Using informative prior based on expert opinion in Bayesian estimation of the transition probability matrix in Markov modelling-an example from the cost-effectiveness analysis of the treatment of patients with predominantly negative symptoms of schizophrenia with cariprazine.

BACKGROUND: When patient health state transition evidence is missing from clinical literature, analysts are inclined to make simple assumptions to complete the transition matrices within a health economic model. Our aim was to provide a solution for estimating transition matrices by the Bayesian statistical method within a health economic model when empirical evidence is lacking. METHODS: We used a previously published cost-effectiveness analysis of the use of cariprazine compared to that of risperidone in patients with predominantly negative symptoms of schizophrenia. We generated the treatment-specific state transition probability matrices in three different ways: (1) based only on the observed clinical trial data; (2) based on Bayesian estimation where prior transition probabilities came from experts' opinions; and (3) based on Bayesian estimation with vague prior transition probabilities (i.e., assigning equal prior probabilities to the missing transitions from one state to the others). For the second approach, we elicited Dirichlet prior distributions by three clinical experts. We compared the transition probability matrices and the incremental quality-adjusted life years (QALYs) across the three approaches. RESULTS: The estimates of the prior transition probabilities from the experts were feasible to obtain and showed considerable consistency with the clinical trial data. As expected, the estimated health benefit of the treatments was different when only the clinical trial data were considered (QALY difference 0.0260), its combination with the experts' beliefs were used in the economic model (QALY difference 0.0253), and when vague prior distributions were used (QALY difference 0.0243). CONCLUSIONS: Imputing zeros to missing transition probabilities in Markov models might be untenable from the clinical perspective and may result in inappropriate estimates. Bayesian statistics provides an appropriate framework for imputing missing values without making overly simple assumptions. Informative priors based on expert opinions might be more appropriate than vague priors.

Direct healthcare cost of schizophrenia - European overview.

PURPOSE: To provide an overview on the magnitude of the impact of schizophrenia on the healthcare system in Europe and to gain a better understanding on the most important factors influencing the variation of costs. METHODS: Studies reporting costs and healthcare utilization among patients with schizophrenia were searched in MEDLINE (via Scopus), EMBASE (via Scopus) and Cochrane Database of Systematic Reviews on 19th January 2017. RESULTS: Twenty-three studies, from the 1075 references initially identified, were included in this review. The annual cost per patient ranged from €533 in Ukraine to €13,704 in the Netherlands. Notably drug costs contributed to less than 25% of the direct healthcare cost per patient in every country, which might be explained by similar pharmaceutical prices among countries due to the reference pricing system applied in Europe. Inpatient costs were the largest component of health service costs in the majority of the countries. Despite methodological heterogeneity across studies, four major themes could be identified (age, severity of symptoms, continuation of treatment/persistence, hospitalization) that have substantial impact on the costs of schizophrenia. CONCLUSIONS: Schizophrenia represents a substantial cost for the healthcare system in Europe driven by the high cost per patient. Substantial savings could potentially be achieved by increasing investment in the following areas: (1) reducing the number of hospitalizations e.g. by increasing the efficiency of outpatient care; (2) working out interventions targeted at specific symptoms; (3) improving patient persistence and adherence in antipsychotic therapy.

A systematic review of health economic models and utility estimation methods in schizophrenia.

INTRODUCTION: There is a growing need for economic evaluations describing the disease course, as well as the costs and clinical outcomes related to the treatment of schizophrenia. AREAS COVERED: A systematic review on studies describing health economic models in schizophrenia and a targeted literature review on utility mapping algorithms in schizophrenia were carried out. Models found in the review were collated and assessed in detail according to their type and various other attributes. Fifty-nine studies were included in the review. Modeling techniques varied from simple decision trees to complex simulation models. The models used various clinical endpoints as value drivers, 47% of the models used quality-adjusted life years, and eight percent used disability-adjusted life years to measure benefits, while others applied various clinical outcomes. Most models considered patients switching between therapies, and therapeutic adherence, compliance or persistence. The targeted literature review identified four main approaches to map PANSS scores to utility values. EXPERT COMMENTARY: Health economic models developed for schizophrenia showed great variability, with simulation models becoming more frequently used in the last decade. Using PANSS scores as the basis of utility estimations is justifiable.

Quality-adjusted life year difference in patients with predominant negative symptoms of schizophrenia treated with cariprazine and risperidone.

AIM: Our study aimed at estimating differences in quality-adjusted life year (QALY) gain for patients with predominant negative symptoms of schizophrenia treated with cariprazine compared with risperidone. MATERIALS & METHODS: A Markov model was built, based on the Mohr-Lenert approach and data derived from clinical trials, to estimate potential QALY gains of patients. RESULTS: Patients had higher probability of reaching better health states treated with cariprazine compared with risperidone. In the model, this resulted in an estimated QALY gain of 0.029 per patient, after 1 year of treatment. CONCLUSION: Cariprazine, which showed clinically meaningful improvement in the symptoms, and personal and social performance, can also provide significant QALY gain in the treatment of patients with predominant negative symptoms of schizophrenia compared with risperidone.

Site-specific protonation microequilibria of penicillin and cephalosporin beta-lactam core molecules.

Acid-base chemistry of 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid (7-ACA), the fundamental units of the two classical antibiotic families is characterised at the macroscopic and microscopic levels. (1)H NMR-pH and pH-potentiometric titrations were combined to monitor the previously unreported extent of the site-specific protonation of 6-APA and 7-ACA. Microscopic protonation constants were derived either from direct multiple fittings of NMR-pH titration curves of adjacent carbon-bound (1)H nuclei, using in situ pH-indicator molecules, or from newly synthesised methyl ester derivatives. The results indicate that even the amino protonation of both structures occurs well below pH 5, the major protonation route includes the zwitterionic forms, and protonation at the carboxylate site brings about a three-fold diminish in the amino basicity and vice versa.

Column selection for pharmaceutical analyses based on a column classification using four test parameters.

This paper focuses on the usability of a previously developed column classification system, applied to pharmaceutical analyses. The separation of two drugs from their respective related substances was investigated on 65 new reversed-phase liquid chromatographic columns. The chromatographic procedure for fluoxetine hydrochloride was performed according to the method prescribed in the European Pharmacopoeia monograph while the separation of gemcitabine hydrochloride was carried out according to the United States Pharmacopeia monograph. It was shown that the column ranking system is a helpful tool in the selection of a suitable column.

[Microspeciation of amphoteric molecules of unusual acid-base properties]. / Szokatlan bázicitású amfoter molekulák mikrospeciációja.

The phisico-chemical properties of bio- and drug molecules greatly influence their interactions in the body and strongly effect the mechanism of drug action. Among these properties, macroscopic and site-specific protonation constants are of crucial importance. Latter one is the tool to calculate the relative concentration of the various microspecies in the compartments of the body at different pH values, and also, it is the versatile parameter to improve the pharmacokinetic properties of a new molecule in a particular family of drugs. In the present thesis work, the microspeciation of three molecules of great pharmaceutical importance and unusual acid-base properties, were carried out. The microconstants of tenoxicam, the non-steroidal anti-inflammatory drug, were described, introducing a novel deductive method using Hammett constants. For this purpose, a total of 8 tenoxicam and piroxicam derivatives were synthesised. To the best of our knowledge, the log k(N)O microconstant of tenoxicam obtained thus is the lowest enolate basicity value, which, however, can be well explained by the effects of the intramolecular environment. The developed evaluation procedure is suitable for microconstant determination of compounds in other molecule families. Besides, prodrug-type compounds and analogues similar to the structures of selective COX-2 isoenzyme inhibitors were synthesised. The other two molecules studied, the 6-aminopenicillanic acid and 7-cephalosporanic acid, the core molecules of the two most important beta-lactam antibiotic-types were derivatised and investigated by 1D and 2D NMR techniques. The NMR-pH titration on the parent compounds and their ester derivatives, combined with in situ pH-measurements allowed the microspeciation of these easily decomposing molecules. One of the protonation constant of 7-ACA (log kN(O) = 4.12), to the best of our knowledge, is the least non-aromatic basic amino-site among the natural compounds.

Facilitated column selection in pharmaceutical analyses using a simple column classification system.

In this paper, the performance of a previously developed classification system applied to pharmaceutical chromatographic analyses, is investigated. The separation of seven different drug substances from their respective impurities was studied. The chromatographic procedure for acetylsalicylic acid, clindamycin hydrochloride, buflomedil hydrochloride, chloramphenicol sodium succinate, nimesulide and phenoxymethylpenicillin was performed according to the corresponding European Pharmacopoeia (Ph. Eur.) monograph. The separation of dihydrostreptomycin sulphate was performed according to the literature. It is shown that the column ranking system is a helpful tool in the selection of a suitable column in these analyses.