Assessment of adherence to corticosteroids in asthma by drug monitoring or fractional exhaled nitric oxide: A literature review.

BACKGROUND: Although the efficacy of corticosteroid treatment in controlling asthma is widely accepted, its effectiveness is undermined by poor adherence. However, the optimal method for measuring adherence to asthma therapy remains unclear. OBJECTIVE: To perform a review of the literature reporting biological, objective methods for assessing adherence to inhaled or oral corticosteroids in asthma; we included studies reporting direct measurement of exogenous corticosteroids in blood, or the effect of adherence on exhaled nitric oxide. DESIGN: We searched three databases MEDLINE (using both PubMed and Ovid), the Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Web of Science for articles published between January 1975 and July 2020. Quality of the studies was assessed using the National Institute of Health checklist. RESULTS: From 2850 screened articles, 26 fulfilled the inclusion criteria. Measurement of blood prednisolone with or without cortisol was used in eight studies as a measure of oral corticosteroid adherence, and fractional exhaled nitric oxide (FeNO) in 17 studies for inhaled corticosteroid adherence. Inhaled corticosteroids were measured directly in the blood in one study. By direct measurement of drug levels in the blood, adherence rates to oral corticosteroids ranged from 47% to 92%, although the performance and timing of the test were often not known, making interpretation of findings and serum prednisolone concentrations difficult. FeNO is generally lower in adherent than non-adherent patients, but no absolute cut-off can be proposed based on the available data. However, a fall in FeNO following supervised inhaled corticosteroid dosing could indicate previous poor adherence. CONCLUSIONS AND CLINICAL RELEVANCE: Despite prednisolone and cortisol levels commonly being used as adherence markers in clinical practice, further work is required to assess the influence of the dose and timing on blood levels. The promising findings of FeNO suppression testing should be explored in further prospective studies.

The prevalence of nonadherence in difficult asthma.

RATIONALE: With the advent of new and expensive therapies for severe refractory asthma, targeting the appropriate patients is important. An important issue is identifying nonadherence with current therapies. The extent of nonadherence in a population with difficult asthma has not been previously reported. OBJECTIVES: To examine the prevalence of nonadherence to corticosteroid medication in a population with difficult asthma referred to a Specialist Clinic and to examine the relationship of poor adherence to asthma outcome. METHODS: General practitioner prescription refill records for the previous 6 months for inhaled combination therapy and short-acting beta-agonists were compared with initial prescriptions and expressed as a percentage. Blood plasma prednisolone and cortisol assay levels were used to examine the utility of these measures in assessing adherence to oral prednisolone. Patient demographics, hospital admissions, lung function, oral prednisolone courses, and quality of life data were analyzed to indentify the variables associated with reduced medication adherence. MEASUREMENTS AND MAIN RESULTS: A total of 182 patients were assessed. Sixty-three patients (35%) filled 50% or fewer inhaled medication prescriptions; 88% admitted poor adherence with inhaled therapy after initial denial. Twenty-one percent of patients filled more than 100% of presciptions, and 45% of subjects filled between 51 and 100% of prescriptions. Twenty-three of 51 patients (45%) prescribed oral steroids were found to be nonadherent. CONCLUSIONS: A significant proportion of patients with difficult-to-control asthma remained nonadherent to corticosteroid therapy. Objective surrogate and direct measures of adherence should be performed as part of a difficult asthma assessment and are important before prescibing expensive novel biological therapies.

Simultaneous determination of cortisol, dexamethasone, methylprednisolone, prednisone, prednisolone, mycophenolic acid and mycophenolic acid glucuronide in human plasma utilizing liquid chromatography-tandem mass spectrometry.

Chronic combination immunosuppressive regimens are commonly prescribed to renal transplant recipients. To develop an assay method for pharmacokinetic studies and therapeutic drug monitoring of multiple immunosuppressives, a liquid chromatography-tandem mass spectrometry (LC/MS/MS) approach for the simultaneous analysis of several glucocorticoids, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) was investigated. The resultant method utilized a gradient reverse phase separation over a Symmetry C18 column using an ammonium acetate-methanol mobile phase at pH 3.5. The analytes were detected by coupling the chromatography system via electrospray to a triple quadrupole mass spectrometer. Multiple-reaction monitoring in the negative mode ion (MH-/product) was employed selecting MPA at 319.1/190.9, MPAG at 495.1/191.0, dexamethasone at 391.0/361.0, hydrocortisone at 361.1/331.1, methylprednisolone at 373.1/343.1, prednisone at 357.1/327.2, and prednisolone at 359.1/329.1. The calibration curve concentrations ranged from 3.60 ng/mL to 50 microg/mL with the lowest limit of quantitation for corticosteroids being 3.60-7.20 ng/mL and 0.656-6.75 microg/mL for MPA and MPAG, respectively. The relative standard deviation for quality control intraday variation and interday variation was between 0.76% and 9.57% for all analytes. This assay offers a versatile, unique method for multi-analyte immunosuppressive determinations during combination immunosuppression.

Use of a radioreceptor assay in the assessment of cushingoid features in patients with juvenile rheumatic diseases.

A marked variation has been observed in severity of cushingoid appearance in patients with rheumatic diseases (RD) following steroid administration. We studied ten children with RD to determine if a relationship exists between cushingoid features and an individual's steroid activity as measured by prednisolone equivalents using a radioreceptor assay. Cushingoid features were clinically assessed by a "cushing score" according to the method of Bergrem. Patients were assigned to either the cushingoid (C) or noncushingoid (NC) group at study entry according to their cushing score. Blood was drawn prior to prednisone ingestion and then at 30, 60, 90, 120, 240, and 360 minutes and each sample was assessed for prednisolone equivalents and also for free and total cortisol. Group comparisons of dose-adjusted area under curve (AUC) and peak response are reported. Cushingoid patients had higher plasma prednisolone equivalents (PE) than noncushingoid patients as measured by peak PE and AUC. The PE.6 h/L average AUC for C patients was 248 micrograms PE.6 h/L versus 134 micrograms PE.6 h/L for NC patients. This nearly twofold difference was also noted between mean peak values (C 82 micrograms/L vs. NC 44 micrograms/L). Spearman correlations of Cushing scores with these two parameters indicated significant (p less than 0.05) relationships. A patient's Cushing score correlated best with peak response (rs = 0.78) and also with AUC (rs = 0.72). Measurement of plasma peak PE or AUC could be valuable for individualizing steroid dosing in children with RD.

Bioavailability assessment of a liquid prednisone preparation.

To assess the relative bioavailability of a recently developed liquid prednisone preparation, prednisolone pharmacokinetics were evaluated after the administration of three separate steroid preparations. On 3 study days, each 2 wk apart, 12 healthy subjects received in random order: prednisone liquid, prednisone tablet, and prednisolone sodium phosphate. Plasma samples were collected over a 12 hr study period and analyzed for prednisolone concentration by high-pressure liquid chromatography. Tablet data demonstrated a time-to-peak concentration of 1.23 +/- 0.68 hr (SD), mean residence time of 5.1 +/- 0.49 hr, and absolute bioavailability (tablet/i.v.) of 97.5% +/-- 17.5%. Liquid data demonstrated a significantly (p less than 0.01) shorter time-to-peak concentration, 0.54 +/- 0.20 hr, and mean residence time 4.6 +/- 0.34 hr, with no significant difference in absolute bioavailability (liquid/i.v.), 88.2% +/- 15.8%. This resulted in significantly (p less than 0.05) higher plasma prednisolone concentrations for the liquid preparation in the first 0.75 hr and significantly lower concentrations after 1.5 hr as compared with the tablet. Prednisolone area under the plasma concentration vs time curve for the liquid prednisone formulation was 90.0% +/- 13.2% of the tablet preparation. Thus prednisone liquid has comparable bioavailability to the tablet, with an earlier peak plasma prednisolone concentration and significantly higher plasma prednisolone concentrations within the first hour of administration.

A thermographic assessment of three intra-articular prednisolone analogues given in rheumatoid synovitis.

1 Three intra-articular prednisolone analogues have been studied in a group of forty-six rheumatoid arthritic subjects. Each compound was tested at 50 mg and 100 mg dose over 3 weeks. 2 The anti-inflammatory effect was assessed by quantitative thermography. Systemic escape of the drug was monitored by plasma prednisolone and cortisol levels. 3 Both the systemic escape from the joint and the duration of effect on injected and uninjected knees were related to drug solubility. 4 Depression of plasma cortisol occurred with all three preparations and was most prolonged with the long-acting preparation. 5 Increasing the dose from 50 mg to 100 mg increased the antiflammatory effect only with the soluble acetate preparation.