Bioequivalence trials for the approval of generic drugs in Saudi Arabia: a descriptive analysis of design aspects.

BACKGROUND: This retrospective analysis aimed to comprehensively review the design and regulatory aspects of bioequivalence trials submitted to the Saudi Food and Drug Authority (SFDA) since 2017. METHODS: This was a retrospective, comprehensive analysis study. The Data extracted from the SFDA bioequivalence assessment reports were analyzed for reviewing the overall design and regulatory aspects of the successful bioequivalence trials, exploring the impact of the coefficient of variation of within-subject variability (CVw) on some design aspects, and providing an in-depth assessment of bioequivalence trial submissions that were deemed insufficient in demonstrating bioequivalence. RESULTS: A total of 590 bioequivalence trials were included of which 521 demonstrated bioequivalence (440 single active pharmaceutical ingredients [APIs] and 81 fixed combinations). Most of the successful trials were for cardiovascular drugs (84 out of 521 [16.1%]), and the 2 × 2 crossover design was used in 455 (87.3%) trials. The sample size tended to increase with the increase in the CVw in trials of single APIs. Biopharmaceutics Classification System Class II and IV drugs accounted for the majority of highly variable drugs (58 out of 82 [70.7%]) in the study. Most of the 51 rejected trials were rejected due to concerns related to the study center (n = 21 [41.2%]). CONCLUSION: This comprehensive analysis provides valuable insights into the regulatory and design aspects of bioequivalence trials and can inform future research and assist in identifying opportunities for improvement in conducting bioequivalence trials in Saudi Arabia.

An exploration of factors influencing the selection of generic and innovator medicines in Saudi Arabia using an observational cross-sectional study.

Background and objectives: Generic medications are cost-effective without compromising therapeutic outcomes. Therefore, the goal of this study was to investigate, using a cross-sectional study design, the factors influencing Saudi Arabian consumers' preferences between innovator and generic medications. Methods: This cross-sectional study was carried out in Saudi Arabia using a Google survey form. For data collection, a simple random sampling strategy was used. The recruited participants were surveyed using a validated questionnaire that focused on six influencing domains: physician, pharmacist, perceived effectiveness, price, information availability, and confidence based on prior experience. The obtained data was used to analyze factors that have an association with any of the six domains using multinomial regression analysis. A correlation analysis was performed to examine the relationship between domains. Results: The 317 participants included 64.4 % females, 52 % aged ≥ 26, and a large proportion of Saudi nationals (82.6 %) and university graduates (78.9 %). Being employed (OR:3.029; P = 0.006; CI: 6.715-1.366), a healthcare providers (OR:2.298; P = 0.043; CI: 5.151-1.025), and having insurance coverage (OR:1.908; P = 0.017; CI: 3.245-1.122) had a greater influence on medication selection. Participants with linguistic and business educational backgrounds (OR:3.443; P = 0.022; CI: 9.950-1.191), those living in the northern region of Saudi Arabia (OR:3.174; P = 0.009; CI: 7.585-1.328), having chronic ailments (OR:3.863; P = 0.013; CI: 11.274-1.324), and possess insurance (OR:1.748; P = 0.039; CI: 2.971-1.028) get readily influenced by pharmacist. People who were married and lived in Saudi Arabia's southern region were influenced by perceived effectiveness when choosing medicine. Participants from the northern region were found to be influenced by the price of the medicines, information about the medicines, and confidence based on previous experience. The price of medicines has a significant impact on those suffering from chronic diseases. At a significant level of P = 0.01, all six influencing domains were found to be positively correlated with each other. Conclusion: The study shows that healthcare providers, drug prices, perceived efficacy, and information availability all have a big influence on the Saudi Arabian population's choice of medications. Educational background, location, and chronic disease status are associated with several influencing domains. Aside from public awareness campaigns, healthcare professionals should be involved in the implementation of the generic medication policy.

Perception of pharmacological equivalence of generics or biosimilars in healthcare professionals in Vienna.

PURPOSE: Due to constantly rising therapy costs, biosimilars and generic drugs have gained tremendous importance through recent decades. Nevertheless, the acceptance among healthcare workers regarding biosimilars and generic drugs in previously published international studies is considerably lower than the scientific data on equivalent safety and efficacy would suggest. The aim of this questionnaire-based survey was to determine the perception and knowledge regarding generic drugs and biosimilars by medical professionals from different healthcare facilities in Vienna, Austria. METHODS: The online questionnaire was sent to public and religious hospitals in Vienna, including the university hospital "Vienna General Hospital." In addition, doctors' offices were reached by sending out the questionnaire in the weekly news of the Vienna Medical Association. RESULTS: A total of 282 physicians and 311 graduated nurses took part in the study. 63% and 62% of the participants were convinced that generic respective biosimilar drugs were clinically equivalent to the original reference drug. On average, 1.6 out of 4 knowledge questions were answered correctly about generics, while only 0.87 out of 4 questions were answered accurately about biosimilars. CONCLUSION: The results of this study support the outcome from previous surveys demonstrating that a large proportion of healthcare professionals is still skeptical about generics and biosimilars. According to the results of this study, better education of the medical staff might ensure greater acceptance of these types of drugs.

A review of new drugs approved by the food and drug administration in 2022.

Introduction: The drugs approved by the Food and Drug Administration (FDA) in 2022, for the first time for any indication or under any brand, were studied under the contexts of indications, mechanism of action, and side effects. Primary care practitioners with considering patients as a composite whole will benefit by acquainting themselves with these drugs and their indications and adverse effects. Observations: The drugs were approved in all, 11 for the management of neoplasia, and 5 each for hematological, neurological, and dermatological conditions. 11 of the approved drugs are monoclonal antibodies and six are small molecule inhibitors. Conclusion: Although the FDA's expedited approval program allows rapid market availability of drugs for difficult to treat conditions, a quarter of the globe does not have access to essential medicines, primarily due to cost. In light of this, approval agencies must reorient approval processes to improve accessibility.

Has the consistency evaluation policy of generic drugs promoted the innovation quality of Chinese pharmaceutical manufacturing industry? An empirical study based on the difference-in-differences model.

Introduction: In March 2016, the Chinese government officially launched a nationwide consistency evaluation of the quality and efficacy of generic drugs. Methods: This paper conducted an empirical study using the Difference-in-Differences method to explore the effect of this policy on the innovation quality of China's pharmaceutical manufacturing industry and further analyzed the underlying mechanism of action. Results: The results of the study show that the generic consistency evaluation policy has a significant promotion effect on the innovation quality of China's pharmaceutical manufacturing industry, and the promotion effect is the largest for non-state-owned enterprises and enterprises in the central region; in addition, the intensity of R&D capital investment and R&D personnel investment which play a mediating role. Discussion: Therefore, we should fully recognize the positive effect of generic drug consistency evaluation policy on improving the innovation quality of the pharmaceutical manufacturing industry and pay attention to the necessity of regional coordination and unification in policy implementation and the formulation of supporting policy tools. This study provides empirical evidence for the implementation effect of the generic drug consistency evaluation policy, which can provide an essential reference for the further improvement of the procedure and the R&D decision-making of pharmaceutical enterprises.

The development of a novel simultaneous in vitro dissolution - in situ perfusion system as a potential tool for studying the absorption of solid oral formulation in rat.

The aim of this work is to develop a novel simultaneous in vitro dissolution - in situ perfusion system (SDPS) as a potential tool to evaluate the in vivo performance of solid oral formulation in rat. The innovative nitrendipine (NTD) tablet of Bayotensin mite® made in Germany was used as reference listed drug (RLD), and five generic products from Chinese market were compared with RLD using the in vitro dissolution test method specified by the orange book and the SDPS method developed in this study. Four self-prepared NTD tablets with different proportions of microcrystalline cellulose/starch were employed to investigate the discriminatory ability of the SDPS for formulation. In addition, the predictivity of the SDPS in relation to data from in vivo pharmaceutics studies was evaluated. The 45-min dissolution test and multiple-pH dissolution profiles of generic product 1 and 2 have no difference compared with the RLD, but their dissolution profiles from the SDPS showed statistically significant differences. A biexponential formula successfully described the concentration profiles of self-prepared formulations in SDPS experiments. The kdis (0.08 ± 0.01 ∼ 0.2 ± 0.03 min-1) and ka (about 2.30 × 10-3 min-1) values calculated by the formulas of F1-F3 suggested that the used excipients had no effect on the intestinal absorption of NTD, and it might be the property of active pharmaceutical ingredient that led to the difference among the generics. Furthermore, the in vivo rat pharmacokinetics study results of F1-F3 showed a good correlation (R2 = 0.99) with the SDPS data. In summary, the SDPS is a promising tool to detect the unexpected quality changes of pharmaceutical products in weakly regulated markets, facilitate formulation screening, and potentially reduce animal testing for estimating the in vivo absorption behavior of solid oral formulations. The absorption performance of generic drugs in vivo should be further investigated.

The story of the development of generic lenalidomide: How one company thwarted the Hatch-Waxman Act to generate billions of dollars in revenue.

Lenalidomide (Revlimid®) was originally approved by the Food and Drug Administration (FDA) in 2005, however, a generic version was not available until 2022. In that time, the price of lenalidomide has increased more than 20 times, and in 2021 alone, it accounted for >$5.8 billion dollars in Medicare Part D spending. This was a direct consequence of legal tactics employed by the manufacturer to thwart development of generic formulations of lenalidomide. In this report, we review the clinical development of lenalidomide, provide background on generic drug manufacturing in the United States (US), describe the steps that the manufacturer took to prevent entry of generic lenalidomide into the US market, and advocate for legislative reform of the FDA approval process and patent law protections in the US.

Discriminative Dissolution Method Using the Open-Loop Configuration of the USP IV Apparatus to Compare Dissolution Profiles of Metoprolol Tartrate Immediate-Release Tablets: Use of Kinetic Parameters.

The use of the USP IV apparatus (flow-through cell) has gained acceptance in recent years due to its versatility and ability to discriminate due to its hydrodynamic conditions. Therefore, the objective of the present study was to develop a discriminative dissolution method in the USP IV apparatus using the open-loop configuration, as well as to propose a method to compare non-cumulative dissolution profiles obtained in the open-loop configuration considering kinetic parameters and validate its predictive power through its comparison with independent and dependent methods using five commercial immediate-release tablet drugs (one reference drug and four generic drugs) of metoprolol tartrate as a model drug. The comparison of the non-accumulated dissolution profiles consisted of determining the geometric ratio of Cmax, AUC0∞, AUC0Cmax, and Tmax (kinetic parameters) of the generic/reference drugs, whereby generic drugs "C" and "D" presented the highest probability of similarity since their 90% confidence intervals were included, or they were very close to the acceptance interval (80.00-125.00%). These results were consistent with the f2, bootstrap f2, and dissolution efficiency approaches (independent models). In conclusion, the proposed comparison method can be an important tool to establish similarity in dissolution profiles and to facilitate the development/selection of new formulations and positively ensure bioequivalence in clinical studies.

Scientific considerations in the regulatory approval of generic (or biosimilar) version of enoxaparin sodium - A lifesaving carbohydrate polymer.

Enoxaparin sodium (Clexane®/Klexane®/Lovenox®) is one amongst the few drugs that have assumed a central role as drug of treatment and/or prevention against thromboembolic complications during COVID-19. The increase in demand resulting in many generic (or biosimilar) versions entering the market has increased the risks of quality and safety (including immunogenicity) related issues. Under the circumstances, development of stringent regulatory approaches has received much attention as investigation of new drug delivery systems for improved therapeutic activity. As one of the measures to increase quality testing and ensure uninterrupted supply of this life-saving drug globally, determination of enoxaparin molecular weight (MW) has been added in the United States Pharmacopoeia (USP) monograph for enoxaparin sodium. In addition, the presence of a unique 1,6-anhydro-ring structure at the reducing end of about 15-25% of the poly (oligo) saccharide chains of the generic (or biosimilar) product has been set as a mandatory requirement. This article presents an overview of the scientific considerations in the quality manufacturing and testing of the generic (or biosimilar) enoxaparin for regulatory review and approval. In certain cases of strong analytical similarity (structural and functional), abandonment of in vivo testing in animals and humans represents a major advancement in the approval of generic (or biosimilar) version of innovator enoxaparin sodium (lovenox®, injections).

Loss of exclusivity of ceftazidime/avibactam in low- and middle-income countries: a test for antibiotic stewardship practice.

Ceftazidime/avibactam is a last-line antibiotic, to be used as a targeted therapy for certain carbapenem-resistant Gram-negative infections and not to be used as an empirical therapy or as a carbapenem-sparing therapy. After a span of 5 years, the antibiotic recently lost its exclusivity and become a generic drug in India. It is assumed that generic players will aggressively market the drug, making it freely available even in pharmacies catering to primary- and secondary-care hospitals. We thus foresee certain potential adverse implications of introducing generic versions of ceftazidime/avibactam into the Indian market; as they will be a challenge to the antibiotic stewardship. In the real world scenario, the stewardship system in India is fragile, therefore, we may see empirical use of ceftazidime/avibactam even in primary and secondary-care hospitals. The existing widespread prevalence of MBL-producing isolates in India, will be further enhanced by the indiscriminate use of ceftazidime/avibactam.

Predicting bioequivalence and developing dissolution bioequivalence safe space in vitro for warfarin using a Physiologically-Based pharmacokinetic absorption model.

OBJECTIVE: Bioequivalence (BE) studies support the approval and clinical use of both new and generic drug products. Narrow therapeutic index (NTI) drugs have relatively high costs and low success rates of BE evaluation clinical trials as high-risk drugs. A physiologically-based pharmacokinetic (PBPK) model can be used to evaluate the BE of two preparations. METHODS: This study inputs the basic physical and chemical property parameters of warfarin sodium available at the present stage into GastroPlus™ software, and combined it with the Advanced Compartmental Absorption and Transit (ACAT™) model built into the software. The PBPK model of Chinese individuals taking 2.5 mg of warfarin sodium orally while fasted condition was developed using the disposal parameters calculated from the clinically measured PK data of the reference preparations. The model was tested using the PK data of other reference preparations and tested preparations from different domestic manufacturers. RESULTS: The results revealed that at least 30% of drugs are released in 30 min under a pH of 4.5 condition, and at least 80% are released in 30 min under a pH of 6.8 condition, which can be used as bioequivalent dissolution limits under fasted conditions. The risk of BE failure in the fed condition will be significantly reduced for the clinical study on the BE of warfarin sodium, which is a NTI drug if the fasted condition is bioequivalent. CONCLUSION: The results revealed that the PBPK models were successfully developed for 2.5 mg of warfarin sodium tablets in Chinese individuals. Developing a PBPK model for NTI drugs based on in vitro dissolution data in software is a promising method for BE evaluation, which can provide great help for developing new drugs and the clinical trial research of BE of generic drugs.

The Rubik's Cube of Manufacturers' Coupons: Making the Case for Sneetches.

Description Asthma maintenance inhalers are inordinately expensive, inhibiting patients from affording their medication and compromising compliance and adherence and optimal health outcomes. The objective of this article was to examine and highlight the competitive world and challenged opportunity of manufacturers' coupons discounting the inordinate cost of respiratory inhalers and asthma treatment. The cost of asthma treatment, in particular the cost of respiratory medicines, even with health insurance, can be prohibitive (upwards of $700 per month for one inhaler). Medication costs restrict medication access. Compliance and adherence suffer attested by monthly maintenance inhalers being filled less than 50% of the time. Pharmaceutical manufacturers of branded drugs competitively offer and market discount programs designed to help offset out-of-pocket medication (copay or coinsurance) costs. However, these programs vary depending on the manufacturer and are contingent on the parameters of individual insurance plans and their respective pharmacy benefit managers (PBMs). In an attempt to gain market advantage, manufacturers, coupons frequently change criteria making the opportunity of savings for patients and prescribing clinicians difficult to discern, implement and sustain.

A Cross-Sectional Study on Self-Medication Prevalence and Usage Patterns: An Alarming Concept Among the Saudi Population.

BACKGROUND: Self-medication (SM) has many potential drawbacks, including toxicity, drug resistance, severe adverse effects, drug interactions, drug abuse, and drug dependence, but it is still widely used for a variety of reasons, including time and money savings, symptom prevention or treatment of minor illnesses, a lack of access to doctors, etc. This study aimed to describe and analyse the usage of antibiotics without a prescription, self-medication practises, and patterns of using them among Saudis. MATERIALS AND METHODS: In 13 provinces of Saudi Arabia, a community-based cross-sectional study was done. After gaining consent, data were gathered from 420 adults during face-to-face interviews using a questionnaire. SPSS was used to analyse the data once it had been entered into Microsoft Excel (Microsoft® Corp., Redmond, WA). RESULTS: Regarding self-medication, among 208 participants, there was a male predominance and among upper lower class with respect to socioeconomic status. The self-medication rate was found to be higher among graduates and professionals with respect to education and occupation. Self-medication was discovered to be more prevalent among metropolitan residents. The majority of those who started using self-medication got their knowledge from various advertisements. The most frequent symptom of self-medication was fever, followed by a common cold. The most commonly used medication was paracetamol, followed by cough syrups. Weight loss advertisements influence participants the most for self-medication, followed by hair loss and diabetes. TV advertisements have the highest influence on people practising self-medication. CONCLUSION: The study calls for greater knowledge of the impacts of antibiotic self-medication, which can be accomplished through efficient measures including behaviour change communication and encouraging more research into its causes and effects.

Switching patterns of immediate-release forms of generic mixed amphetamine salts products among privately and publicly insured individuals aged 15-64 years in the United States, 2013-2019.

PURPOSE: Immediate-release forms of generic mixed amphetamine salts (MAS) have been the subject of passive surveillance reports signaling lack of effectiveness. We examined switching patterns that might suggest whether long-term users of specific MAS are more likely to switch away or switch back after use of the MAS of interest in the FDA's Sentinel Distributed Database. METHODS: We required at least 60-day continuous supply of selected MAS grouped by Abbreviated New Drug Application (ANDA) to describe patterns of switching away from and to generics approved under the ANDAs of interest among individuals ages 15-64 years with attention deficit hyperactivity disorder or narcolepsy during 2013-2019. RESULTS: We observed the greatest number of treatment episodes for ANDA 040422 (n = 525 771), followed by ANDA 202424 (n = 181 693), ANDA 040439 (n = 62 363), ANDA 040440 (n = 21 143), and ANDA 040480 (n = 8792). Of those with switches away from their original ANDA, episodes initiated on generic products under ANDA 040422 (48.6%) and ANDA 202424 (43.0%) were most likely to switch back, while those initiated on generic product under ANDA 040480 were least likely (24.1%). Of those episodes with switches to a generic under an ANDA of interest, about one-third (range 27.1% to 37.0%) switched back to the same product. These switches back had a median time to switch of about 30 days. CONCLUSIONS: These descriptive analyses, although subject to limitations, did not suggest increased switching away or switching back after use of the generics of interest. Continued post-marketing surveillance is warranted.

Effects of the pharmaceutical formulation of topical medications on corneal epithelial healing after phototherapeutic keratectomy.

PURPOSE: To determine the effect of the formulation of topical medications on the healing of corneal epithelial cells after phototherapeutic keratectomy (PTK). STUDY DESIGN: Retrospective cohort study. METHODS: We studied 271 eyes of 189 consecutive patients (aged 67.6 ± 11.8 years) who had undergone PTK for granular corneal dystrophy (n = 140), band keratopathy (n = 47), or lattice corneal dystrophy (n = 2). Postoperatively, generic or brand-named levofloxacin, 0.1% betamethasone, or 0.1% bromfenac sodium hydrate was applied topically. Patients were examined on postoperative days 1, 2, and 5 and weekly thereafter. The time to re-epithelialization was assessed by use of Kaplan-Meier and Cox proportional hazards analyses. RESULTS: The time to re-epithelialization was significantly longer with generic 0.5% levofloxacin, at 8.2 ± 3.5 days, than with 0.5% Cravit (levofloxacin), at 6.7 ± 3.5 days (P = 0.018), or with 1.5% Cravit, at 6.3 ± 2.6 days (P = 0.000). In addition, the time to re-epithelialization was significantly longer with generic 0.1% betamethasone (Sanbetason), at 7.3 ± 3.4 days, than with brand-name 0.1% betamethasone (Rinderon), at 6.1 ± 2.5 days (P = 0.0002). The Cox proportional hazards model indicated that the use of generic formulations for levofloxacin eye drops and 0.1% betamethasone was a significant factor that delayed corneal re-epithelialization (hazard ratio [HR] = 0.72, P = 0.002 and HR = 0.77, P = 0.006, after adjustment for age). Re-epithelialization was significantly shorter in band keratopathy than in corneal dystrophy (HR = 1.56, P = 0.004). No other factors, including age, bandage contact lens, and diabetes mellitus, were significantly associated with time to re-epithelialization. CONCLUSION: Corneal epithelial healing can be significantly affected by different antibacterial or steroid eye drops. Clinicians need to be aware that a generic formulation may affect corneal epithelial healing.

Medicamentos intercambiables en Perú. Un estudio de revisión

La intercambiabilidad de medicamentos representa una necesidad en países en vías de desarrollo, porque brinda la posibilidad de acceder a productos de menor costo, además, permite asegurar eficacia y seguridad en los tratamientos farmacoterapéuticos. El estudio recolectó investigaciones realizadas en el estado peruano, publicadas en bases de datos de alto impacto como Scielo, Sciencedirect, Scopus y Pubmed. De las 553 investigaciones encontradas, sólo diez artículos cumplieron con los criterios de inclusión y exclusión, se identificaron medicamentos como diazepam, prednisona, amoxicilina, doxiciclina, fluconazol, fenitoína sódica, alprazolam, amlodipino, carbamazepina sódica, glibenclamida, moxifloxacino y ácido acetilsalicílico. Todos los artículos analizaron el perfil de disolución mediante el cálculo del factor de similitud f2, mientras, en otros casos, estimaron parámetros como variación de peso, friabilidad, dureza, cuantificación, uniformidad de contenido y perfil de disolución. Los resultados evidencian que nueve medicamentos incluidos en el estudio fueron analizados mediante estudios in vitro a diferentes pH (1,2; 4,5 y 6,8), y cumplieron con presentar un factor de similitud f2 mayor a 50. Se concluye que aún se encuentra en proceso la intercambiabilidad de medicamentos en el estado peruano, y que, mediante alianzas estratégicas con el sector privado, se podría tener una mayor cantidad de alternativas farmacéuticas en la recuperación del paciente.

The medicines' interchangeability represents a necessity in developing countries, because it offers the possibility of accessing lower cost products, it allows to ensure efficacy and safety in pharmacotherapeutic treatments. The study gather researches carried out in the Peruvian state published in high-impact databases such as Scielo, Sciencedirect, Scopus and Pubmed. Of the 553 researches found, only 10 articles met the inclusion and exclusion criteria, drugs such as diazepam, prednisone, amoxicillin, doxycycline, fluconazole, phenytoin sodium, alprazolam, amlodipine, carbamazepine sodium, glibenclamide, moxifloxacin and acetylsalicylic acid were identified. All the articles analyzed the dissolution profile by calculating the similarity factor f2, while, in other cases, they estimated parameters such as weight variation, friability, hardness, quantification, content uniformity, and dissolution profile. The results show that 9 drugs included in the study were analyzed by in vitro studies at different pH (1.2; 4.5 and 6.8), and complied with presenting a similarity factor f2 greater than 50. It is concluded that, the interchangeability of medicines in the Peruvian state is still in process, and that, through strategic alliances with the private sector, a greater number of pharmaceutical alternatives could be had in the patient's recovery.

Assessment of community pharmacists' knowledge of the differences between generic drugs and biosimilars: A pilot cross-sectional study.

Background: Pharmacists' knowledge of the differences in the characteristics between generic drugs and biosimilars is essential to ensure good practice and lower pharmaceutical bills. Objectives: This study aimed to evaluate community pharmacists' knowledge and perception of using and substituting biosimilars and generic drugs. Design: A pilot cross-sectional study was performed over 2 months (August-September 2022) targeting community pharmacists in their work site. Method: Data were collected using a uniform survey given to 75 pharmacists. Afterward, a knowledge score was generated by summing several individual scores of statements regarding generic drugs and biosimilars. Results: Overall, pharmacists had moderate to low knowledge scores, namely, with the statements tackling biosimilars. No significance was reported between these scores and their general characteristics. As regards their substitution, most pharmacists agreed to substitute generic drugs if the brand was not available, while the doctor's approval was crucial for biosimilar switching. Most participants perceived equal effectiveness of generic drugs but similar to a lower one for biosimilars compared to the reference medication. Pharmacists highlighted the need to include generic drugs and biosimilars in the continuing education program and workshops. Conclusion: To promote their use, improving pharmacists' knowledge can help overcome misconceptions about generic drugs and biosimilars. It is recommended that health care stakeholders focus on fostering good understanding among pharmacists to enhance access to medication.

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

OBJECTIVE: Generic medications are widely used because of their low cost. However, some generic medications show lower quality and clinical efficacy compared with brand-name medications, 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. METHODS: 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; the cumulative fraction of response) calculated by Monte Carlo simulation were investigated. RESULTS: Our results demonstrated that compared with generics, brand-name levofloxacin not only had higher drug content, it also showed higher antimicrobial susceptibility, higher resistance to mutation ability, and higher percentage of each dosage interval wherein plasma concentration of antimicrobial agents exceeded the MPC90 (mutant prevention concentration to prevent the mutation of 90% strains) against various clinical isolates. Although the differences in AUC0∼24 between brand-name levofloxacin and generics were not statistically significant (P > 0.05, F test), Monte Carlo simulation results showed cumulative fraction of response values for PK/PD of brand-name medications were higher than generics. CONCLUSION: Our results indicated that PK or PD equivalence did not imply therapeutic equivalence; thus, we suggest including PK/PD analysis in the bioequivalence evaluation system, which benefits prediction of clinical outcome with high application value.

Treating COVID-19: Targeting the Host Response, Not the Virus.

In low- and middle-income countries (LMICs), inexpensive generic drugs like statins, ACE inhibitors, and ARBs, especially if used in combination, might be the only practical way to save the lives of patients with severe COVID-19. These drugs will already be available in all countries on the first pandemic day. Because they target the host response to infection instead of the virus, they could be used to save lives during any pandemic. Observational studies show that inpatient statin treatment reduces 28-30-day mortality but randomized controlled trials have failed to show this benefit. Combination treatment has been tested for antivirals and dexamethasone but, with the exception of one observational study in Belgium, not for inexpensive generic drugs. Future pandemic research must include testing combination generic drug treatments that could be used in LMICs.