Patients perspectives on drug shortages in six European hospital settings - a cross sectional study.

BACKGROUND: It is known that drug shortages represent a major challenge for all stakeholders involved in the process, but there is little evidence regarding insights into patients' awareness and perspectives. This study aimed to investigate the patients-perceived drug shortages experience and their view on outcomes in different European hospital settings. Furthermore, we wanted to explore information preferences on drug shortages. METHODS: A retrospective, cross sectional, a mixed method study was conducted in six European hospital settings. One hospital (H) from each of this country agreed to participate: Bosnia and Herzegovina (H-BiH), Croatia (H-CR), Germany (H-GE), Greece (H-GR), Serbia (H-SE) and Poland (H-PO). Recruitment and data collection was conducted over 27 months from November 2017 until January 2020. Overall, we surveyed 607 patients which completed paper-based questionnaire. Questions related to: general information (demographic data), basic knowledge on drug shortages, drug shortages experienced during hospitalization and information preferences on drug shortage. Differences between hospital settings were analyzed using Chi-squared test or Fisher's exact test. For more complex contingency tables, Monte Carlo simulations (N = 2000) were applied for Fisher's test. Post-hoc hospital-wise analyses were performed using Fisher's exact tests. False discovery rate was controlled using the Bonferroni method. Analyses were performed using R: a language and environment for statistical computing (v 3.6.3). RESULTS: 6 % of patients reported experiences with drug shortages while hospitalized which led to a deterioration of their health. The majority of affected patients were hospitalized at hematology and/or oncology wards in H-BiH, H-PO and H-GE. H-BiH had the highest number of affected patients (18.1 %, N = 19/105, p < 0.001) while the fewest patients were in H-SE (1 %, N = 1/100, p = 0.001). In addition, 82.5 %, (N = 501/607) of respondents wanted to be informed of alternative treatment options if there was a drug shortage without a generic substitute available. Majority of these patients (66.4 %, N = 386/501) prefer to be informed by a healthcare professional. CONCLUSIONS: Although drug shortages led to serious medical consequences, our findings show that most of the patients did not perceive shortages as a problem. One possible interpretation is that good hospital management practices by healthcare professionals helped to mitigate the perceived impact of shortages. Our study highlights the importance of a good communication especially between patients and healthcare professionals in whom our patients have the greatest trust.

Analysis of Case II drug transport with radial and axial release from cylinders.

Analysis is presented for Case II drug transport with axial and radial release from cylinders. The previously reported [J. Control Release 5 (1987) 37] relationships for radial release from films and slabs are special cases of the general solution derived in this study. The widely used exponential relation M(t)/M(infinity) = kt(n) describes nicely the first 60% of the fractional release curve when Case II drug transport with axial and radial release from cylinders is operating.

The mean dissolution time depends on the dose/solubility ratio.

PURPOSE: To investigate the relationship between mean dissolution time (MDT) and dose/solubility ratio (q) using the diffusion layer model. METHODS: Using the classic Noyes-Whitney equation and considering a finite dose, we derived an expression for MDT as a function of q under various conditions. q was expressed as a dimensionless quantity by taking into account the volume of the dissolution medium. Our results were applied to in vitro and in vivo data taken from literature. RESULTS: We found that MDT depends on q when q < 1 and is infinite when q > 1 and that the classic expression of MDT = 1/k. where k is the dissolution rate constant, holds only in the special case of q = 1. For the case of perfect sink conditions, MDT was found to be proportional to dose. Using dissolution data from literature with q < 1, we found better estimates of MDT when dependency on dose/ solubility ratio was considered than with the classic approach. Prediction of dissolution limited absorption was achieved for some of the in vivo drug examples examined. CONCLUSION: The mean dissolution time of a drug depends on dose/ solubility ratio, even when the model considered is the simplest possible. This fact plays an important role in drug absorption when absorption is dissolution limited.

Quantitative biopharmaceutics classification system: the central role of dose/solubility ratio.

PURPOSE: To develop a quantitative biopharmaceutics drug classification system (QBCS) based on fundamental parameters controlling rate and extent of absorption. METHODS: A simple absorption model that considers transit flow, dissolution, and permeation processes stochastically was used to illustrate the primary importance of dose/solubility ratio and permeability on drug absorption. Simple mean time considerations for dissolution, uptake, and transit were used to identify relationships between the extent of absorption and a drug's dissolution and permeability characteristics. RESULTS: The QBCS developed relies on a (permeability, dose/ solubility ratio) plane with cutoff points 2 x 10(-6)-10(-5) cm/s for the permeability and 0.5-1 (unitless) for the dose/solubility ratio axes. Permeability estimates, P(app) are derived from Caco-2 studies, and a constant intestinal volume content of 250 ml is used to express the dose/solubility ratio as a dimensionless quantity, q. A physiologic range of 250-500 ml was used to account for variability in the intestinal volume. Drugs are classified into the four quadrants of the plane around the cutoff points according to their P(app), q values, establishing four drug categories. i.e., I (P(app) > 10(-5) cm/s, q < or = 0.5), II (P(app) > 10(-5) cm/s, q > 1), III (P(app) < 2 x 10(-6) cm/s. q < or = 0.5), and IV (P(app) < 2 x 10(-6) cm/s, q > 1). A region for borderline drugs (2 x 10(-6) < P(app) < 10(-5) cm/s, 0.5 < q < 1) was defined too. For category I, complete absorption is anticipated, whereas categories II and III exhibit dose/ solubility ratio-limited and permeability-limited absorption, respectively. For category IV, both permeability and dose/solubility ratio are controlling drug absorption. Semiquantitative predictions of the extent of absorption were pointed out on the basis of mean time considerations for dissolution, uptake, and transit in conjunction with drug's dose/solubility ratio and permeability characteristics. A set of 42 drugs were classified into the four categories, and the predictions of intestinal drug absorption were in accord with the experimental observations. CONCLUSIONS: The QBCS provides a basis for compound classification into four explicitly defined drug categories using the fundamental biopharmaceutical properties, permeability, and dose/solubility ratio. Semiquantitative predictions for the extent of absorption are essentially based on these drug properties, which either determine or are strongly related to the in vivo kinetics of drug dissolution and intestinal wall permeation.

Identification of biowaivers among Class II drugs: theoretical justification and practical examples.

PURPOSE: To set up a theoretical basis for identifying biowaivers among Class II drugs and apply the methodology developed to nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: The dynamics of the two consecutive drug processes dissolution and wall permeation are considered in the time domain of the physiologic transit time using a tube model of the intestinal lumen. The model considers constant permeability along the intestines, a plug flow fluid with the suspended particles moving with the fluid, and dissolution in the small particle limit. The fundamental differential equation of drug dissolution-uptake in the intestines is expressed in terms of the fraction of dose dissolved. RESULTS: The fundamental parameters, which define oral drug absorption in humans resulting from this analysis, are i) the formulation-related factors, dose, particle radius size, and ii) the drug-related properties, dimensionless solubility/dose ratio (1/q), and effective permeability. Plots of dose as a function of (1/q) for various particle sizes unveil the specific values of these meaningful parameters, which ensure complete absorption for Class II drugs [(1/q) < 1]. A set of NSAIDs were used to illustrate the application of the approach in identifying biowaivers among the NSAIDs. CONCLUSIONS: The underlying reason for a region of fully absorbed drugs in Class II originates from the dynamic character of the dissolution-uptake processes. The dynamic character of the approach developed allows identification of biowaivers among Class II drugs. Several biowaivers among the NSAIDs were identified using solubility data at pH 5.0 and in fed-state-simulated intestinal fluid at pH 5.0. The relationships of formulation parameters, dose, particle radius, and the drug properties, dimensionless solubility/dose ratio (1/q), and permeability with the fraction of dose absorbed for drugs with low 1/q values [(1/q) < 1] can be used as guidance for the formulation scientist in the development phase.