Bioequivalence of a New Pediatric Paracetamol Oral Suspension Compared With a Marketed Formulation in Healthy Adults: A Randomized, Open-Label Study.

Background: A new oral paracetamol formulation with the same paracetamol quantity (24 mg/mL) as a marketed formulation but with finer active ingredient particle size and lower amounts of maltitol (5.85 g/dose in the test formulation vs 7.25 g/dose in the reference formulation) and sorbitol (2.4 g/dose vs 2.83 g/dose) was developed. Objective: Establish the bioequivalence of the new pediatric formulation (test treatment) compared with the marketed formulation (reference treatment). Methods: This Phase I, open-label trial assigned healthy adult volunteers to a single 42-mL (1 g para-cetamol) dose of test or reference treatment. Participants received both treatments in a randomized order separated by a 72-hour washout period. The primary endpoints were AUC0-tlast (AUC vs time curve from time 0 to last measurable sampling timepoint), Cmax, and tmax. Safety assessments included adverse event, clinical laboratory, and physical examination data. Results: Thirty-five participants were randomized and treated. The study population was 42.9% women (57.1% men) with a median age of 30 years; most participants were non-Hispanic White. Mean Cmax values were comparable between test and reference products, with a median tmax of 1.00 hour for both. The test/reference ratios (%) (90% CI) for AUC0-tlast and Cmax were 98.69% (96.46, 100.97) and 100.73% (95.63, 106.10), respectively. There were no adverse events or deaths. Conclusions: The new paracetamol formulation is bioequivalent to the marketed formulation.

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.

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.

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.

Bioequivalence of 2 formulations of montelukast (5 mg chewable tablet) in the fasting state: an open-label randomized, single-dose, 2-period, crossover study / Estudo de bioequivalência entre duas formulações de comprimidos mastigáveis de Montelucaste de 5 mg em condições de jejum: um estudo randomizado, de dose única, aberto, dois períodos, cruzado

Introduction: Montelukast, a selective and active leukotriene receptor antagonist, is one of the most common agents in asthma treatment for both adults and children. Objective: To assess whether the pharmacokinetic profiles of two formulations of montelukast were similar after a single 5 mg dose (chewable tablets), administered orally under fasting conditions, sampling blood before and 36 hours after administration. Methods: This was a randomized, 2-sequence, 2-period, crossover study of 2 chewable tablet formulations of the drug: Singulair®, provided by Merck Sharp and Dohme Farmacêutica Ltda. (reference), and generic montelukast, manufactured by Eurofarma Laboratórios S.A. (test). Plasma samples obtained from 35 participants were analyzed for montelukast through high-performance liquid chromatography coupled to tandem mass spectrometry, with montelukast-d6 as the internal standard. Peak montelukast concentrations were 299.313 (SD, 11.039) ng/mL for the reference formulation and 279.803 (SD, 10.085) ng/mL for test formulation. Results: Statistical analysis showed no significant differences between AUC0-36h, AUC0-inf, or Cmax between formulations, with the following test/reference ratios: 102.458 for AUC0-36h, 102.522 for AUC0-inf, and 93.490 for Cmax. No serious adverse events were reported during the trial. Our results demonstrated the bioequivalence of Singulair® and Eurofarma's generic montelukast. Conclusions: Our results revealed that the new generic tablets are clinically safe and can be used interchangeably with the brand name product. Eurofarma's montelukast offers a safe, effective, and cheaper treatment option for people with asthma or allergic rhinitis.

Introdução: O montelucaste, um antagonista seletivo e ativo dos receptores de leucotrienos, é um dos agentes mais comumente usados na prática clínica no tratamento da asma, tanto em adultos quanto em crianças. Objetivo: Avaliar se os perfis farmacocinéticos de duas formulações de montelucaste eram semelhantes após uma dose única de comprimidos mastigáveis de 5 mg, administrados por via oral em jejum, coletando amostras de sangue desde antes da administração até 36 horas depois disso. Métodos: Estudo comparativo randomizado, 2 sequências e 2 períodos, cruzado, de dois medicamentos em comprimidos mastigáveis: Singulair®, fornecido pela Merck Sharp e Dohme Farmacêutica Ltda. (referência) e Montelucaste 5 mg, fabricado pela Eurofarma Laboratórios S.A. (teste). Amostras de plasma obtidas de 35 indivíduos elegíveis foram analisadas para montelucaste por cromatografia líquida de alta eficiência acoplada a espectrometria de massa em tandem, tendo Montelucaste-d6 como padrão interno. As concentrações máximas de montelucaste foram 299,313±11,039 ng/mL para referência e 279,803±10,085 ng/mL para formulação de teste. Resultados: A análise estatística não mostrou diferenças significativas para AUC0-36h, AUC0-inf e nem para Cmax entre as formulações, apresentando as razões Teste/Referência: 102,458 para AUC0-36h, 102,522 para AUC0-inf e 93,490 para Cmax. Nenhum evento adverso grave foi relatado durante o estudo. De acordo com a regulamentação brasileira, o atual estudo farmacocinético demonstrou bioequivalência entre os agentes individuais e forneceu evidências de bioequivalência entre Singulair® e Montelukast fabricado pela Eurofarma. Resultado: Os resultados mostraram que os novos comprimidos genéricos são clinicamente seguros e podem ser trocados pela marca original. O montelucaste da Eurofarma oferece uma opção de tratamento mais barata, segura e eficaz para indivíduos com asma ou rinite alérgica.

Evaluating Therapeutic Equivalence of Generic and Original Levetiracetam in Patients with Epilepsy: A Retrospective Study.

The brand interchangeability of antiepileptic drugs (AEDs) is a topic of debate, especially regarding their therapeutic equivalence. This study evaluates the efficacy and tolerability of generic levetiracetam compared to the brand-name equivalent in a routine clinical setting. We conducted a retrospective study, examining patients with stable seizure frequency who received generic levetiracetam after the brand-name drug. During the six-month substitution period, changes in seizure frequency, hospitalization due to seizure exacerbation, adverse events, composite outcomes related to adjusting the AED dosage, and switching back to original levetiracetam were analyzed. Seventy-five patients were enrolled; the majority (85.3%) had focal onset seizures, and almost half (49.3%) had refractory epilepsy. Six months after the substitution, the mean seizure frequency per month was not significantly different (3.15 ± 14.47 vs. 2.77 ± 11.41; p = 0.970). In patients with controlled seizures before the change, the seizure frequency increased significantly (0.56 ± 1.83 vs. 0.03 ± 0.16; p = 0.012). Adverse events occurred in six patients. We have observed recurrent seizures or adverse events from 14 days after the transition. The original drug return rates due to recurrent seizures and adverse events were 5.3% and 1.3%, respectively. Generic levetiracetam might not show therapeutic equivalence to the original molecule, especially in patients adequately controlled by the brand-name drug.

Therapeutic equivalence of vildagliptin 100 mg once daily modified release to 50 mg twice daily immediate release formulation: An open-label, randomized, two-period, single- and multiple-dose, 6-day crossover study.

BACKGROUND AND AIMS: Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor to treat type 2 diabetes mellitus, is available as immediate release (IR) tablets administered at 50 mg twice daily (BID). A 100 mg modified release (MR) formulation was developed for once daily (QD) dosing. This study aimed to compare the therapeutic equivalence of vildagliptin 100 mg MR QD (test) and 50 mg IR BID (reference) formulations at steady state under fasting conditions. METHODS: This was an open-label, randomized, two-period, single- and multiple-dose, two-way crossover, steady state study conducted in healthy adult subjects. Both vildagliptin formulations were administered for six days. Endpoints included pharmacodynamic equivalence, pharmacokinetic parameters, and tolerability of both formulations. RESULTS: Thirty subjects were enrolled and 26 completed both treatments. Maximum plasma concentration and exposure achieved with test was lower than reference formulation on day 1 and 6. The DPP-4 enzyme inhibition over time (DPP-4-AUEC0-24) was comparable between the formulations. Both formulations were well tolerated. CONCLUSION: This study confirms the therapeutic equivalence of vildagliptin IR and MR formulations for DPP-4 enzyme inhibition over time. The study supports vildagliptin 100 mg MR QD as a useful therapeutic alternative to 50 mg IR BID formulation to possibly improve treatment adherence and patient compliance. Long-term safety of the vildagliptin 100 mg MR QD formulation is not evaluated in this study.

Dissolution test for oral suspension: an overview about use and importance

Abstract This work aims to ascertain the comprehensiveness of dissolution tests for oral suspensions registered in Brazil and the USA. After consulting literature since 1994, a paucity of information about dissolution methods for suspensions was detected. It makes it difficult to establish the most appropriate test parameters. In January, 2019, there were 46 drugs registered in Anvisa (Brazil) as oral suspension, being 47 reference, 173 generic and 114 interchangeable similar (IS) medicines; while in the USA, 90 drugs were registered as oral suspension by FDA, 235 Abreviatted New Drug Application and 111 New Drug Application medicines. Out of 46 and 90, only six and 15 drugs as oral suspension had a pharmacopeial dissolution test, corresponding to 70 (20.9%) and 82 (23.7%) products in Brazil and the USA, respectively. Dissolution studies were found for 17 drugs as oral suspension in the non-compendial literature. Dissolution test conditions were established to few marketable oral suspension drugs, most of which are BCS class II or IV. Thus, investing in dissolution studies could subsidize the registration of these products by regulators, especially for generic and IS drugs, by comparing dissolution profiles, and predicting their in vivo behavior to avoid exposure of healthy individuals to clinical research.

A multicentre, multi-national, double-blind, randomised, active-controlled, parallel-group clinical study to assess the safety and efficacy of PDA10 (Epoetin-alpha) vs. Eprex® in patients with anaemia of chronic renal failure.

BACKGROUND: Erythropoietin stimulating agent (ESA) has been standard of care in treating renal anaemia for the past 20 years. Many patients have limited access to ESA in view of long-term costs leading to suboptimal ESA dosage. Biosimilar epoetin is a potential cost-effective alternative to originator for optimal renal anaemia management. OBJECTIVE: To determine efficacy and safety of PDA10 in treating renal anaemia in haemodialysis patients, in comparison to the originator epoetin-α, Eprex®. METHODS: A phase 3, multicentre, multi-national, double-blind, randomised, active-controlled and parallel group study conducted over 40 weeks in Malaysia and Korea. End stage kidney disease patients undergoing regular haemodialysis who were on erythropoietin treatment were recruited. The study has 3 phases, which included a 12-week titration phase, followed by 28-week double-blind treatment phase and 24-week open-label extension phase. RESULTS: The PDA10 and Eprex® were shown to be therapeutically equivalent (p < 0.0001) with mean absolute change in haemoglobin from baseline of - 0.176 (± 0.91) g/dl and - 0.118 (± 1.114) g/dl, respectively. Weekly dose change was 10.01 IU/kg/week in PDA10 group and 10.30 IU/kg/week in Eprex® group, which has no significant difference. There were no significant differences in the safety profile between PDA10 and Eprex® groups. CONCLUSION: This study has confirmed the therapeutic equivalence between PDA10 and Eprex® in terms of efficacy, dosage requirement and safety profile in haemodialysis patients with renal anaemia. TRIAL REGISTRATION: The study was registered with the National Medical Research Register ( NMRR-13-400-16313 ). This study has been registered retrospectively with Clinical Research Information Service ( CRiS ), Republic of Korea on 25 March 2021.

Therapeutic Equivalence of a New Preparation of Liquid Levothyroxine with Tablets in Patients with Overt Primary Hypothyroidism.

BACKGROUND: A new liquid levothyroxine (LT4) dissolved in glycerol and water has recently been developed by a Greek pharmaceutical company (Uni-Pharma, Athens, Greece). OBJECTIVES: To evaluate the therapeutic equivalence of this new liquid LT4 preparation versus the already existing tablet formulation of the same manufacturer, in order to obtain approval by the Greek National Organization for Medicines. METHODS: This was a prospective, randomized, cross-over phase III study. The study included 50 patients (9 men and 41 non-pregnant women, with a mean age of 42.5 ± 12.5 years), with documented overt primary hypothyroidism. All subjects were well controlled on substitution therapy with various LT4 formulations. None of the patients had known LT4 malabsorption. The patients were randomized into 2 groups (A and B). The individuals of group A initially received T4® tablets for 10 ± 2 weeks and subsequently switched to T4® drops (100 µg/mL solution) at the same dose for another 10 ± 2 weeks. In group B, the reverse procedure was followed. Total T3 (T3), free T4 (fT4), and TSH were measured in all participants at enrollment and at the end of each 10 ± 2-week trial period. RESULTS: Out of the 50 recruited patients, 6 were lost to follow-up and 5 were excluded due to non-compliance with the study protocol. In the 39 patients who completed the study, the serum TSH levels after 10 ± 2 weeks of treatment either with T4® tablets or with T4® drops did not differ (1.759 ± 1.104 vs. 2.076 ± 1.334 mIU/L, mean ± SD). CONCLUSIONS: In hypothyroid patients, the new liquid LT4 preparation (T4® drops) is therapeutically equivalent to the tablet form (T4® tablets).

Efficacy and safety of a switch from twice-daily tacrolimus to once-daily generic tacrolimus in stable liver transplant patients.

Background: Once-daily tacrolimus reduces non-compliance relative to twice-daily tacrolimus. However, little is known about the safety and efficacy of conversion from twice-daily tacrolimus to generic once-daily tacrolimus in liver transplantation (LT). Herein, we investigated the efficacy and safety of a switch from twice-daily tacrolimus to generic once-daily tacrolimus in patients with stable liver graft function. Methods: This prospective, multicenter, open-label, single-arm study was conducted in 17 medical centers for 1 year from July 2019 to July 2020 (NCT04069065). Primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) for 24 weeks after conversion. Secondary endpoints were graft failure, patient death, and adverse events (AEs). Results: Of 151 screened LT patients, 144 patients were enrolled. BPAR, graft failure, and patient death did not occur in this patient population. There were no statistical differences in blood tests, liver function tests, or biochemical tests between visits in any of the patients. Median tacrolimus trough level decreased abruptly from 4.7 ng/mL to 3.2 ng/mL after generic once-daily tacrolimus conversion, but median tacrolimus dose increased due to low tacrolimus trough level. Ninety-two adverse events occurred in 54 patients. Liver enzyme levels increased in seven patients (4.9%) after the switch to generic once-daily tacrolimus, but the liver function tests of these patients normalized thereafter. There were three cases of severe AEs not related to investigational drug. Conclusions: Present study suggests that conversion from twice-daily tacrolimus to generic once-daily tacrolimus is effective and safe in stable LT patients.

Non-biological Complex Drugs (NBCDs): Complex Pharmaceuticals in Need of Individual Robust Clinical Assessment Before Any Therapeutic Equivalence Decision.

Non-Biological Complex Drugs (NBCDs) are complex non-biological drugs comprised of large high molecular weight molecules and, often, nanoparticular structures (including liposomes and block-copolymer micelles). In the case of NBCDs, the entire complex is the active pharmaceutical ingredient and its properties cannot be fully characterized by physicochemical analysis. Moreover, the manufacturing process is fundamental in creating the correct originator product. The same is true for generic versions of the product. A recent appraisal of approval procedures for NBCDs "follow-on products" approved in Europe shows a diversity of regulatory pathways. In fact, three different abridged application procedures, under European legislation, were used: the generic application procedure of Article 10(1), the hybrid application procedure of Article 10(3), and the biosimilar application procedure of Article 10(4). Three informed consent applications via Article 10(c) from innovator companies of glatiramer acetate and sevelamer carbonate were submitted shortly after the approval of the first follow-on products. Furthermore, a number of "well-established use" applications [via Article 10(a)] were approved for iron sucrose and iron dextran complexes. In order to protect patients from the increased risks of NBCD products and NBCD follow-on products, two complementary approaches should be considered: (i) improving the regulatory procedures and their guidance documents within the pre-registration phase, and (ii) not considering interchangeability whenever clinical data is not available. With regards to the latter, the need for adequate safety and efficacy data might also include risk management programmes within post-approval pharmacovigilance actions. This, however, would depend on a risk appraisal that must be considered for individual medicinal products, based on the nature of the submitted relevant set of safety/efficacy data.

The "Square Box": Therapeutic Equivalence as a Foundation of the WHO Model List of Essential Medicines.

Every two years, the World Health Organization (WHO) updates its Model List of Essential Medicines, intended as a guide for countries to adopt or adapt in accordance with local priorities and treatment guidelines, for the development of national essential medicines lists. When more than one therapeutic option is available for a given indication, the WHO Model List often includes a single medicine as representative of a group of equivalent and interchangeable medicines. The representative medicine of that group is listed with an accompanying 'square box' symbol. The intended purpose of the square box is to highlight pharmacological classes or groups of medicines for which countries, institutions and health professionals can assume homogeneous therapeutic efficacy and safety and select the most appropriate single medicine based on price, local availability, and acceptability. Though this concept of therapeutic equivalence within a therapeutic class has been endorsed by most authoritative textbooks of pharmacology since Goodman & Gilman's The Pharmacological Basis of Therapeutics and evidence-based guidelines, marketing forces have often made claims on individual drugs to distinguish them beyond relevant differences shown by reliable evidence: this has generated the concept of "me-too drugs" with its double meaning-i.e., market latecomers differing minimally from products preceding them and whose marketing budgets have significant opportunity costs, or medicines which may be useful to substitute for equivalent products in the event of shortages. The square box concept is applied in the context of a comprehensive list: therapeutic equivalence or interchangeability cannot always be easily established. Different interpretations have been applied to different groups of medicines over the 40+ year history of the Model List. This paper presents the concept of the square box, provides key examples and guidance on how square box listings should be practically interpreted in the development and implementation of national essential medicine lists, considers the applicability of a square box listing concept to biologic medicines and proposes that an updated review of the square box concept and listings is warranted.

Comparación de la equivalencia terapéutica de dos productos de bisoprolol - hidroclorotiazida en pacientes con hipertensión arterial / Comparison of two products containing bisoprolol - hydrochlorothiazide therapeutic equivalence in patients with arterial hypertension

Resumen Objetivo: Evaluar la equivalencia terapéutica de dos marcas comerciales de bisoprolol -hidroclorotiazida como terapia antihipertensiva. Método: Estudio prospectivo, doble ciego, doble falso, aleatorizado, de grupos paralelos, en el que se evaluó el efecto antihipertensivo de la combinación de bisoprolol-hidroclorotiazida 2,5-6,25 y 5-6,25 mg (comprimidos BHL, formulación test) y bisoprolol-hidroclorotiazida 2,5-6,25 y 5-6,25 mg tabletas (BHM, formulación de referencia), administrados en pacientes con hipertensión arterial. Variables de efectividad: Presiones arteriales medidas mediante mediante esfigmomanómetro de mercurio al inicio y después del período placebo, a las 4 y 8 semanas del inicio del tratamiento; cambios horarios de la presión arterial durante 24 horas, mediante monitorización ambulatoria de la presión arterial. Resultados: El control de los valores de presión arterial se logró en ambas formulaciones, principalmente a partir de la cuarta semana de tratamiento. Los pacientes del grupo test ingresaron con presiones arteriales sistólicas más elevadas. Después del tratamiento no hubo diferencias entre los grupos, a ninguno de los tiempos. La relación V/P del grupo test fue 0,5-1. Los índices de suavidad de ambos fueron mayores a 1,75. Conclusiones: La formulación test de la combinación de bisoprolol-hidroclotiazida demostró acción antihipertensiva similar al compararla con la formulación de referencia.

Abstract Objective: To evaluate the therapeutic equivalence of two commercial brands of bisoprolol -hydrochlorothiazide as antihypertensive therapy. Method: A prospective, double blind, double placebo, randomised, parallel group study was conducted, in which the antihypertensive effect of the bisoprolol -hydrochlorothiazide 2.5 - 6.25 mg and 5 - 6.25 mg (tablets BHL, test formula) and bisoprolol -hydrochlorothiazide 2.5 - 6.25 mg and 5 - 6.25 mg tablets (BHM, reference formula), was compared by administering it to patients with arterial hypertension given to patients with arterial hypertension. Effectivity variables: blood pressures measured using a mercury sphygmomanometer at the beginning and after the placebo period, at 4 weeks and 8 weeks from the start of the treatment; blood pressure hours change during 24 hours using an ambulatory blood pressure monitoring device. Results: Control of the blood pressure values was achieved with both formulas, mainly from the fourth week of treatment. The patients of the test group were admitted with higher systolic blood pressures. After the treatment, there were no differences between the groups at any of the times. The V/P ratio of the test group was 0.5 - 1. The smoothness index in both groups was greater than 1.75 of fit of both was greater than 1.75. Conclusions: The test formula of the bisoprolol-hydrochlorothiazide demonstrated an antihypertensive action similar to that achieved with the reference formula.

Are antibiotics substandard in Lebanon? Quantification of active pharmaceutical ingredients between brand and generics of selected antibiotics.

BACKGROUND: In developing countries, brand-generic substitution is not based on validated scientific evidence that confirm the therapeutic equivalence of the generic to the originator. Rather, decisions are made based on the availability of generic medications. Substitution by inappropriate preparations applies to antibiotics, which may increase the risk of resistance in case of underdosing. This analytical study aims to dose and assess for the accuracy of labeling three oral antibiotic preparations, namely ciprofloxacin hydrochloride, amoxicillin trihydrate and amoxicillin trihydrate-clavulanate potassium, the active pharmaceutical ingredients (APIs) found in brand and generic tablets available on the Lebanese market. METHODS: One brand and 4 generics of ciprofloxacin tablets, 3 generic amoxicillin tablets, and 1 brand and 4 generics of amoxicillin-clavulanic acid medications, were quantified, taking 2 batches of each. According to the United States Pharmacopeia (USP) guidelines, ultra-high pressure liquid chromatography was used to measure the APIs content within tablets. The USP required assay limit of the API was taken as the main comparison criteria. RESULTS: Out of the 5 ciprofloxacin medications tested, all 5 were out of the 2% required range, thus being substandard. For amoxicillin, all 3 medications were within the 20% range. As for amoxicillin-clavulanic acid medications, 4 out of 5 medications met the 30% required range of clavulanic acid and one exceeded the claimed amount of clavulanic acid, while all 5 met the assay limit for amoxicillin. CONCLUSION: These findings raise safety and efficacy concerns, providing solid grounds for potential correlations of antibiotic resistance/substandard antibiotics.

Sensitivity of Different In Vitro Performance Tests and Their In Vivo Relevance for Calcipotriol/Betamethasone Ointment.

PURPOSE: We compared results of in vitro performance testing with results of therapeutic equivalence study for calcipotriol/betamethasone ointment, to evaluate their sensitivity and in vivo relevance. METHODS: Different in vitro methods were used to evaluate drug release and permeation from the test and reference ointment. Moreover, 444 psoriasis patients were randomized in the therapeutic equivalence study and the parameters of efficacy and safety were compared with in vitro results. RESULTS: In vitro release and permeation rate of calcipotriol and betamethasone from the test formulation was higher than from the reference product for all methods used (p ≤ 0.05 for calcipotriol and p < 0.01 for betamethasone). Observed batch-to-batch variability of reference product confirmed high sensitivity and discriminatory power of in vitro methods. Higher release and permeation rate of calcipotriol and betamethasone from test product was reflected in the efficacy assessment (mean response difference 4.78 mPASI percentage points), but the observed difference was within the equivalence margins. Systemic exposure to calcipotriol and betamethasone was similar in both treatment groups. CONCLUSION: The results of in vitro experiments rank orderly correlated with the results of clinical study. In vitro methods are more sensitive and highly discriminatory when compared to in vivo performance.

Coexistence of oil droplets and lipid vesicles in propofol drug products.

Propofol is intravenously administered oil-in-water emulsion stabilized by egg lecithin phospholipids indicated for the induction and maintenance of general anesthesia or sedation. It is generally assumed to be structurally homogenous as characterized by commonly used dynamic light scattering technique and laser diffraction. However, the excessive amount of egg lecithin phospholipids added to the propofol formulation may, presumably, give rise to additional formation of lipid vesicles (i.e., vesicular structures consisting of a phospholipid bilayer). In this study, we investigate the use of high-resolution cryogenic transmission electron microscopy (cryo-TEM) in morphological characterization of four commercially available propofol drug products. The TEM result, for the first time, reveals that all propofol drug products contain lipid vesicles and oil droplet-lipid vesicle aggregated structures, in addition to oil droplets. Statistical analysis shows the size and ratio of the lipid vesicles varies across four different products. To evaluate the impact of such morphological differences on active pharmaceutical ingredient (API)'s distribution, we separate the lipid vesicle phase from other constituents via ultracentrifuge fractionation and determine the amount of propofol (2,6-diisopropylphenol) using high performance liquid chromatography (HPLC). The results indicate that a nearly negligible amount of API (i.e., NMT 0.25% of labeled content) is present in the lipid vesicles and is thus primarily distributed in the oil phase. As oil droplets are the primary drug carriers and their globule size are similar, the findings of various lipid vesicle composition and sizes among different propofol products do not affect their clinical outcomes.

Acceptability and barriers to implementation of N-of-1 tests in Ethiopia - a qualitative study.

BACKGROUND: Locally produced generic drugs offer a cost-effective alternative to imported drugs to treat patients in Ethiopia. However, due to a lack of bioequivalence testing, additional assurance tests are needed to build trust in cheaper, locally made drugs. By testing bioequivalence of local drugs to gold standard, N-of-1 tests have the potential to promote patient centred quality use of medicines. METHOD: We sought to assess the acceptability of, and explore barriers to, conducting N-of-1 tests to evaluate local medicines in a resource limited clinical setting. We conducted a descriptive qualitative study, analysing four focus group discussions and five key informant interviews. Participants were senior drug regulatory authority members, institutional review board members, physicians and patients. All interviews were audio taped and transcribed verbatim. Patient interviews were conducted in Amharic and translated to English prior to analysis. Data analysis used an inductive, thematic process. RESULTS: Five major themes were identified; (1) Appropriateness of N-of-1 tests to determine the therapeutic equivalence of local drugs, (2) N-of-1 therapeutic equivalence tests: clinical care or research? (3) Ethical and regulatory requirements (IRB), (4) Potential barriers to implementing N-of-1 tests and (5) Possible solutions to identified challenges. The study demonstrated considerable support for using N-of-1 tests for clinical equivalence studies between local and imported medicines, but important impediments were very likely to impact the feasibility of conducting N-of-1 tests in Ethiopia. Key informants from the regulatory authority did not support additional tests of local drugs. There were also mixed opinions regarding ethical requirements for conducting N-of-1 tests. The Institutional Review Board (IRB) members believed that IRB approval was sufficient to conduct N-of-1 tests, however, the regulatory authority members considered that N-of-1 tests constituted a clinical trial, and required approval at the regulatory level. CONCLUSION: This study showed that there were key uncertainties that could impact the feasiblity of using N-of-1 testing local drugs in Ethiopia. Therefore, a number of protocol amendments to address contextual threats and regulatory challenges, would be needed before progressing to conducting these tests.

A Dose-Response Study to Examine the Methodology for Demonstrating the Local Therapeutic Equivalence of the Fluticasone Propionate Component of an Orally Inhaled Combination Therapy of Fluticasone Propionate/Salmeterol Dry Powder.

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta-agonist combinations, such as fluticasone propionate/salmeterol (FPS) dry powder inhaler. Some regulators require generic medications to demonstrate local therapeutic equivalence (LTE) for each component of the FPS reference product. Fractional exhaled nitric oxide (FeNO) was developed as a possible LTE endpoint for the fluticasone propionate (FP) component of FPS in a randomized, double-blind, crossover study in steroid-naive asthma patients with elevated FeNO (≥45 parts per billion). Methods: Thirty-four patients received three of five treatments: FPS 100/50 µg once daily (QD), FPS 100/50 µg twice daily (BID), FPS 250/50 µg BID, FPS 500/50 µg BID, or placebo, each for 2 weeks separated by 14-day washout. FeNO was measured on days 1, 2, 3, 5, 7, and 14 of each period, according to American Thoracic Society standards. Results: FPS treatments decreased FeNO compared with placebo, with the largest differentiation between doses noted on day 14; the mean decreases from days 1 to 14 ranged from -46.6% to -64.5% with FPS versus -9.1% with placebo. The dose-response plateaued at 200 µg/day (FPS 100/50 µg BID). Linear regression analysis revealed significant slopes between FPS doses, with the steepest between 100/50 µg QD and 100/50 µg BID (-0.0039, p = 0.020). An estimated sample size (SS) of 160 or 48 patients would be required to demonstrate LTE of generic and FPS reference products (0.80-1.25 and 0.67-1.50 bioequivalence limits, respectively). However, as the slope between BID FPS doses was shallow, a larger SS may be needed if only an approved dose regimen was used. Conclusion: FeNO could be a valid endpoint to determine LTE between the FP component of generic and reference FPS products, but only if QD dosing and wide equivalence limits are included. As QD dosing is not an approved regimen, this approach is unlikely to be acceptable.

A Dose-Response Study Examining the Use of Methacholine Challenge to Demonstrate Local Therapeutic Equivalence of the Salmeterol Component of Generic Inhaled Fluticasone Propionate/Salmeterol Combination Products.

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair® Diskus®. Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS. Methods: Forty-six patients with asthma received single doses of albuterol (active control; 90 or 180 µg), FPS (100/50 or 200/100 µg), and placebo on 5 separate study days. Spirometry and MeCh were performed 1, 6, and 10 hours after study drug inhalation. Primary endpoint was provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC20). Study entry required screening PC20 ≤8 mg/mL, with a greater than fourfold increase (and PC20 ≤128 mg/mL) after 180 µg albuterol. Results: Both albuterol (90 and 180 µg) and FPS (100/50 and 200/100 µg) significantly increased PC20 compared with placebo (sustained 6 and 10 hours postdose with FPS but not albuterol). The dose-response slopes (95% confidence interval) estimated 1 hour after treatment were 0.374 (-0.068 to 0.815) and 0.310 (-0.135 to 0.754) between low and high doses of albuterol and FPS, respectively, both nonsignificant. Slopes were shallower than those available in the literature for albuterol and formoterol, but similar to those for salmeterol. Conclusions: These data confirm that the bronchoprotective effect of FPS lasts longer than that of albuterol. The shallow dose-response slope we observed for albuterol is contrary to previous reports, probably due to the measurement of PC20 beginning at 1 hour postdose. The results suggest that use of MeCh to assess LTE for salmeterol formulations may be more difficult to accomplish than it is for albuterol and formoterol products.

Overview of Brazilian Requirements for Therapeutic Equivalence of Orally Inhaled and Nasal Drug Products.

Brazil has established a framework for provision of generic pharmaceuticals including for orally inhaled and nasal drug products (OINDP) to its populace. This includes the development of guidelines or "resolutions" and normative instructions describing the Brazilian medicines agency's (Anvisa) expectations for demonstrating OINDP therapeutic equivalence. The Anvisa regulatory framework for OINDP therapeutic equivalence, challenges, and comparisons with the US Food and Drug Administration and European Medicines Agency approaches are assessed and discussed.