RESUMO
The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.
Assuntos
Biofarmácia , Relatório de Pesquisa , Preparações Farmacêuticas , Biofarmácia/métodos , Equivalência Terapêutica , Excipientes , Permeabilidade , SolubilidadeRESUMO
Early characterization of new drug substances intended for oral application includes not only physicochemical properties and stability but also the ability of the substance to permeate through the intestinal mucosa. In this work, a rapid screening method, surface activity profiling (SAP), is proposed as an alternative to animal studies and screening in cell cultures. Measurements are made with a multichannel tensiometer and require only 50⯵l of stock solution for the complete permeability analysis. Correlation of SAP results with human absorption was demonstrated for marketed drugs and with absorption in rats for development compounds of Boehringer Ingelheim. Cross-laboratory results for marketed drugs showed excellent agreement. For early stage investigations of lead compounds, where only small amounts of the compound are available, the SAP method appears to be an effective and fast tool to accurately predict fa, provided the compound is amphiphilic.
Assuntos
Permeabilidade da Membrana Celular/fisiologia , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Animais , Feminino , Humanos , Masculino , Membranas Artificiais , Ratos , Ratos WistarRESUMO
The EU research initiative OrBiTo (oral biopharmaceutics tools) involving partners from academia, pharmaceutical industry, small medium enterprises and a regulatory agency was launched with the goal of improving tools to predict the absorption of drugs in humans and thereby accelerating the formulation development process. The OrBiTo project was divided into four work packages (WP), with WP2 focusing on characterization of drug formulations. The present work introduces the OrBiTo WP2 Decision Tree, which is designed to assist the investigator in choosing the most appropriate in vitro methods for optimizing the oral formulation design and development process. The WP2 Decision Tree consists of four stages to guide the investigator. At the first stage, the investigator is asked to choose the formulation type of interest. At the second stage, the investigator is asked to identify which type of equipment (compendial/modified/noncompendial) is preferred/available. At the third stage, characteristics of the active pharmaceutical ingredient (API) are evaluated and in the fourth stage of the decision tree, suitable experimental protocols are recommended. A link to the living Decision Tree document is provided, and we now invite the pharmaceutical sciences community to apply it to current research and development projects and offer suggestions for improvement and expansion.
Assuntos
Biofarmácia/métodos , Árvores de Decisões , Preparações Farmacêuticas/administração & dosagem , Administração Oral , Desenho de Fármacos , Indústria Farmacêutica/métodos , Liberação Controlada de Fármacos , Humanos , Preparações Farmacêuticas/metabolismoRESUMO
OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
Assuntos
Biofarmácia/métodos , Trato Gastrointestinal/metabolismo , Absorção Intestinal , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Administração Oral , Animais , Química Farmacêutica , Simulação por Computador , Formas de Dosagem , Humanos , Modelos Biológicos , Permeabilidade , Preparações Farmacêuticas/química , Desenvolvimento de Programas , SolubilidadeRESUMO
In preclinical development, salt forms are often screened to assess their ability to improve drug candidate properties. In this study albendazole was used as a model for poorly soluble, weak basic compounds typical of current drug discovery programs. Four salts, the hydrochloride, mesylate, sulfate und tosylate, were prepared and characterized with respect to their physicochemical properties. Identity was confirmed by 1H NMR spectroscopy, ion chromatography and vibrational spectroscopy. The solid state forms of the albendazole salts were examined by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), laser diffraction measurement of particle size distribution (PSD), B.E.T. measurement of the specific surface area and 13C solid state NMR spectroscopy. Thermal behaviour and hygroscopicity were assessed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), Karl Fischer titration (KFT) and by variable temperature XRPD. Additionally, solubility and dissolution experiments were carried out in water and buffers. The different salt forms show pronounced differences in their physicochemical behaviour, especially with respect to hygroscopicity (sulfate > hydrochloride > tosylate > mesylate) and dissolution (rank order is pH dependent, all better than the free base). A salt form with highly improved physicochemical properties, the mesylate, was identified. The results demonstrate that extensive physicochemical characterization is needed to select the salt form most appropriate for further pharmaceutical development.
Assuntos
Albendazol/química , Anti-Helmínticos/química , Adsorção , Álcalis , Cloretos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Mesilatos , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Sais , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Sulfatos , Propriedades de Superfície , Termogravimetria , Difração de Raios XRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing lamivudine as the only active pharmaceutical ingredient were reviewed. The solubility and permeability data of lamivudine as well as its therapeutic index, its pharmacokinetic properties, data indicating excipient interactions, and reported BE/bioavailability (BA) studies were taken into consideration. Lamivudine is highly soluble, but its permeability characteristics are not well-defined. Reported BA values in adults ranged from 82% to 88%. Therefore, lamivudine is assigned to the biopharmaceutics classification system (BCS) class III, noting that its permeability characteristics are near the border of BCS class I. Lamivudine is not a narrow therapeutic index drug. Provided that (a) the test product contains only excipients present in lamivudine IR solid oral drug products approved in the International Conference on Harmonization or associated countries in usual amounts and (b) the test product as well as the comparator product fulfills the BCS dissolution criteria for very rapidly dissolving; a biowaiver can be recommended for new lamivudine multisource IR products and major post-approval changes of marketed drug products.
Assuntos
Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Fenômenos Químicos , Excipientes , Humanos , Lamivudina/química , Lamivudina/toxicidade , Solubilidade , Equivalência Terapêutica , Distribuição TecidualRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing mefloquine hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. The solubility and permeability data of mefloquine hydrochloride as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability studies were taken into consideration. Mefloquine hydrochloride is not a highly soluble API. Since no data on permeability are available, it cannot be classified according to the Biopharmaceutics Classification System with certainty. Additionally, several studies in the literature failed to demonstrate BE of existing products. For these reasons, the biowaiver cannot be justified for the approval of new multisource drug products containing mefloquine hydrochloride. However, scale-up and postapproval changes (HHS-FDA SUPAC) levels 1 and 2 and most EU type I variations may be approvable without in vivo BE, using the dissolution tests described in these regulatory documents.
Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Mefloquina/administração & dosagem , Mefloquina/farmacocinética , Administração Oral , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Disponibilidade Biológica , Formas de Dosagem , Aprovação de Drogas , Excipientes , Humanos , Mefloquina/química , Mefloquina/uso terapêutico , Solubilidade , Equivalência TerapêuticaRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing ciprofloxacin hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ciprofloxacin hydrochloride's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and BA data indicate that ciprofloxacin hydrochloride is a BCS Class IV drug. Therefore, a biowaiver based approval of ciprofloxacin hydrochloride containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacocinética , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Disponibilidade Biológica , Ciprofloxacina/química , Ciprofloxacina/uso terapêutico , Formas de Dosagem , Aprovação de Drogas , Excipientes , Humanos , Absorção Intestinal , Permeabilidade , Solubilidade , Equivalência TerapêuticaRESUMO
Literature and new experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemide's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the biowaiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products.
Assuntos
Furosemida/farmacocinética , Disponibilidade Biológica , Biofarmácia , Formas de Dosagem , Excipientes , Humanos , Permeabilidade , Solubilidade , Equivalência TerapêuticaRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for "very rapidly dissolving" or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are "rapidly dissolving.".
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Doxiciclina/análogos & derivados , Antibacterianos/química , Antibacterianos/uso terapêutico , Formas de Dosagem , Doxiciclina/administração & dosagem , Doxiciclina/química , Doxiciclina/farmacocinética , Doxiciclina/uso terapêutico , Aprovação de Drogas , Humanos , Solubilidade , Equivalência TerapêuticaRESUMO
The suitability of various media to forecast the solubility of ketoconazole and dipyridamole in the fed stomach at various periods after meal administration was evaluated. Solubilities were measured with the shake-flask method in gastric fluids aspirated 30, 60 and 120 min after administration of 500 ml Ensure plus to healthy fasted adults, in three sets of simulated gastric fluids based on milk, and in simple aqueous buffered media. Simple aqueous buffered media vastly underestimated the intragastric solubility of model compounds in the fed state. When using undigested milk-based media, the solubilities of model compounds in aspirates were also underestimated by a factor of 2.5-27. Solubility in milk digested with pepsin was useful for estimating the intragastric solubility of ketoconazole (within 20%) but overestimated the intragastric values of dipyridamole by a factor of 2-19. For both drugs, the solubility in milk digested with pepsin and lipase predicted the solubility in aspirates collected 60 min after meal administration, whereas at other times it overestimated the intragastric solubility (by a factor of <5). Both the use of biorelevant media and simulation of intragastric digestion are necessary for the prediction of drug solubility in the fed stomach. Milk digested with pepsin and lipase enabled the estimation of the intragastric solubility of dipyridamole and ketoconazole at 1 h after meal intake. Simulation of vesicle/micellar structures seems to be key for the prediction of intragastric solubility in the fed stomach.
Assuntos
Suco Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Preparações Farmacêuticas/metabolismo , Saciação/fisiologia , Adulto , Feminino , Alimentos , Interações Alimento-Droga/fisiologia , Humanos , Masculino , Preparações Farmacêuticas/química , SolubilidadeRESUMO
The importance of intragastric lipolysis to felodipine release from a hydrophilic, extended release tablet in the fed stomach was assessed in USP II apparatus with the tablet fixed on a steel wire above the paddle. The release medium, homogenized long-life milk, was gradually digested with shots of acidic solutions of pepsin over the course of the experiment in absence and in presence of biorelevant concentrations of a lipase that was similar to human gastric lipase. Percentage tablet erosion at specific times in the same media was measured in separate experiments. The data were compared to published data for intragastric release in fed healthy adults. In all cases, felodipine release occurred under sink conditions. Lipase facilitated felodipine release from the eroded polymer, bringing the release profile closer to the in vivo data. Likewise, the relationship between tablet erosion and amount of released felodipine reflected the in vivo data only when lipase was added to the medium. It was concluded that modelling intragastric lipolysis is necessary in order to simulate felodipine release from the extended release tablets in the fed stomach.
Assuntos
Felodipino/farmacocinética , Mucosa Gástrica/metabolismo , Comprimidos , Humanos , Lipólise , SolubilidadeRESUMO
The importance of hydrodynamics in the development of in vitro-in vivo correlations (IVIVCs) for a BCS Class II compound housed in a hydrophilic matrix formulation and for a BCS Class I compound housed in an osmotic pump formulation was assessed. In vitro release data were collected in media simulating the fasted state conditions in the stomach, small intestine and the ascending colon using the USP II, the USP III and the USP IV release apparatuses. Using the data collected with the USP II apparatus, the plasma profiles were simulated and compared with human plasma profiles obtained after administration of the same dosage forms to healthy fasted volunteers. Data obtained with the USP III and USP IV apparatuses were directly correlated with the deconvoluted human plasma profiles. In vitro hydrodynamics affected the release profile from the hydrophilic matrix. For both formulations, based on the values of the difference factor, all three apparatuses were equally useful in predicting the actual in vivo profile on an average basis. Although some hydrodynamic variability is likely with low solubility drugs in hydrophilic matrices, the hydrodynamics of USP II, III and IV may all be adequate as a starting point for generating IVIVCs for monolithic dosage forms in the fasted state.
Assuntos
Química Farmacêutica/instrumentação , Química Farmacêutica/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/metabolismo , Albuterol/administração & dosagem , Albuterol/química , Albuterol/metabolismo , Preparações de Ação Retardada/química , Avaliação Pré-Clínica de Medicamentos/instrumentação , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/química , Tiazolidinedionas/metabolismoRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing rifampicin as the only Active Pharmaceutical Ingredient (API) are reviewed. Rifampicin's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and absolute BA data indicate that rifampicin is a BCS Class II drug. Of special concern for biowaiving is that many reports of failure of IR solid oral dosage forms of rifampicin to meet BE have been published and the reasons for these failures are yet insufficiently understood. Moreover, no reports were identified in which in vitro dissolution was shown to be predictive of nonequivalence among products. Therefore, a biowaiver based approval of rifampicin containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.
Assuntos
Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/farmacocinética , Hansenostáticos/administração & dosagem , Hansenostáticos/farmacocinética , Rifampina/administração & dosagem , Rifampina/farmacocinética , Administração Oral , Antibióticos Antituberculose/química , Antibióticos Antituberculose/uso terapêutico , Disponibilidade Biológica , Formas de Dosagem , Aprovação de Drogas , Estabilidade de Medicamentos , Excipientes , Interações Alimento-Droga , Humanos , Hansenostáticos/química , Hansenostáticos/uso terapêutico , Permeabilidade , Rifampina/química , Rifampina/uso terapêutico , Solubilidade , Equivalência TerapêuticaRESUMO
Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing either diclofenac potassium and diclofenac sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs). However, a biowaiver can be recommended for IR drug products of each salt form, due to their therapeutic use, therapeutic index, pharmacokinetic properties, potential for excipient interactions, and performance in reported BE/bioavailability (BA) studies, provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of the test and comparator is identical; (c) the test product contains only excipients present in diclofenac drug products approved in ICH or associated countries in the same dosage form, for instance as presented in this paper; (d) test drug product and comparator dissolve 85% in 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Fenômenos Químicos , Diclofenaco/efeitos adversos , Diclofenaco/química , Excipientes/química , Humanos , Solubilidade , Comprimidos , Equivalência TerapêuticaRESUMO
Solid solutions of felodipine with EUDRAGIT E and EUDRAGIT E/NE were shown to dramatically increase the dissolution rate of felodipine in biorelevant media. Of the two polymer systems, extrudates containing 5% EUDRAGIT NE showed a faster dissolution rate and less recrystallization (no precipitation within 2 h). Although differential scanning calorimetry (DSC) and conventional X-ray powder diffraction (XRPD) were able to verify the amorphous state of the drug after melt extrusion, it was not possible to differentiate the two extrudate compositions further with these methods. We then applied pair distribution function (PDF) analysis to investigate extrudates. It was possible to more closely characterize the solid state of the amorphous extrudates in terms of local structural order: PDF analysis revealed that addition of minor amounts of EUDRAGIT NE to the main component EUDRAGIT E during extrusion changed the local structure of EUDRAGIT E in a nonadditive way. We conclude that local ordering can be important to the release characteristics of extrudates, even when the components are present in the amorphous state.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Excipientes/química , Felodipino/química , Metacrilatos/química , Polímeros/química , Ácidos Polimetacrílicos/química , Bloqueadores dos Canais de Cálcio/administração & dosagem , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Felodipino/administração & dosagem , Espectroscopia de Ressonância Magnética , Transição de Fase , Difração de Pó , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Temperatura de TransiçãoRESUMO
Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products.
Assuntos
Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Quinidina/administração & dosagem , Quinidina/farmacocinética , Administração Oral , Antiarrítmicos/química , Antiarrítmicos/uso terapêutico , Antimaláricos/química , Antimaláricos/uso terapêutico , Disponibilidade Biológica , Formas de Dosagem , Aprovação de Drogas , Excipientes , Humanos , Permeabilidade , Quinidina/química , Quinidina/uso terapêutico , Solubilidade , Equivalência TerapêuticaRESUMO
OBJECTIVE: To determine the cholesterol-lowering efficacy of hydroxypropylmethylcellulose (HPMC) in mildly hypercholesterolemic humans. SUBJECTS: Trial one: entry mean (range) total serum cholesterol values of eight female and four male subjects were 6.48 (5.57-7.51) mmol l(-1) (250 (215-290) mg dl(-1)) and 6.60 (5.57-7.64) mmol l(-1) (255 (215-295) mg dl(-1)), respectively. Trial two: corresponding values for 20 women and 20 men were 5.96 (5.43-6.48) mmol l(-1) 230 (210-250) mg dl(-1)) and 6.05 (5.46-6.63) mmol l(-1) 233 (211-256) mg dl(-1)), respectively. RESULTS: Trial one: HPMC decreased (P< or =0.05) total and LDL-cholesterol 9.3 and 15.3% (medium), 16.9 and 23.5% (high) and 13.8 and 19.4% (ultra-high), respectively, over placebo. Trial two: total and LDL-cholesterol decreased (P< or =0.05) throughout the 8 weeks, with mean (weeks 4-8) reductions of 7 and 8% at 5 g day(-1), and 12 and 15% at 15 g day(-1), respectively, over placebo. Adverse effects were minimal. Trial one: medium, high and ultra-high viscosity HPMC at 15 g day(-1) for 1 week each;1-week wash-out between treatments. Trial two: ultra-high viscosity HPMC at 5 or 15 g day(-1) for 8 weeks. CONCLUSIONS: HPMC soluble fiber, especially high-viscosity grades, significantly lowers cholesterol at well-tolerated doses, showing promise as a treatment of hypercholesterolemia.
Assuntos
Anticolesterolemiantes/uso terapêutico , Fibras na Dieta/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Metilcelulose/análogos & derivados , Adulto , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colo/fisiologia , Estudos Cross-Over , Fibras na Dieta/efeitos adversos , Fibras na Dieta/farmacologia , Feminino , Humanos , Derivados da Hipromelose , Masculino , Metilcelulose/efeitos adversos , Metilcelulose/farmacologia , Metilcelulose/uso terapêutico , Pessoa de Meia-Idade , Análise de Regressão , Triglicerídeos/sangueRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which fall just within BCS Class IV. Aciclovir seems not to be critical with respect to a risk for bioinequivalence, as no examples of bioinequivalence have been identified. It has a wide therapeutic index and is not used for critical indications. Hence, if: (a) the test product contains only excipients present in aciclovir solid oral IR drug products approved in ICH or associated countries, for instance as presented in this article; and (b) the comparator and the test product both are very rapidly dissolving, a biowaiver for IR aciclovir solid oral drug products is considered justified for all tablet strengths.
Assuntos
Aciclovir/administração & dosagem , Antivirais/administração & dosagem , Aciclovir/farmacocinética , Administração Oral , Antivirais/farmacocinética , Disponibilidade Biológica , Equivalência TerapêuticaRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing pyrazinamide as the only active pharmaceutical ingredient (API) are reviewed. Pyrazinamide is BCS Class III, with linear absorption over a wide dosing range. The risk of bioinequivalence is estimated to be low. Depending on the definition used, pyrazinamide can be classified as a narrow therapeutic index (NTI) drug, which is usually a caveat to biowaiving but may be deemed acceptable if the Summary of Product Characteristics (SmPCs) of the test product stipulates the need for regular monitoring of liver function. It is concluded that a biowaiver can be recommended for IR solid oral dosage only when the test product (a) contains only excipients present in pyrazinamide IR solid oral drug products approved in ICH or associated countries, (b) these excipients are present in amounts normally used in IR solid oral dosage forms, (c) the test product is very rapidly dissolving, (d) the SmPC of the test product indicates the need for monitoring of the patient's liver function.