Koen Boussery

Development and validation of a fast and uniform approach to quantify β-lactam antibiotics in human plasma by solid phase extraction-liquid chromatography-electrospray-tandem mass spectrometry.

Monitoring of plasma antibiotic concentrations is necessary for individualization of antimicrobial chemotherapy dosing in special patient populations. One of these special populations of interest are the post-bariatric surgery patients. Until today, little is known on the effect of this procedure on drug disposition and efficacy. Therefore, close monitoring of antimicrobial plasma concentrations in these patients is warranted. A fast and uniform ultra-high-performance liquid chromatography (UPLC) method with tandem mass spectrometric detection (MS/MS) has been developed and qualified for the simultaneous quantification of β-lactam antibiotics in human plasma. Compounds included in this multi-component analysis are: amoxicillin, ampicillin, phenoxymethylpenicillin, piperacillin, cefuroxime, cefadroxil, flucloxacillin, meropenem, cefepime, ceftazidime, tazobactam, linezolid and cefazolin. After spiking of five different stable isotope labelled internal standards, plasma samples were prepared for UPLC-MS/MS analysis by mixed-mode solid phase extraction. The developed method was proven to be free of (relative) matrix effects and proved to be reliable for the quantification of 12 out of 13 β-lactam antibiotics. As a proof of concept the method has been applied to plasma samples obtained from a healthy volunteer treated with amoxicillin. The analytical method is suitable for use in a therapeutic drug monitoring setting, providing the clinician with reliable measurements on β-lactam antibiotic plasma concentrations in a timely manner.

Pharmacokinetics of fluoroquinolones in critical care patients: A bio-analytical HPLC method for the simultaneous quantification of ofloxacin, ciprofloxacin and moxifloxacin in human plasma.

A high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed and validated for the simultaneous quantification of ofloxacin, ciprofloxacin and moxifloxacin in human plasma. Sarafloxacin was used as internal standard. Chromatography was carried out using a Waters XBridge C(18) HPLC column and a gradient mobile phase consisting of CH(3)CN/MeOH/0.025M TBA.Cl/TFA (eluent A at 75/25/899/1 (v/v); eluent B at 150/50/799/1 (v/v); both at pH 3.5). Excitation/emission wavelengths were 279/442nm for ciprofloxacin and 290/500nm for ofloxacin, moxifloxacin and internal standard. Prior to chromatography, plasma samples were treated with acetonitrile for protein precipitation, followed by evaporation of the liquid layer and reconstitution in eluent A. The method was validated for the three fluoroquinolones over the clinically relevant concentration range from 0.02 to 7.50mug/ml. The method showed acceptable linearity with correlation coefficients, r(2)>0.995, as well as high precision (RSD% <7% in each case), accuracy (90.4-105.4%) and selectivity. The limit of quantification for the three fluoroquinolones was established at 0.02mug/ml. Ofloxacin, ciprofloxacin and moxifloxacin were extracted from plasma with a mean recovery of 95%, 86.4% and 94.2%, respectively. During validation, the concentration of the three fluoroquinolones was found to be stable after 3 freeze-thaw cycles and for at least 15h after extraction. This bio-analytical method was finally applied to the analysis of samples which have been obtained from patients, participating in a pharmacokinetic study on moxifloxacin.

Tablet‐splitting: a common yet not so innocent practice

AIM  This paper is a report of a study conducted to quantify (i) the mean deviation from theoretical weight and (ii) the mean weight loss, after tablet-splitting with three different, commonly used splitting methods. BACKGROUND  Tablet-splitting is a widespread practice among all sectors of health care for different reasons: it increases dose flexibility, makes tablet parts easier to swallow and allows cost savings for both patients and healthcare providers. However, the tablet parts obtained are often not equal in size, and a substantial amount of tablet can be lost during splitting. METHOD Five volunteers were asked to mimic the situation in nursing homes and to split eight tablets of different sizes and shapes using three different routine methods: (i) with a splitting device (Pilomat® ), (ii) with scissors for unscored tablets or manual splitting for scored tablets and (iii) with a kitchen knife. Before and after splitting, tablets and tablet parts were weighed using an analytical balance. The data were collected in 2007. RESULTS For all tablets, method 1 gave a statistically significantly lower mean deviation from theoretical weight. The difference between method 2 and method 3 was not statistically significant. When pooling the different products, method 1 also induced significantly less weight loss than the two other methods. CONCLUSION  Large dose deviations or weight losses can occur while splitting tablets. This could have serious clinical consequences for medications with a narrow therapeutic-toxic range. On the basis of the results in this report, we recommend use of a splitting device when splitting cannot be avoided.

Effectiveness of pharmaceutical care for patients with chronic obstructive pulmonary disease (PHARMACOP): a randomized controlled trial

AIMS Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD. METHODS The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥ 50 years and with a smoking history of ≥ 10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour. RESULTS From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8-16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63-12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12-0.64; P = 0.003). No other significant between-group differences were observed. CONCLUSIONS Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.

Factors associated with medication adherence to oral hypoglycaemic agents in different ethnic groups suffering from Type 2 diabetes: a systematic literature review and suggestions for further research

Diabet. Med. 28, 262–275 (2011)

Self-medication of regular headache: a community pharmacy-based survey.

Background:  This observational community pharmacy‐based study aimed to investigate headache characteristics and medication use of persons with regular headache presenting for self‐medication.

COPD Management in Primary Care: An Observational, Community Pharmacy–Based Study

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent disease that is frequently treated in primary care. However, data regarding the primary care management of COPD are scarce. Such observational data are necessary to detect problem areas and to develop targeted interventions for improvement of COPD management. Objective: To provide a detailed description of (1) drug therapy, (2) drug adherence, (3) inhalation technique, and (4) health status of patients with COPD recruited via community pharmacies. Methods: A cross-sectional, observational study was conducted in 93 pharmacies in Belgium. Participants (N = 555) completed a questionnaire collecting information on personal characteristics, smoking history, influenza vaccination, COPD medication, and adverse effects. Adherence to COPD maintenance medication was analyzed 1 year retrospectively through prescription refill rates. Inhalation technique was scored using a checklist. Health status was evaluated with the St. Georges Respiratory Questionnaire, the Clinical COPD Questionnaire, and the Modified Medical Research Council dyspnea scale. Results: The mean age of the patients was 68.6 years; 73.7% were men and 37.2% were current smokers. The influenza vaccination status was significantly lower in patients aged less than 65 years (65.7%) than in patients aged 65 years or more (86.2%) (p < 0.001). Fixed combinations of inhaled corticosteroids and long-acting β2-agonists were the most frequently used COPD medications (75.4%). About 48% of patients were underadherent (<80% adherence), 47% were adherent (80–120% adherence) and 5% were overadherent (>120% adherence). Predictors for underadherence were age and number of drugs. Twenty-one percent of patients made major inhalation technique errors with rescue medication; these were all errors in handling pressurized metered-dose inhalers (pMDIs). Conclusions: This observational study on COPD management in primary care highlights 4 main aspects that could be improved: (1) drug adherence, (2) inhalation technique with pMDIs, (3) influenza vaccination in COPD patients younger than 65 years, and (4) smoking cessation.

Effectiveness of PHARMAceutical care for patients with COPD (PHARMACOP): a randomized controlled trial

AIMS Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD. METHODS The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥ 50 years and with a smoking history of ≥ 10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour. RESULTS From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8-16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63-12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12-0.64; P = 0.003). No other significant between-group differences were observed. CONCLUSIONS Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.

Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery

OBJECTIVES Roux-en-Y gastric bypass surgery is the most commonly performed procedure for the treatment of morbid obesity. This anatomical alteration may affect the absorption and consequently the bioavailability of oral drugs. This study aims to investigate the oral bioavailability of moxifloxacin in 12 healthy volunteers who underwent gastric bypass surgery. PATIENTS AND METHODS In this randomized crossover study, each subject received two single standard doses of 400 mg of moxifloxacin orally or intravenously administered on two occasions separated by a washout period of 1 week. Serial venous blood samples were drawn up to 72 h after dosing and moxifloxacin plasma levels were measured by a validated HPLC method with fluorescence detection. [clinicaltrials.gov database (identifier: NCT01130922).] RESULTS After oral dosing, moxifloxacin plasma concentrations reached a maximum (C(max)) of 3.38 ± 1.41 mg/L after 1.75 h (0.75-4.00). After intravenous dosing, C(max) and T(max) were 4.53 ± 1.43 mg/L and 1.03 h (0.75-2.50), respectively. The mean areas under the plasma concentration time curve extrapolated to infinity (AUC(∞)) were 46.2 ± 1.4 mg · h/L after oral dosing and 52.3 ± 1.3 mg · h/L after intravenous dosing, resulting in a mean oral bioavailability of 88.32% [90% confidence interval (CI) 85.64%-91.08%]. CONCLUSIONS This study confirms that exposure to moxifloxacin is equivalent for oral and intravenous administration of 400 mg dosages in healthy volunteers who underwent gastric bypass surgery. But these exposures were more than 50% higher than those described for subjects without gastric bypass. This may suggest a higher enterohepatic recirculation of moxifloxacin after gastric bypass.

Evaluation of Three State-of-the-Art Metabolite Prediction Software Packages (Meteor, MetaSite, and StarDrop) through Independent and Synergistic Use

The aim of this study was to evaluate three different metabolite prediction software packages (Meteor, MetaSite, and StarDrop) with respect to their ability to predict loci of metabolism and suggest relative proportions of metabolites. A chemically diverse test set of 22 compounds, for which in vivo human mass balance studies and metabolic schemes were available, was used as basis for the evaluation. Each software package was provided with structures of the parent compounds, and predicted metabolites were compared with experimentally determined human metabolites. The evaluation consisted of two parts. First, different settings within each software package were investigated and the software was evaluated using those settings determined to give the best prediction. Second, the three different packages were combined using the optimized settings to see whether a synergistic effect concerning the overall metabolism prediction could be established. The performance of the software was scored for both sensitivity and precision, taking into account the capabilities/limitations of the particular software. Varying results were obtained for the individual packages. Meteor showed a general tendency toward overprediction, and this led to a relatively low precision (∼35%) but high sensitivity (∼70%). MetaSite and StarDrop both exhibited a sensitivity and precision of ∼50%. By combining predictions obtained with the different packages, we found that increased precision can be obtained. We conclude that the state-of-the-art individual metabolite prediction software has many advantageous features but needs refinement to obtain acceptable prediction profiles. Synergistic use of different software packages could prove useful.