, in the early period of this viral infection, there were no indications for antibiotic therapy, while later, when a bacterial process is attached, a rational choice of the drug is important, taking into account the potential resistance of the pathogen, including the production of beta-lactamase. In the current version of the guidelines on COVID-19, the topic of bacterial infections has been carefully worked out. It is clearly stated that antibiotic therapy is prescribed only if there are convincing signs of a bacterial infection. On the one hand, it was noted that most patients with COVID-19 do not need antibiotic therapy, and on the other hand, for patients who do not need hospitalization with signs of a bacterial infection, amoxicillin and amoxicillin/clavulanate are the drugs of choice. The latter combination is also approved for hospitalized patients. Literature analysis has shown that amoxicillin/clavulanate remains a highly effective antibiotic for the initial treatment of community-acquired respiratory tract infections. In the conditions of import substitution, the creation of effective and safe, affordable domestic generics that have therapeutic equivalence with original drugs is a significant achievement of the Russian pharmaceutical science and industry. This review assesses the efficacy and safety of antibiotic use during a pandemic, as well as the place of amoxicillin/clavulanate in modern clinical practice.

COMPARAÇÃO DO USO DE IECA E BRA EM PACIENTES COM INSUFICIÊNCIA CARDÍACA – REVISÃO INTEGRATIVA

Heart failure (HF) is an inability of the heart to surprise tissue metabolism. The Brazilian Society of Cardiology, in 2020, 100 thousand new public health diagnoses and a rate of 50 thousand citizens/year, configuring a public health problem. Therefore, compare the diligence of Angiotensin Converting Enzyme Inducers (ACEI) and Angiotensin Receptor Blockers (ARB) in HF, for results: clinical stability, hospitalizations and deaths. Searches of 1789 randomized clinical trials were carried out on the platforms: Cochrane, PubMed and LILACS, based on indexed descriptors, with the terms MESH/Decs, of which 8 were in full. Perindopril functional hospitalization (HR 0.928; P 0.033), mortality (HR 0.98; P 0.928) and class (P 0.030). Both enalapril and candesartan reduced deaths and hospitalizations. Discontinuation of ACEI/ARB increased 4-fold mortality in 180 days. Therefore, there is evidence of therapeutic equivalence among the drugs analyzed in the CI.

Thrombopoietin receptor agonists in pharmacotherapy of pediatric immune thrombocytopenia

Introduction: Thrombopoietin receptor agonists are commonly second-line drugs in immune thrombocytopenia (ITP) pharmacotherapy in children and prescribed for chronic ITP refractory to first-line therapy.&#x0D; Standard ITP pharmacotherapy in children: includes prescribing glucocorticoids or intravenous immunoglobulins.&#x0D; Thrombopoietin receptor agonists: Currently Romiplostim and Eltrombopag are used in the Russian Federation pediatrics. Their pharmacodynamic features in comparison with other drugs used in ITP are presented in the paper. Increased thrombocytopoiesis is the dominant, but not the only component of Romiplostim and Eltrombopag mechanism of action. It is relevant to study their effect on immune tolerance in ITP, which may be associated with a persistent platelet response in some patients after drug discontinuation.&#x0D; Conclusion: The issue of thrombopoietin receptor agonist efficacy and safety as well as the mode of their use in ITP children treatment continues to be studied. The high cost of drugs continues to be a limiting factor to their earlier prescription. Generic drugs – Romiplostim and Eltrombopag partly solve the problem, promote their earlier prescription in ITP, but require additional study of their bioequivalence and therapeutic equivalence in comparison with the original drugs.&#x0D; Graphical Abstract&#x0D; &#x0D;

Pharmacokinetic/pharmacodynamic comparison between generic and brand-name levofloxacin based on Monte Carlo simulation

The generic drugs are widely used due to its substantially low price. However, some generic drugs showed lower efficiency in terms of quality and clinical efficacy compared with brand-name drugs, especially for antimicrobial drugs. Levofloxacin is a fluoroquinolone antimicrobial drug with excellent antimicrobial activity and wide antimicrobial spectrum, while it is susceptible to drug resistance. Our study aims to evaluate the bioequivalence of generic and brand-name levofloxacin. The pharmacokinetic (PK) parameters (Cmax, AUC0∼24, Tmax and t1/2), pharmacodynamic (PD) parameters (in vitro antibacterial activity and the inhibition of resistant mutation), and PK/PD analysis (the probability of target attainment, PTA; the cumulative fraction of response, CFR) calculated by Monte Carlo simulation (MCS) were investigated. Our results demonstrated that compared with the generics, the brand-name levofloxacin not only had higher drug content, but also showed higher antimicrobial susceptibility, higher resistance to mutation ability and higher percentage of each dosage interval that plasma concentration of antimicrobial agents exceeded the MPC90 (mutant prevention concentrations to prevent the mutation of 90% strains) against various clinical isolates. Although the PK results showed the differences in AUC0∼24 between brand-name levofloxacin and generics were not statistically significant (p > 0.05, F-test), the MCS results showed CFR of PK/PD of brand-name drugs were higher than generics. Our results indicated that PK or PD equivalence did not imply the therapeutic equivalence, thus, we suggest to include PK/PD analysis in bioequivalence evaluation system, which is beneficial to the prediction of clinical out come with high application value.

Patenting Strategies on Inhaler Delivery Devices

Patients with asthma and COPD rely on inhalers to control symptoms. Yet, these products remain expensive, in part because brand-name manufacturers have obtained numerous patents on inhalers, including on their delivery devices. Recent antitrust litigation has raised questions about the boundaries of listing device patents with the US Food and Drug Administration (FDA), particularly when patents do not claim any active ingredients. How have manufacturers relied on device patents to preserve market exclusivity on brand-name inhalers? We identified patents on brand-name inhalers approved for asthma and COPD between 1986 and 2020 using the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). We extracted information about patents from LexisNexis TotalPatent One and Google Patents and searched device patents for mention of active ingredients or other prespecified features linking the patent to the relevant drug. For each inhaler, we determined the duration of protection added by device patents. The FDA approved 53 brand-name inhalers for asthma and COPD from 1986 through 2020, 39 of which had at least one device patent. One hundred thirty-seven distinct device patents were in the final cohort, representing 49%of all patents listed on inhalers. Seventy-seven percent of device patents made no mention of active ingredients or their molecular structures, and 72%made no mention of any relevant prespecified feature connecting the device patent to the drug product. For the 39 brand-name inhalers with one or more device patents listed in the Orange Book, device patents extended the duration of market protection by a median of 5.5 years (interquartile range, 0.0-10.5 years) beyond the last-to-expire nondevice patent. Patent and regulatory reform is needed to promote generic competition and to ensure that patients with asthma and COPD have access to affordable medications.