| 1. |
- Bergström, Christel A. S., et al.
(författare)
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Early pharmaceutical profiling to predict oral drug absorption : Current status and unmet needs
- 2014
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57, s. 173-199
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Tidskriftsartikel (refereegranskat)abstract
- Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silica and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. (C) 2013 Elsevier B.V. All rights reserved.
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| 2. |
- Cristofoletti, Rodrigo, et al.
(författare)
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Biowaiver monographs for immediate release solid oral dosage forms : efavirenz
- 2013
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 102:2, s. 318-329
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Tidskriftsartikel (refereegranskat)abstract
- Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products.
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| 3. |
- Kostewicz, Edmund S., et al.
(författare)
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PBPK models for the prediction of in vivo performance of oral dosage forms
- 2014
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57:SI, s. 300-321
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Forskningsöversikt (refereegranskat)abstract
- Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration! estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications.
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| 4. |
- Polentarutti, Britta, et al.
(författare)
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Modification of gastric pH in the fasted dog
- 2010
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Ingår i: Journal of Pharmacy and Pharmacology (JPP). - 0022-3573 .- 2042-7158. ; 62:4, s. 462-469
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim was to compare the ability of pretreatments to consistently adjust gastric conditions to low or high pH in the fasted state in dogs. METHODS: Four male Labrador/Labrador-cross dogs weighing 25-35 kg were surgically equipped with a ventricle fistula cannula in the stomach and a jejunal nipple valve stoma. Dogs were fasted overnight before the experiments, with free access to water. The pH in the dogs' stomach was modified either orally with buffers (0.1 mol/l HCl-KCl, 0.05 mol/l glycine-HCl, 0.1 mol/l citrate or 0.1 mol/l BIS-TRIS) or intravenously with pharmacological agents (pentagastrin 4-6 microg/kg, ranitidine 50 mg or omeprazole 1 mg/kg). Intragastric pH was recorded continuously for 2 h with an electrode connected to an ambulatory pH meter. Chyme was collected simultaneously from the jejunal stoma as an approximate measure of gastric emptying. KEY FINDINGS: 0.1 mol/l HCl-KCl buffer p.o. and 1 mg/kg omeprazole i.v. attained low and high gastric pH more reproducibly (11/11 and 6/7 experiments met target values of pH < 3 and > 4, respectively) and for a longer duration (average time exceeding target value 90 and 103 min, respectively) than the other buffers and pharmacological pretreatments. The starting pH did not alter the modifiers' capacity to increase or decrease the pH. However, the lag time before chyme appeared at the jejunal stoma appeared to be longer when the pH was low and shorter when the pH was high. CONCLUSIONS: To achieve a consistently low gastric pH in fasting dogs, 0.1 mol/l HCl-KCl buffer should be administered orally, 15 min before the dosage form. To elevate the gastric pH reproducibly, omeprazole 1 mg/kg should be administered intravenously at least 90 min before oral administration of the dosage form.
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| 5. |
- Selen, Arzu, et al.
(författare)
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The Biopharmaceutics Risk Assessment Roadmap for Optimizing Clinical Drug Product Performance
- 2014
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 103:11, s. 3377-3397
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Tidskriftsartikel (refereegranskat)abstract
- The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate learning and confirming studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.
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| 6. |
- Soares, Kelen C C, et al.
(författare)
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Biowaiver monographs for immediate-release solid oral dosage forms : Zidovudine (azidothymidine)
- 2013
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 102:8, s. 2409-2423
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Tidskriftsartikel (refereegranskat)abstract
- Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation.
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| 7. |
- Vertzoni, Maria, et al.
(författare)
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Biorelevant media to simulate fluids in the ascending colon of humans and their usefulness in predicting intracolonic drug solubility
- 2010
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 27:10, s. 2187-2196
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To develop media simulating human colonic fluids(HCFs), to evaluate their use in predicting intracolonic solubilityof ketoconazole, danazol and felodipine and to comparesolubilities in HCFs with previously determined solubilities ingastric (HGFs) and small intestinal (HIFs) fluids. Methods Fasted state simulated colonic fluid (FaSSCoF) andfed state simulated colonic fluid (FeSSCoF) were designed toreflect fluids previously collected from the ascending colon inhealthy adults. Solubilities of the three model compounds weredetermined in HCFs, simulated HCFs, and plain buffers. Results For ketoconazole, solubilities in FaSSCoF and FeS-SCoF were closer than those in the corresponding plain buffersto the solubility in HCFs. For danazol and felodipine, solubilitiesin FaSSCoF and FeSSCoF predicted solubilities in HCFs. In thefasted state, solubilities of danazol and felodipine in HCFs werehigher than or similar to in HGFs or HIFs, while theketoconazole solubility was lower. In the fed state, solubilities of all three model compounds in HCFs were lower than inHGFs or HIFs. Conclusions FaSSCoF and FeSSCoF more closely predictsolubility of poorly soluble compounds in HCFs than plainbuffers. In most cases, solubility in HCFs differs from those inHGFs and HIFs.
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| 8. |
- Vertzoni, Maria, et al.
(författare)
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Characterization of the ascending colon fluids in ulcerative colitis
- 2010
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 27:8, s. 1620-1626
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To characterize the fluid composition in ascending colon of fasted adults with ulcerative colitis in relapse and in remission with a view to predicting variations on dosage form performance in the lower inflamed gut. Methods: Twelve patients participated in a two-phase, crossover study. Enrolment to the relapse phase (Phase A) and designation of the remission state for the second colonoscopy (Phase B) were based on Clinical Rachmilewicz Index values. Samples were analyzed for pH and buffer capacity immediately upon collection. After ultracentrifugation, osmolality, surface tension, soluble protein, soluble carbohydrates, and the levels of ten bile acids, seven short-chain fatty acids (SCFAs), three long-chain fatty acids, triglycerides, diglycerides, monoglycerides, phosphatidylcholine, and cholesterol were measured. Results: Total SCFAs are significantly decreased in relapse, but pH remains unaffected. Regardless of remission/relapse status, pH and isobutyric acid levels are lower than in healthy adults. Buffer capacity, osmolality, and soluble protein are higher than in healthy adults. Treatment with prednisolone increases the volume of intracolonic contents. Conclusion: Variations in fluid composition of the ascending colon with activity and severity of ulcerative colitis may have an impact on the performance of orally administered products that are targeted to release the therapeutic agent in the colon.
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