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1.
Urologiia ; (5): 41-47, 2020 Nov.
Artigo em Russo | MEDLINE | ID: mdl-33185345

RESUMO

AIM: In order to evaluate the bioequivalence and benefits of a new dosage form of the type 5 phosphodiesterase inhibitor, sildenafil, two open-label studies in healthy male volunteers were carried out. MATERIALS AND METHODS: An open, randomized, crossover study to compare the pharmacokinetics after a single dose of sildenafil at a dosage of 50 mg on an empty stomach in a new spray form (test drug) and in a traditional tablet form (comparison drug) on 44 volunteers (18 to 43 years old) was done. To assess the effect of food intake on pharmacokinetics, an open, non-randomized study was conducted on 6 healthy male volunteers (from 23 to 35 years old) who received sildenafil (50 mg) after a meal in timely fashion: 1) spray, under the tongue, without drinking, 2) spray , in the mouth, drinking water and 3) the tablet form, drinking water. For pharmacokinetic analysis, blood was analyzed for 24 hours. Plasma concentration of sildenafil was determined by high performance liquid chromatography with tandem mass spectrometric detection (HPLC/TM/SD). The main parameters were the rate (maximum concentration; Cmax) and the degree of absorption (area under the pharmacokinetic curve "concentration-time" during the observation period; AUC0-t) after a single dose of drugs. In addition, the pharmacokinetic profiles of the bioavailability of sildenafil and its active metabolite, N-desmethyl sildenafil, as well as the safety of the different dosage forms, were evaluated. RESULTS: When comparing taking drugs on an empty stomach, the 90% confidence intervals (CI) of the ratios of the mean Cmax and AUC0-t values of sildenafil were 82-106% and 82-101%, respectively. An earlier achievement of the maximum concentration of sildenafil was detected when taking the test drug compared with the standard form (51 and 62 minutes, respectively, Z-value=-2.25, p-value=0.0244). In addition, it was shown that when taking Viagra after a meal, the determination of sildenafil in plasma was delayed (after 30 minutes) compared to the tested drugs (after 10 minutes), however, significant differences in Tmax between the dosage forms were not seen. In two studies, most adverse events were mild to moderate and resolved uneventfully. DISCUSSION: The bioavailability of the new dosage form, the sildenafil spray, is equivalent to the traditional form, however, it has an advantage in terms of onset of action. For example, when taking a spray, an earlier achievement of the maximum concentration of sildenafil and an earlier detection of sildenafil in plasma are shown compared to the traditional tablet form. CONCLUSIONS: Our results suggest that the new dosage form of sildenafil is a reliable alternative therapeutic option for the treatment of erectile dysfunction.


Assuntos
Ingestão de Alimentos , Citrato de Sildenafila , Vasodilatadores , Administração Oral , Adolescente , Adulto , Estudos Cross-Over , Humanos , Masculino , Citrato de Sildenafila/farmacocinética , Equivalência Terapêutica , Vasodilatadores/farmacocinética , Adulto Jovem
3.
PLoS One ; 15(9): e0238951, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32898192

RESUMO

The aim of the study was to determine the various pharmacokinetic parameters of the newly developed cost-effective aceclofenac 100 mg tablet formulation (F-15) and to establish the bioequivalence against the marketed brand (ACEMED). Both products (test and reference) were given to 12 healthy non-smokers male subjects with overnight fasting of >10hr. The study was a randomized, single-dose, open-label, two sequence, and two treatment crossover design, with a washout period of 2 weeks. Blood samples (5 mL) from the human subjects were collected before (0 hr) and after drug administration at 13different time points (0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12 and 18 hrs). The drug plasma concentration was analyzed by a validated RP-HPLC method using a solvent system containing acetonitrile and deionized water (60:40% v/v). Linearity was found to be 0.999 over the drug concentration range of 50µg/mL to 0.05µg/mL with LLOQ and LOD of 0.05µg/mL and 0.025µg/mL respectively. Non-compartmental pharmacokinetic analysis was performed using Kinetica® (ver. 5.1) software. Using the log-transformed data Cmax, AUC0-t, AUC0-∞, AUMCtot, and MRT were calculated. The Cmax of the test and brand was found to be 8.629±1.251µg/mL and 8.478±0.913µg/mL. The AUC0-t and AUC0-∞ of the test and the reference were computed to be 20.890 ±2.2021µg/mL.h, 23.272 ±1.914 µg/mL.h and 19.850 ±2.911 µg/mL.h, 22.890 ± 2.110 µg/mL.h correspondingly. Two-way analysis of variance (ANOVA) test and two one-sided t-test (p>0.05; non-significant) were applied to assess the variation in the period, sequence, subjects, and treatment. Geometric mean ratios for above mentioned pharmacokinetic parameters of reference/test were found within the acceptable FDA limits of 80-125% using 90% CI. There was no inter and intrasubject variation (p> 0.05) that was observed. Therefore, the directly compressible aceclofenac (100 mg) test formulation and the commercial reference tablets were declared to be biosimilar.


Assuntos
Diclofenaco/análogos & derivados , Adulto , Análise de Variância , Área Sob a Curva , Química Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão/métodos , Estudos Cross-Over , Diclofenaco/metabolismo , Diclofenaco/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Comprimidos/farmacocinética , Equivalência Terapêutica
4.
AAPS PharmSciTech ; 21(7): 245, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32856178

RESUMO

The purpose of this study was to investigate the impacts of the formulation parameters on the pharmacokinetics and bioequivalence of risperidone orodispersible film (ODF) using physiologically based pharmacokinetic model. The pharmacokinetic profiles of two risperidone ODFs, which exhibit different in vitro dissolution, were examined in Beagle dogs after supralingual administration. Subsequently, a physiologically based pharmacokinetic (PBPK) model was constructed to evaluate the in vivo performance of risperidone ODF. The parameter sensitivity analysis (PSA) was used to access the impacts of formulation parameters on the pharmacokinetics of risperidone. Moreover, the validated PBPK model was applied to predict human pharmacokinetic profiles and examine the bioequivalence of these two ODFs. These two ODFs displayed similar risperidone pharmacokinetic profiles in dogs. The parameter sensitivity analysis indicated that the changes in the solubility, particle size, particle density, and diffusion coefficient did not have obvious influence on the in vivo properties of risperidone ODF. Alternation of the in vitro complete dissolution time in water from 15 to 30 min led to a 30% decrease in Cmax and 20% of increase in Tmax. AUC0-∞ would be decreased if risperidone was not fully released within 1 h. As both ODFs completely released risperidone within 15 min, the difference in the extent of in vivo absorption, intestinal regional absorption location, and plasma concentration-time curves between these two ODFs was almost negligible. Consequently, a bioequivalence was foreseen in humans. The in vitro cumulative dissolution percentage in water at 15 min was found to be the major determinant on the in vivo properties of risperidone ODF. PBPK modeling appears to be an innovative strategy to guide the development of risperidone ODF.


Assuntos
Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Modelos Biológicos , Risperidona/administração & dosagem , Risperidona/farmacocinética , Administração Oral , Animais , Cães , Feminino , Humanos , Masculino , Tamanho da Partícula , Risperidona/química , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinética , Solubilidade , Equivalência Terapêutica
5.
PLoS One ; 15(7): e0235205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658918

RESUMO

BACKGROUND: Generic medicines are similar to innovator medicine in terms of safety, quality, efficacy, dosage form, strength, and route of administration. They have the same therapeutic use to innovator medicines and available at a far lower price. However, health professionals' poor knowledge and attitude may limit its utilization. The present study aimed at assessing the knowledge, attitude, and practice of pharmacy professionals towards generic medicines in Harar city, Eastern Ethiopia. METHODS: A cross-sectional survey was conducted among community pharmacists in Harar city. A self-administered thirty-three item questionnaire on Knowledge, attitude, and practice of community pharmacists was utilized. Logistic regression analysis was performed to predict the determinants of knowledge and attitude of pharmacists. An odds ratio at 95% confidence interval along with a p-value < 0.05 was considered significant. RESULTS: Among 80 community pharmacists' approached, 74 completed the survey, providing a response rate of 92.5%. Sixty-seven percent of the respondents knew that generic drugs are bioequivalent to brand drugs and claimed generic medicines are cheaper (86.5%). Nearly half (48.6%) of participants believe that generic medicines are less effective and slower in the onset of action (58.1%). More than half (54.1%) of study participants revealed their lack of belief in generic medicine as a factor hindering the selection and dispensing of generic medicines. In multivariate logistic regression, experience in community pharmacy practice (Adjusted odds ratio (AOR = 2.18, 95%CI: 1.21-63.1) and Sex (AOR = 3.88, 95%CI: 2.12-39.62) were significantly associated with knowledge and attitude toward generic medicines, respectively. CONCLUSION: The current study revealed that there is a gap in the knowledge and attitude of community pharmacists towards generic and brand drugs. More than averages of the respondents have known the concept of generic medicine including their right to perform generic substitution and had a positive attitude toward generics. Female pharmacists were more likely to have a positive attitude and the overall knowledge was higher in those who have more than 5 years of work experience.


Assuntos
Serviços Comunitários de Farmácia/estatística & dados numéricos , Medicamentos Genéricos/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Farmacêuticos/psicologia , Competência Profissional/estatística & dados numéricos , Adulto , Estudos Transversais , Substituição de Medicamentos , Medicamentos Genéricos/farmacologia , Etiópia , Feminino , Humanos , Masculino , Farmacêuticos/estatística & dados numéricos , Fatores Sexuais , Inquéritos e Questionários/estatística & dados numéricos , Equivalência Terapêutica , Adulto Jovem
6.
Int J Clin Pharmacol Ther ; 58(10): 583-594, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32716291

RESUMO

OBJECTIVES: To establish the relative bioavailability between a newly developed oral gel and a marketed oral lyophilisate-containing rizatriptan benzoate. MATERIALS AND METHODS: A total of 47 out of 48 healthy subjects, aged 34 ± 10 (SD) years and body mass index 24.7 ± 3.3 (SD) kg/m2 completed this single-center, open-label, randomized, 2-period cross-over trial with single-dose fasted administrations. Intake of both investigational products was separated by a washout period of at least 6 days. For pharmacokinetic evaluation, blood samples were withdrawn until 24 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for the determination of rizatriptan in plasma. The lower limit of quantitation (LLOQ) was 0.100 ng/mL. Adverse events (AEs) were descriptively analyzed in the study population. Palatability of the new product was investigated based on a questionnaire. RESULTS: The geometric means of the parameters related with the extent of total exposure, i.e., AUC0-tlast and AUC0-∞, were 60.285 ng × h/mL and 60.865 ng × h/mL for test and 62.729 ng × h/mL and 63.312 ng × h/mL for reference, respectively. The geometric means of the peak exposure, i.e., Cmax, were 21.262 ng/mL for test and 21.447 ng/mL for reference. The point estimates (PEs) of the test/reference (T/R) adjusted geometric mean ratios of AUC0-tlast, Cmax, and AUC0-∞ (secondary parameter) were 96.11%, 99.12%, and 96.15%, respectively, and all of them showed 90% confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment. In total, 13 subjects experienced 20 AEs during the trial; the most frequently reported AEs were headache (5 cases) and dizziness (3 cases). No AEs of severe intensity were reported. Palatability assessment of the new product provided sufficient data to discuss its acceptability. CONCLUSION: Bioequivalence was demonstrated in terms of rate and extent of absorption after administration of test and reference products. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined. Based on ratings by the subjects no relevant problem concerning acceptability of the new formulation in particular regarding taste and smell is to be expected.


Assuntos
Disponibilidade Biológica , Espectrometria de Massas em Tandem , Administração Oral , Adulto , Área Sob a Curva , Cromatografia Líquida , Estudos Cross-Over , Humanos , Comprimidos , Equivalência Terapêutica , Triazóis , Triptaminas , Adulto Jovem
7.
Int J Clin Pharmacol Ther ; 58(10): 575-582, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32729819

RESUMO

PURPOSE: Memantine is currently the only drug that acts on the glutamate energy system to treat Alzheimer's disease. A generic memantine tablet was developed to offer an alternative to the marketed tablet formulation. The purpose of this study was to assess the bioequivalence of two different memantine formulations among healthy male Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: We carried out single-center, randomized, single-dose, open-label, two-period, cross-over studies which including 20 healthy male Chinese subjects under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 240 hours after dosing. Key pharmacokinetic parameters including area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t), area from time zero to infinite (AUC0-∞), and Cmax were used for bioequivalence assessment. RESULTS: Under fasting condition, the 90% CIs of the geometric mean ratios of the test/reference drug for memantine were 106.5 - 114.0% for Cmax, 99.4 - 107.9% for AUC0-t, and 100.0 - 109.6% for AUC0-∞. Under fed condition, the 90% CIs of the geometric mean ratios of the test/reference drug for memantine were 94.8 - 104.3% for Cmax, 98.2 - 110.5% for AUC0-t, and 99.2 - 113.0% for AUC0-∞. CONCLUSION: The observed pharmacokinetic parameters of memantine of the test drug were similar to those of the reference formulation both in the fasting and fed state. That is to say, the test formulation of memantine 10-mg tablet is bioequivalent to the reference formulation (Ebixa 10-mg tablet).


Assuntos
Jejum , Área Sob a Curva , Estudos Cross-Over , Humanos , Masculino , Memantina , Comprimidos , Equivalência Terapêutica
8.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(3): 397-402, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32543150

RESUMO

Objective: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of a rapid-acting insulin analog-insulin aspart (the tested formulation) which was manufactured by The United Laboratories and to evaluate the bioequiavailability to the reference formulation (NovoRapid ®) produced by Novo Nordisk in Chinese healthy volunteers. Methods: A total of 24 male healthy volunteers were recruited from February to April 2016 to participant in this before-after, single dose, and randomized crossover study. And the experimental observation was conducted on 2 test days respectively with a between-period from 7 to10 d. According to a random number table, the volunteers were divided into group A or B, group A was administrated with tested insulin aspart (IAsp) for the first time and reference NovoRapid ® for the second time and group B had the revered order differed from group A. The PK/PD of these insulin analogs were estimated by euglycemic clamp study. Results: The relative biological effectiveness (reflecting gloucose-lowing effect) and bioavailability on behalf of plasma-drug concentration were 98.3±18.8% and 97.3%±8.3% respectively. For PK parameters, the 90% confidence interval ( CI) of peak plasma insulin concentration ( C max) and area under the curve of insulin aspart concentration from 0 to 10 hours ( AUC IAsp, 0-10 h) of IAsp were 88.8%-106% (equivalent range 70%-143%) and 94.0%-100% (equivalent range 80%-125%) respectively; for PD parameters, the 90% CI of the maximum glucose infusion rate ( GIR max) and AUC GIR, 0-10 h were 95.5%-113% (equivalent range 70%-143%) and 89.9%-104% (equivalent range 80%-125%) respectively, which indicated that IAsp and NovoRapid® was bioequivalent. One of the subjects discovered hyperuricemia without clinical symptoms and the rest had no clinically significant abnormalities in the safety indexes before and after the tests. No hypoglycemic events, allergic reactions, or local injection adverse reaction occurred in this trial. Conclusion: The tested IAsp has comparable relative bioavailability to the reference NovoRapid ®.


Assuntos
Hipoglicemiantes , Insulina Aspart , Área Sob a Curva , Estudos Cross-Over , Método Duplo-Cego , Técnica Clamp de Glucose , Humanos , Hipoglicemiantes/farmacologia , Insulina Aspart/farmacologia , Masculino , Equivalência Terapêutica
11.
Transl Res ; 224: 71-77, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32504825

RESUMO

Clinical trials serve as the gold standard to evaluate the efficacy and safety of tested drugs prior to marketing authorization. Nevertheless, there have been a few challenging issues well noted in traditional clinical trials such as tedious processing duration and escalating high costs among others. To improve the efficiency of clinical studies, a spectrum of expedited clinical trial modes has been designed, and selectively implemented in contemporary drug developing landscape. Herein this article presents an update on the innovated human trial designs that are corroborated through coming up with approval of notable therapeutic compounds for clinical utilization including delivery of several blockbuster products. It is intended to inspire clinical investigators and pharmaceutical development not only timely communicating with the regulatory agencies, but also insightful translating from cutting-edge scientific discoveries.


Assuntos
Ensaios Clínicos como Assunto , Invenções , Reposicionamento de Medicamentos , Humanos , Produção de Droga sem Interesse Comercial , Equivalência Terapêutica
12.
AAPS PharmSciTech ; 21(5): 161, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488427

RESUMO

Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [µg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [µg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [µg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.


Assuntos
Desenvolvimento de Medicamentos , Inibidores de Captação de Serotonina/administração & dosagem , Trazodona/administração & dosagem , Adulto , Área Sob a Curva , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Masculino , Inibidores de Captação de Serotonina/farmacocinética , Solubilidade , Equivalência Terapêutica , Trazodona/farmacocinética
13.
AAPS J ; 22(3): 72, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415524

RESUMO

A recent paper reviewed clinical studies intending to bridge a prefilled syringe (PFS) to an autoinjector (AI) based on regulatory submission packages sent to the FDA. An AI generally uses the identical PFS within the AI and the AI typically results in a more consistent injection than can be achieved with a PFS. It is noted that several studies submitted to the FDA did not demonstrate bioequivalence (BE) between the PFS and AI, yet the products were approved anyway. The author of this Commentary believes that formal BE studies should not be required for such bridging studies.


Assuntos
Medicamentos Biossimilares , Seringas , Injeções Subcutâneas , Equivalência Terapêutica
14.
Int J Clin Pharmacol Ther ; 58(7): 408-414, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32352368

RESUMO

OBJECTIVE: The objective of this study was to use LC-MS/MS to compare the pharmacodynamic properties and bioequivalence of two 200-mg formulations of racecadotril: suspension formulation (test) and granule formulation (reference) in healthy Chinese subjects. MATERIALS AND METHODS: A single-dose, randomized, two-period crossover study was conducted in fasted healthy Chinese subjects, who received a single oral dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. RESULTS: The rapid and highly sensitive LC-MS/MS method exhibited a reasonable linearity range (2.324 - 952.000 ng/mL) and high sensitivity (LLOQ of 2.324 ng/mL). The within- and between-run precision, accuracy, and stability results were within the acceptable limits, and no matrix effect was observed. The 90% CI of the ratio of geometric means for AUC0-t, AUC0-∞, and Cmax were 88.1 - 102.3%, 87.9 - 101.5% and 99.5 - 113%, respectively, which met the regulatory criteria for bioequivalence. CONCLUSION: The method is suitable for quantification of thiorphan in human plasma. In addition, the results indicated that the test and reference formulations were bioequivalent in terms of both rate and extent of absorption.


Assuntos
Inibidores de Proteases , Espectrometria de Massas em Tandem , Tiorfano/análogos & derivados , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida , Estudos Cross-Over , Humanos , Inibidores de Proteases/sangue , Comprimidos , Equivalência Terapêutica , Tiorfano/sangue
15.
Int J Clin Pharmacol Ther ; 58(8): 457-464, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32469305

RESUMO

OBJECTIVE: To perform a comparative bioavailability study between a test (re-formulation) and a reference acetylsalicylic acid formulation (Ecasil-81, 81 mg coated tablet) in healthy subjects under fed condition. MATERIALS AND METHODS: Healthy subjects (n = 48) were included in this monocentric, open-label, randomized, two-way crossover pharmacokinetic study. They received a single 81-mg oral dose of a test or a reference formulation of acetylsalicylic acid under fed condition, with a 7-day washout period between the treatments. Blood samples were collected over a period of 36 hours. The salicylic acid plasma concentration was measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Pharmacokinetic analysis was performed using WinNonlin software. RESULTS: The geometric mean and 90% confidence interval of test/reference formulation ratios were 109.32% (102.54 - 116.54%) and 106.94% (102.97 - 111.07%) for salicylic acid Cmax and AUC0-last, respectively. Food decreased the AUC and Cmax (p < 0.001) and delayed the tmax (p = 0.0077). The investigated women presented higher AUC0-∞ and Cmax values (p < 0.001) than men. The clinical and laboratory exams did not show significant alterations. CONCLUSION: The re-formulation is bioequivalent to the reference formulation regarding the absorption extent and rate in fed healthy subjects. The administration of acetylsalicylic acid with food decreased its bioavailability. Moreover, differences in salicylic acid disposition related to sex were observed. The treatments were well tolerated by the investigated subjects.


Assuntos
Aspirina/farmacologia , Administração Oral , Área Sob a Curva , Aspirina/efeitos adversos , Disponibilidade Biológica , Cromatografia Líquida , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Masculino , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica
16.
J Med Chem ; 63(11): 6134-6143, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32406685

RESUMO

Native insulin is susceptible to biophysical aggregation and fibril formation, promoted by manual agitation and elevated temperatures. The safety of the drug and its application to alternative forms of administration could be enhanced through the identification of chemical modifications that strengthen its physical stability without compromising its biological properties. Complex polysialic acids (PSAs) exist naturally and provide a means to enhance the physical properties of peptide therapeutics. A set of insulin analogues site-specifically derivatized with sialic acid were prepared in an overall yield of 50-60%. Addition of a single or multiple sialic acids conferred remarkable enhancement to the biophysical stability of human insulin while maintaining its potency. The time to the onset of fibrillation was extended by more than 10-fold relative to that of the native hormone. These results demonstrate that simplified sialic acid conjugates represent a viable alternative to complex natural PSAs in increasing the stability of therapeutic peptides.


Assuntos
Insulina/análogos & derivados , Ácido N-Acetilneuramínico/química , Animais , Glicemia/análise , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Células HEK293 , Humanos , Insulina/farmacocinética , Insulina/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligopeptídeos/síntese química , Oligopeptídeos/química , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Ácidos Siálicos/química , Equivalência Terapêutica
17.
Postgrad Med ; 132(4): 337-345, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366156

RESUMO

OBJECTIVES: Fixed-dose combination (FDC) therapy can improve outcomes in type 2 diabetes (T2D). We evaluated the bioequivalence of 2 doses of an FDC of extended-release metformin (metformin XR), empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and linagliptin, a dipeptidyl peptidase-4 inhibitor, versus corresponding free tablet combinations. METHODS: Two randomized, open-label, two-way crossover studies in healthy adults compared: 2 FDC tablets of empagliflozin 5 mg/linagliptin 2.5 mg/metformin XR 1000 mg (Study 1; N = 30), 1 FDC tablet of empagliflozin 25 mg/linagliptin 5 mg/metformin XR 1000 mg (Study 2; N = 30) versus corresponding dose of free combinations. Subjects received study medication under fed conditions; washout was ≥35 days between treatments. Primary endpoints: area under the plasma concentration-time curve (AUC) from time 0 to last quantifiable data point for empagliflozin and metformin; AUC from time 0 to 72 hours for linagliptin, and peak plasma concentration (Cmax) for empagliflozin, linagliptin, and metformin. Bioequivalence was defined as adjusted geometric mean ratios (FDC: free combination) and two-sided 90% confidence intervals (CIs) of AUC and Cmax for each component within 80.00-125.00%. RESULTS: Study 1: 27/29 and 28/30 treated participants were included in the pharmacokinetic analysis for the FDC and free combination periods, respectively. Study 2: 29/29 treated participants were included in the pharmacokinetic analysis for both periods. The adjusted geometric mean ratios of FDCs to their respective free tablet combinations and two-sided 90% CIs were all within the predefined range. The shapes of the mean plasma concentration-time profile of empagliflozin, linagliptin, and metformin XR were similar for subjects in the FDC and free combination groups in both studies. No serious adverse events were reported. CONCLUSION: The evaluated doses of empagliflozin/linagliptin/metformin XR FDC tablets were bioequivalent to the corresponding free combinations. Based on these two bioequivalence studies and existing phase 3 data, the FDA has recently approved this triple FDC to improve glycemic control in adults with T2D.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/terapia , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Linagliptina/uso terapêutico , Metformina/uso terapêutico , Adolescente , Adulto , Área Sob a Curva , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Estudos Cross-Over , Preparações de Ação Retardada , Combinação de Medicamentos , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Linagliptina/administração & dosagem , Linagliptina/efeitos adversos , Masculino , Adesão à Medicação , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Equivalência Terapêutica , Adulto Jovem
18.
Phytomedicine ; 72: 153236, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32464544

RESUMO

BACKGROUND: Intestinal obstruction (IO) is a kind of acute abdomen with high morbidity and mortality. Patients suffer from poor quality of life and tremendous financial pressure. Da-Cheng-Qi decoction (DCQD), a classical purgation prescription, has clinically been proven to be an effective treatment for IO. PURPOSE: Network pharmacology integrated with bioactive equivalence assessment was used to discover the quality marker (Q-marker) of DCQD against IO. METHODS: As there is hardly any targets recorded in database, thus the collection of IO targets was conducted by searching those of alternative diseases which have similar pathological symptoms with IO. In order to improve the reliability of the obtained targets, IO metabolomics data was introduced. Active compounds combination (ACC) was focused as potential Q-markers via component-target network analysis and function query from the identified components corresponding to the common targets. Bioequivalence between ACC and DCQD was assessed from the aspects of intestine motility (somatostatin secretion), inflammation (IL-6 secretion) and injury (wound healing assay) in vitro and was further validated in ileus rat model. PPI network analysis of core targets followed by gene pedigree classification and experimental validation confirmed the potential intervention pathway. RESULTS: A combination of 11 ingredients, including emodin, physcion, aloe-emodin, rhein, chrysophanol, gallic acid, magnolol, honokiol, naringenin, tangeretin, and nobiletin was finally confirmed bioequivalence with DQCD to some extent and could serve as Q-markers for DCQD to attenuate IO. PI3K/AKT was verified as a possible affected pathway that DCQD exerted the effectiveness against IO. CONCLUSION: For the disease with few recorded targets, searching those of alternative diseases which have similar pathological symptoms could be a feasible and effective approach. The proposed network pharmacology integrated bioactive equivalence evaluation paradigm is efficient to discover Q-marker of herbal formulae.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Obstrução Intestinal/tratamento farmacológico , Algoritmos , Animais , Antraquinonas/análise , Antraquinonas/farmacocinética , Biomarcadores Farmacológicos/análise , Compostos de Bifenilo/análise , Compostos de Bifenilo/farmacocinética , Mineração de Dados , Flavanonas/análise , Flavanonas/farmacocinética , Células HT29 , Humanos , Lignanas/análise , Lignanas/farmacocinética , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Equivalência Terapêutica
19.
AAPS PharmSciTech ; 21(5): 147, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32435854

RESUMO

The objective of this work was to study the performance of the modified chi-square ratio statistic (mCSRS test) proposed for cascade impactor (CI) profile equivalence testing. The test (T) and reference (R) CI profile datasets were generated from different typical CI profile patterns either with or without inter-site correlation (ISC) through Monte Carlo simulations. The mCSRS test pass rate outcome employing previously published critical values was compared with that of critical values derived from different types of datasets. The influence of number of bootstrap iterations (B) on the consistency of the outcome was assessed within the range of 10-10,000 iterations. Power curves were constructed to study the effect of differences in T and R mean stage deposition, T/R variance ratios, differences between T and R profiles in high/low deposition sites, and sample size on the performance of the mCSRS test. The derived critical values exhibited trends based on R product variability: M1 rank-ordered without ISC (at low variability) and the previously published M8 critical values (at high variability) resulted in lowest pass rate outcomes. The precision of the outcome did not increase considerably beyond B = 2000 (default). The probability of showing equivalence between T and R CI profiles increased with (1) a decrease in mean deposition differences, (2) a decrease in T product variability, and (3) an increase in sample size. The mCSRS outcome is less sensitive to low deposition sites that are prone to analytical variability. In conclusion, the mCSRS test is a sensitive and robust method under most conditions.


Assuntos
Distribuição de Qui-Quadrado , Método de Monte Carlo , Equivalência Terapêutica , Humanos , Probabilidade
20.
Int J Clin Pharmacol Ther ; 58(6): 354-362, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32271144

RESUMO

OBJECTIVE: Asthma patients often have co-existing symptoms of allergic rhinitis and are often prescribed with both asthma and rhinitis treatments such as montelukast and levocetirizine. The objective of this study was to compare the pharmacokinetic profiles of a montelukast/levocetirizine fixed-dose combination chewable tablet with individual administration of montelukast and levocetirizine in healthy subjects. MATERIALS AND METHODS: A randomized, open-label, single-dose crossover study was conducted in healthy male subjects. One of the following treatments was administered in each period: co-administration of 1 chewable tablet of montelukast 5 mg and 1 tablet of levocetirizine 5 mg or administration of 1 chewable tablet of montelukast/levocetirizine 5/5 mg fixed-dose combination. Serial blood samples were collected up to 48 hours post dose. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from dosing to the last measurable concentration (AUClast), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of Cmax and AUClast were calculated to evaluate pharmacokinetic equivalence. RESULTS: A total of 22 subjects were included in pharmacokinetic analysis. The GLSM ratios and 90% CIs of Cmax and AUClast were 1.0054 (0.9535 - 1.0601) and 1.0628 (1.0013 - 1.1281) for montelukast and 1.0105 (0.9488 - 1.0764) and 1.0396 (0.9935 - 1.0879) for levocetirizine, respectively. CONCLUSION: The pharmacokinetic parameters of montelukast and levocetirizine when administered as separate tablets or as a fixed-dose combination were compared, and the parameters met the pharmacokinetic equivalence criteria. (ClinicalTrials.gov Identifier: NCT03371849).


Assuntos
Acetatos/farmacocinética , Cetirizina/farmacocinética , Quinolinas/farmacocinética , Acetatos/administração & dosagem , Administração Oral , Área Sob a Curva , Cetirizina/administração & dosagem , Estudos Cross-Over , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Quinolinas/administração & dosagem , República da Coreia , Comprimidos , Equivalência Terapêutica
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