PMC:7554011 / 1957-7585 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7554011","sourcedb":"PMC","sourceid":"7554011","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7554011","text":"INTRODUCTION\nUnderstanding the dissolution profile of a pharmaceutical dosage form and linking it to its in vivo pharmacokinetic (PK) profile is a vital requirement for ensuring product quality and safety of use (1–3). Dissolution profiles can be analysed through different approaches: using model-dependent methods where experimental data are fitted using mathematical equations, model-independent methods (single values such as mean dissolution time and area under the dissolution curve (AUC) are used for data evaluation) and/or statistical methods (e.g. ANOVA and multivariate analysis) (4,5).\nDrug dissolution profiles may be used to establish in vitro-in vivo correlations (IVIVC). The development of an IVIVC for a pharmaceutical dosage form is of great interest to the pharmaceutical industry and plays a key role in the pharmaceutical development of dosage forms (1). It can serve as a surrogate for in vivo bioavailability and be used to request biowaiver status for formulations or production changes within a product lifecycle (1–3). This reduces the need for expensive bioequivalence (BE) testing in humans.\nDefining appropriate biorelevant drug dissolution conditions requires an understanding of the relationship between the various physicochemical and physiological factors that have an impact on the rate and extent to which an orally administered dosage form is absorbed (4). Since clinical research with adults cannot simply be generalised or extrapolated to the paediatric population, research involving paediatric patients is essential (6). Age-related PK studies are normally required due to differences in anatomy or drug handling/manipulation practices, which might lead to different dose requirements to achieve efficacy or to avoid adverse effects (7). Moreover, changes in developmental physiology throughout childhood complicate pharmacotherapy, due to its impact on drug absorption, distribution, metabolism and excretion of drugs and excipients (8). Thus, better understanding of physiological developmental changes is important for paediatric drug testing. Data characterising the GI environment of the different paediatric age groups is very difficult to be obtained due to ethical constraints, associated co-morbidities in paediatric patients and the need for parental consent. Challenges in paediatric medicine development further include (i.) the need for appropriate outcome measures for paediatric patients, (ii.) the complexities of paediatric administration practices (e.g. drug manipulation and mixing with food and drinks (vehicles)), (iii.) the parental involvement and (iv.) the adaptations of required research procedures and settings to accommodate paediatric anatomic/cognitive development (8).\nDevelopment of a physiologically relevant in vitro dissolution setup would be crucial for the prediction of the in vivo performance after the administration of a formulation to a paediatric patient. Moreover, it would be beneficial for the investigation of formulation sensitivity to different foods and drinks, so that the risks associated with its co-administration can be predicted. In 2018, the FDA issued a draft guidance addressing the recommended approaches for determination of the suitability of the vehicles intended for co-administration of paediatric medicines. In this guidance, standardised in vitro methods for evaluating possible vehicle effects on in vivo product performance were described (9). These tests could help reduce the number of in vivo studies required for paediatric formulation development, and ultimately help tackle ethical issues related to paediatric clinical research (10). To this extent, in vitro test conditions should address the parameters relevant to drug release and dissolution in the paediatric gastrointestinal (GI) tract, including media composition, prandial state, hydrodynamics and current administration practices. The possible effect of these parameters on the in vivo drug behaviour should be considered during paediatric drug development (6,11). Recently, in vitro dissolution studies, performed with a mini-paddle apparatus and a two-stage approach, showed that this setup could be a useful biopharmaceutical tool for estimating drug release/dissolution in paediatric conditions (12,13). With this setup, it is possible to address pH, fluid volumes and transit times representative of the GI tract of infants, as well as different paediatric administration practices such as medicine co-administration with food and drinks.\nThe aims of this study were (i.) to investigate the impact of co-administration of montelukast formulations (granules and chewable tablets) with food and drinks on drug dissolution performance, under paediatric physiological relevant conditions, and (ii.) to evaluate the in vitro dissolution studies in terms of their predictability of the in vivo formulation performance.\nMontelukast was chosen as the model drug; it is an amphoteric compound, with high lipophilicity (clogP 8.79), and classified as a BCS class II compound (14). Montelukast is a potent leukotriene receptor antagonist that has demonstrated efficacy and tolerability in the treatment of patients with chronic asthma (15–17). For approved paediatric use, it is available in two dosage forms (granules and chewable tablets), and is used in very young ages from 1 month old (17). The PK profile of montelukast is dose proportional and not substantially altered by age (18). As shown in different in vivo studies in infant subgroups, montelukast formulations are often mixed with drinks or soft foods to facilitate administration (7,16,17,19).","divisions":[{"label":"title","span":{"begin":0,"end":12}},{"label":"p","span":{"begin":13,"end":597}},{"label":"p","span":{"begin":598,"end":1120}},{"label":"p","span":{"begin":1121,"end":2740}},{"label":"p","span":{"begin":2741,"end":4519}},{"label":"p","span":{"begin":4520,"end":4893}}],"tracks":[{"project":"2_test","denotations":[{"id":"33051713-22547350-26774","span":{"begin":213,"end":214},"obj":"22547350"},{"id":"33051713-26721731-26774","span":{"begin":213,"end":214},"obj":"26721731"},{"id":"33051713-23988843-26774","span":{"begin":213,"end":214},"obj":"23988843"},{"id":"33051713-28011342-26775","span":{"begin":594,"end":595},"obj":"28011342"},{"id":"33051713-22547350-26776","span":{"begin":873,"end":874},"obj":"22547350"},{"id":"33051713-22547350-26777","span":{"begin":1040,"end":1041},"obj":"22547350"},{"id":"33051713-26721731-26777","span":{"begin":1040,"end":1041},"obj":"26721731"},{"id":"33051713-23988843-26777","span":{"begin":1040,"end":1041},"obj":"23988843"},{"id":"33051713-24189013-26778","span":{"begin":1558,"end":1559},"obj":"24189013"},{"id":"33051713-27704550-26779","span":{"begin":1775,"end":1776},"obj":"27704550"},{"id":"33051713-17725846-26780","span":{"begin":3646,"end":3648},"obj":"17725846"},{"id":"33051713-24189013-26781","span":{"begin":4034,"end":4035},"obj":"24189013"},{"id":"33051713-28495584-26782","span":{"begin":4036,"end":4038},"obj":"28495584"},{"id":"33051713-18560996-26783","span":{"begin":5047,"end":5049},"obj":"18560996"},{"id":"33051713-16707408-26784","span":{"begin":5206,"end":5208},"obj":"16707408"},{"id":"33051713-18296556-26784","span":{"begin":5206,"end":5208},"obj":"18296556"},{"id":"33051713-18296556-26785","span":{"begin":5361,"end":5363},"obj":"18296556"},{"id":"33051713-27704550-26786","span":{"begin":5616,"end":5617},"obj":"27704550"},{"id":"33051713-16707408-26787","span":{"begin":5618,"end":5620},"obj":"16707408"},{"id":"33051713-18296556-26788","span":{"begin":5621,"end":5623},"obj":"18296556"},{"id":"33051713-15102869-26789","span":{"begin":5624,"end":5626},"obj":"15102869"}],"attributes":[{"subj":"33051713-22547350-26774","pred":"source","obj":"2_test"},{"subj":"33051713-26721731-26774","pred":"source","obj":"2_test"},{"subj":"33051713-23988843-26774","pred":"source","obj":"2_test"},{"subj":"33051713-28011342-26775","pred":"source","obj":"2_test"},{"subj":"33051713-22547350-26776","pred":"source","obj":"2_test"},{"subj":"33051713-22547350-26777","pred":"source","obj":"2_test"},{"subj":"33051713-26721731-26777","pred":"source","obj":"2_test"},{"subj":"33051713-23988843-26777","pred":"source","obj":"2_test"},{"subj":"33051713-24189013-26778","pred":"source","obj":"2_test"},{"subj":"33051713-27704550-26779","pred":"source","obj":"2_test"},{"subj":"33051713-17725846-26780","pred":"source","obj":"2_test"},{"subj":"33051713-24189013-26781","pred":"source","obj":"2_test"},{"subj":"33051713-28495584-26782","pred":"source","obj":"2_test"},{"subj":"33051713-18560996-26783","pred":"source","obj":"2_test"},{"subj":"33051713-16707408-26784","pred":"source","obj":"2_test"},{"subj":"33051713-18296556-26784","pred":"source","obj":"2_test"},{"subj":"33051713-18296556-26785","pred":"source","obj":"2_test"},{"subj":"33051713-27704550-26786","pred":"source","obj":"2_test"},{"subj":"33051713-16707408-26787","pred":"source","obj":"2_test"},{"subj":"33051713-18296556-26788","pred":"source","obj":"2_test"},{"subj":"33051713-15102869-26789","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ecc393","default":true}]}]}}