A multiple methods approach to determine adherence with prescribed mycophenolate in children with kidney transplant.

AIMS: The aim of this study was, to use a multiple methods approach, including, for the first time, dried blood spot (DBS) sampling with population pharmacokinetic interpretation, to assess adherence to mycophenolate in children with kidney transplant. A second aim was to identify patient/parental factors that influenced adherence and to link adherence behaviour to clinical outcomes. METHODS: A convenience sample of 33 children with kidney transplant (age ≤ 18 years) who had been prescribed mycophenolate for at least 3 months were recruited from participating outpatient clinics in the UK and Jordan. Medication adherence was determined via self-report questionnaires, medication refill data from dispensing records, and via mycophenolic acid concentrations in plasma and DBS samples obtained from children during a clinic visit. RESULTS: Through triangulation of results from the different methodological approaches a total of 12 children (36.4%) were deemed to be nonadherent with their prescribed mycophenolate treatment. Logistic regression analysis indicated that nonadherence was significantly associated with the presence of mycophenolate side effects. Poor adherence was positively linked to measures of poor clinical outcomes (hospitalisation and the need for kidney biopsy). CONCLUSIONS: Despite the imperative regarding medication adherence to help prevent organ rejection, a significant proportion of children are not fully adherent with their therapy. Side-effects appear to be an important factor leading to nonadherence. Measurement of mycophenolate in DBS samples, coupled with the use of population pharmacokinetics modelling, was a convenient direct approach to assessing adherence in children with kidney transplant and has the potential to be introduced into routine practice.

The pharmacokinetics of intravenous ketorolac in children aged 2 months to 16 years: A population analysis.

BACKGROUND: Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC50 for analgesia of 0.37 mg. L-1 is described in adults. AIMS: The aim of this study was to review age- and weight-related effects on ketorolac pharmacokinetic parameters in children and current dosing schedules. METHODS: Pooled intravenous ketorolac (0.5 mg. kg-1 ) concentration-time data in children aged 2 months to 16 years were analyzed using nonlinear mixed-effects models. Allometry was used to scale to a 70 kg person. RESULTS: There were 64 children aged 2 months to 16 years (641 plasma concentrations) available for analysis. A two-compartment mammillary model was used to describe pharmacokinetics. Clearance was 2.53 (CV 45.9%) L. h-1. 70 kg-1 and intercompartment clearance was 4.43 (CV 95.6%) L. h-1. 70 kg-1 . Both central (V1) and peripheral (V2) volumes of distribution decreased with age over the first few years of postnatal life to reach V1 6.89 (CV 30.3%) L. 70 kg-1 and V2 5.53 (CV 47.6%) L. 70 kg-1 . CONCLUSION: Clearance, expressed as L. h-1. kg-1 , decreased with age from infancy. A dosing regimen of 0.5 mg. kg-1 every 6 hours maintains a trough concentration larger than 0.37 mg. L-1 in children 9 months to 16 years of age. This dosing regimen is consistent with current recommendations.

Pharmacogenetics and the print media: what is the public told?

BACKGROUND: Pharmacogenetics is a rapidly growing field that aims to identify the genes that influence drug response. This science can be used as a powerful tool to tailor drug treatment to the genetic makeup of individuals. The present study explores the coverage of the topic of pharmacogenetics and its potential benefit in personalised medicine by the UK newsprint media. METHODS: The LexisNexis database was used to identify and retrieve full text articles from the 10 highest circulation national daily newspapers and their Sunday equivalents in the UK. Content analysis of newspaper articles which referenced pharmacogenetic testing was carried out. A second researcher coded a random sample (21%) of newspaper articles to establish the inter-rater reliability of coding. RESULTS: Of the 256 articles captured by the search terms, 96 articles (with pharmacogenetics as a major component) met the study inclusion criteria. The majority of articles over-stated the benefits of pharmacogenetic testing while paying less attention to the associated risks. Overall beneficial effects were mentioned 5.3 times more frequently than risks (p < 0.001). The most common illnesses for which pharmacogenetically based personalised medicine was discussed were cancer, cardiovascular disease and CNS diseases. Only 13% of newspaper articles that cited a specific scientific study mentioned this link in the article. There was a positive correlation between the size of the article and both the number of benefits and risks stated (P < 0.01). CONCLUSION: More comprehensive coverage of the area of personalised medicine within the print media is needed to inform public debate on the inclusion of pharmacogentic testing in routine practice.

Adherence to treatment in children and adolescents with cystic fibrosis: a cross-sectional, multi-method study investigating the influence of beliefs about treatment and parental depressive symptoms.

BACKGROUND: Adherence to treatment is often reported to be low in children with cystic fibrosis. Adherence in cystic fibrosis is an important research area and more research is needed to better understand family barriers to adherence in order for clinicians to provide appropriate intervention. The aim of this study was to evaluate adherence to enzyme supplements, vitamins and chest physiotherapy in children with cystic fibrosis and to determine if any modifiable risk factors are associated with adherence. METHODS: A sample of 100 children (≤18 years) with cystic fibrosis (44 male; median [range] 10.1 [0.2-18.6] years) and their parents were recruited to the study from the Northern Ireland Paediatric Cystic Fibrosis Centre. Adherence to enzyme supplements, vitamins and chest physiotherapy was assessed using a multi-method approach including; Medication Adherence Report Scale, pharmacy prescription refill data and general practitioner prescription issue data. Beliefs about treatments were assessed using refined versions of the Beliefs about Medicines Questionnaire-specific. Parental depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. RESULTS: Using the multi-method approach 72% of children were classified as low-adherers to enzyme supplements, 59% low-adherers to vitamins and 49% low-adherers to chest physiotherapy. Variations in adherence were observed between measurement methods, treatments and respondents. Parental necessity beliefs and child age were significant independent predictors of child adherence to enzyme supplements and chest physiotherapy, but parental depressive symptoms were not found to be predictive of adherence. CONCLUSIONS: Child age and parental beliefs about treatments should be taken into account by clinicians when addressing adherence at routine clinic appointments. Low adherence is more likely to occur in older children, whereas, better adherence to cystic fibrosis therapies is more likely in children whose parents strongly believe the treatments are necessary. The necessity of treatments should be reinforced regularly to both parents and children.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients.

AIMS: To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. METHODS: The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. RESULTS: The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)(0.75) x EXP(-0.00158 x TPT) x EXP(0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h(-1) kg(-1) (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. CONCLUSION: Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.

Adherence to antiepileptic medicines in children: a multiple-methods assessment involving dried blood spot sampling.

PURPOSE: To evaluate adherence to prescribed antiepileptic drugs (AEDs) in children with epilepsy using a combination of adherence-assessment methods. METHODS: A total of 100 children with epilepsy (≤17 years old) were recruited. Medication adherence was determined via parental and child self-reporting (≥9 years old), medication refill data from general practitioner (GP) prescribing records, and via AED concentrations in dried blood spot (DBS) samples obtained from children at the clinic and via self- or parental-led sampling in children's own homes. The latter were assessed using population pharmacokinetic modeling. Patients were deemed nonadherent if any of these measures were indicative of nonadherence with the prescribed treatment. In addition, beliefs about medicines, parental confidence in seizure management, and the presence of depressed mood in parents were evaluated to examine their association with nonadherence in the participating children. KEY FINDINGS: The overall rate of nonadherence in children with epilepsy was 33%. Logistic regression analysis indicated that children with generalized epilepsy (vs. focal epilepsy) were more likely (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.37-15.81) to be classified as nonadherent as were children whose parents have depressed mood (OR 3.6, 95% CI 1.16-11.41). SIGNIFICANCE: This is the first study to apply the novel methodology of determining adherence via AED concentrations in clinic and home DBS samples. The present findings show that the latter, with further development, could be a useful approach to adherence assessment when combined with other measures including parent and child self-reporting. Seizure type and parental depressed mood were strongly predictive of nonadherence.

Pharmacokinetics of melatonin in preterm infants.

AIMS: Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. METHODS: Melatonin was administered to 18 preterm infants in doses ranging from 0.04-0.6 µg kg(-1) over 0.5-6 h. Pharmacokinetic profiles were analyzed individually and by population methods. RESULTS: Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 µg kg(-1) h(-1) for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml(-1) . On population pharmacokinetics, clearance was 0.045 l h(-1) , volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. CONCLUSIONS: A 2 h infusion of 0.1 µg kg(-1) h(-1) increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants.

Prophylactic ranitidine treatment in critically ill children--a population pharmacokinetic study.

AIMS: To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. METHODS: Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. RESULTS: A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. CONCLUSIONS: Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

What the newspapers say about medication adherence: a content analysis.

BACKGROUND: This study investigates the coverage of adherence to medicine by the UK and US newsprint media. Adherence to medicine is recognised as an important issue facing healthcare professionals and the newsprint media is a key source of health information, however, little is known about newspaper coverage of medication adherence. METHODS: A search of the newspaper database Nexis®UK from 2004-2011 was performed. Content analysis of newspaper articles which referenced medication adherence from the twelve highest circulating UK and US daily newspapers and their Sunday equivalents was carried out. A second researcher coded a 15% sample of newspaper articles to establish the inter-rater reliability of coding. RESULTS: Searches of newspaper coverage of medication adherence in the UK and US yielded 181 relevant articles for each country. There was a large increase in the number of scientific articles on medication adherence in PubMed® over the study period, however, this was not reflected in the frequency of newspaper articles published on medication adherence. UK newspaper articles were significantly more likely to report the benefits of adherence (p = 0.005), whereas US newspaper articles were significantly more likely to report adherence issues in the elderly population (p = 0.004) and adherence associated with diseases of the central nervous system (p = 0.046). The most commonly reported barriers to adherence were patient factors e.g. poor memory, beliefs and age, whereas, the most commonly reported facilitators to adherence were medication factors including simplified regimens, shorter treatment duration and combination tablets. HIV/AIDS was the single most frequently cited disease (reported in 20% of newspaper articles). Poor quality reporting of medication adherence was identified in 62% of newspaper articles. CONCLUSION: Adherence is not well covered in the newspaper media despite a significant presence in the medical literature. The mass media have the potential to help educate and shape the public's knowledge regarding the importance of medication adherence; this potential is not being realised at present.

Development of an enantiomer selective microsampling assay for the quantification of ketorolac suitable for paediatric pharmacokinetic studies.

BACKGROUND: Ketorolac, a potent nonsteroidal anti-inflammatory drug used for pain control in children, exists as a racemate of inactive R (+) and active S (-) enantiomers. AIM: To develop a microsampling assay for the enantioselective analysis of ketorolac in children. METHODS: Ketorolac enantiomers were extracted from 50 µl of plasma by liquid­liquid extraction and separated on a ChiralPak AD-RH. Detection was by a TSQ quantum triple quadrupole mass spectrometer with an electrospray ionisation source operating in a positive ion mode. Five children (age 13.8 (1.6) years, weight 52.7 (7.2) kg), were administered intravenous ketorolac 0.5mg/kg (maximum 10mg) and blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h post administration. CL, VD and t1/2 were calculated based on non-compartmental methods. RESULTS: The standard curves for R (+) and S (-) ketorolac were linear in the range 0­2000 ng/ml. The LLOQs of the method were 0.15 ng on column and 0.31 ng on column for R (+) and S (-) ketorolac, respectively. The median (range) VD and CL of R (+) and S (-) ketorolac were 0.12 l/kg (0.07­0.17), 0.017 l/h/kg (0.12­0.29) and 0.17 (0.09­0.31) l/kg, 0.049 (0.02­0.1) l/h/kg, p = 0.043), respectively. The median (range) elimination half-life (t1/2) of the R (+) and S (-) ketorolac was 5.0 h (2.5­5.8) and 3.1 h (1.8­4.4), p = 0.043), respectively. CONCLUSION: The development of a simple, rapid and reliable ketorolac assay suitable for paediatric PK studies is reported.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS: A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS: Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16-28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS: A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h(-1) ) = 11.4 × (WT/70.0)(0.75) and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h(-1) and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS: The range of estimated CL/F in the study population was 0.67-7.38 l h(-1) . The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Children's views on unlicensed/off-label paediatric prescribing and paediatric clinical trials.

OBJECTIVES: To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. METHODS: Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A purposeful sample was chosen to facilitate representation of various socioeconomic groupings. RESULTS: A total of 123 pupils, aged from 10 to 16 years, from six schools, participated in 16 focus groups. In general, pupils viewed the unlicensed/off-label use of medicines in children as unsafe and unethical and felt it is necessary to test medicines in children to improve the availability of licensed products. The majority felt that older children should be told, and that parents should be told, about the unlicensed/off-label use of medicines in children, yet they recognised some implications of this, such as potential medication non-adherence. CONCLUSIONS: This is the first study to explore the views of healthy children on unlicensed medicine use in children. Children were able to recognise potential risks associated with the unlicensed use of medicines and felt it is necessary to test and license more medicines in children. PRACTICE IMPLICATIONS: Health care professionals should consider the views of children in decisions that affect their health.

Potential risk factors for medication non-adherence in patients with chronic obstructive pulmonary disease (COPD).

AIMS: To investigate the effect of a range of demographic and psychosocial variables on medication adherence in chronic obstructive pulmonary disease (COPD) patients managed in a secondary care setting. METHODS: A total of 173 patients with a confirmed diagnosis of COPD, recruited from an outpatient clinic in Northern Ireland, participated in the study. Data collection was carried out via face-to-face interviews and through review of patients' medical charts. Social and demographic variables, co-morbidity, self-reported drug adherence (Morisky scale), Hospital Anxiety and Depression (HAD) scale, COPD knowledge, Health Belief Model (HBM) and self-efficacy scales were determined for each patient. RESULTS: Participants were aged 67 ± 9.7 (mean ± SD) years, 56 % female and took a mean (SD) of 8.2 ± 3.4 drugs. Low adherence with medications was present in 29.5 % of the patients. Demographic variables (gender, age, marital status, living arrangements and occupation) were not associated with adherence. A range of clinical and psychosocial variables, on the other hand, were found to be associated with medication adherence, i.e. beliefs regarding medication effectiveness, severity of COPD, smoking status, presence of co-morbid illness, depressed mood, self-efficacy, perceived susceptibility and perceived barriers within the HBM (p < 0.05). Logistic regression analysis showed that perceived ineffectiveness of medication, presence of co-morbid illness, depressed mood and perceived barriers were independently associated with medication non-adherence in the study (P < 0.05). CONCLUSIONS: Adherence in COPD patients is influenced more by patients' perception of their health and medication effectiveness, the presence of depressed mood and co-morbid illness than by demographic factors or disease severity.

Adherence to metformin in adults with type 2 diabetes: a combined method approach.

BACKGROUND: Medication adherence, one of the most important aspects in the process of optimal medicines use, is unfortunately still a major challenge in modern healthcare, and further research is required into how adherence can be assessed and optimised. The aim of this study was to use a combined method approach of self-report and dried blood spot (DBS) sampling coupled with population pharmacokinetic (PopPK) modelling, to assess adherence to metformin in adult patients with type 2 diabetes. Further aims were to assess metformin exposure levels in patients, determine factors associated with non-adherence with prescribed metformin, and to explore the relationship between adherence and therapeutic outcomes. METHODS: A combined method approach was used to evaluate metformin adherence in patients with type 2 diabetes who had been prescribed metformin for a minimum period of 6 months. Patients were recruited from consultant-led diabetic outpatient clinics at three hospitals in Northern Ireland, UK. Data collection involved self-reported questionnaires [Medication Adherence Report Scale (MARS), Beliefs about Medicines Questionnaire and Centre for Epidemiologic Studies Depression Scale], direct measurement of metformin concentration in DBS samples, and researcher-led patient interviews. The DBS sampling approach was coupled with population pharmacokinetic (PopPK) modelling, which took account of patient characteristics, metformin dosage and type of formulation prescribed (immediate or sustained release). RESULTS: The proportion of patients considered to be adherent to their prescribed metformin, derived from self-reported MARS scores and metformin concentration in DBS samples, was 61.2% (74 out of 121 patients). The majority (n = 103, 85.1%) of recruited patients had metformin exposure levels that fell within the therapeutic range. However, 17 patients (14.1%) had low exposure to metformin and one patient (0.8%) had undetectable metformin level in their blood sample (non-exposure). Metformin self-administration and use of a purchased adherence pill box significantly increased the probability of a patient being classified as adherent based on logistic regression analysis. Both HbA1c and random glucose levels (representing poor glycaemic control) in the present research were, however, not statistically linked to non-adherence to metformin (P > 0.05). CONCLUSIONS: A significant proportion of participating patients were not fully adherent with their therapy. DBS sampling together with the use of a published PopPK model was a useful, novel, direct, objective approach to estimate levels of adherence in adult patients with type 2 diabetes (61.2%).

Healthcare professional experiences and attitudes on unlicensed/off-label paediatric prescribing and paediatric clinical trials.

OBJECTIVES: To investigate the knowledge and views of a range of healthcare professionals (consultant paediatricians, general practitioners (GPs), community pharmacists and paediatric nurses) regarding the use of unlicensed/off-label medicines in children and the participation of children in clinical trials. METHODS: A regional study in which a survey instrument with 39 items was issued to 500 randomly selected GPs, all community pharmacists (n = 512), 50 hospital consultants and 150 paediatric nurses in Northern Ireland. RESULTS: Approximately half (46.5%) of the 1,212 healthcare professionals approached responded to the questionnaire. The majority of respondents indicated their familiarity with the term unlicensed (82.9%) or off-label (58.6%) prescribing with the most frequently quoted reason for such prescribing being younger age (33.6%). Apart from community pharmacists, most respondents reported having gained their knowledge through personal experience. Even though a large percentage of respondents expressed concerns about the safety (77.8%) or efficacy (87.9%) of unlicensed/off-label prescribing in children, only 30.7% reported informing parents/guardians of these concerns on the use of such medicines in children. In addition, only 56% of respondents believed that unlicensed/off-label medicines should undergo clinical trials in children. Overall, 28.4% of respondents (20.1% of GPs, 41.4% of community pharmacists, 27.7% of paediatric nurses and 94% of consultant paediatricians) indicated their willingness to be actively involved in, and recruit their patients for paediatric clinical research. CONCLUSION: The use of unlicensed and off-label medicines remains a major issue in paediatric medicine. Until such times as more licensed medicines are available for children, clear guidance should be developed to allow consistency in practice across the spectrum of healthcare professionals who are involved with such medicines in their routine practice.

Provision of pharmaceutical care by community pharmacists: a comparison across Europe.

OBJECTIVE: To investigate the provision of pharmaceutical care by community pharmacists across Europe and to examine the various factors that could affect its implementation. METHODS: A questionnaire-based survey of community pharmacies was conducted within 13 European countries. The questionnaire consisted of two sections. The first section focussed on demographic data and services provided in the pharmacy. The second section was a slightly adapted version of the Behavioral Pharmaceutical Care Scale (BPCS) which consists of three main dimensions (direct patient care activities, referral and consultation activities and instrumental activities). RESULTS: Response rates ranged from 10-71% between countries. The mean total score achieved by community pharmacists, expressed as a percentage of the total score achievable, ranged from 31.6 (Denmark) to 52.2% (Ireland). Even though different aspects of pharmaceutical care were implemented to different extents across Europe, it was noted that the lowest scores were consistently achieved in the direct patient care dimension (particularly those related to documentation, patient assessment and implementation of therapeutic objectives and monitoring plans) followed by performance evaluation and evaluation of patient satisfaction. Pharmacists who dispensed higher daily numbers of prescriptions in Ireland, Germany and Switzerland had significantly higher total BPCS scores. In addition, pharmacists in England and Ireland who were supported in their place of work by other pharmacists scored significantly higher on referral and consultation and had a higher overall provision of pharmaceutical care. CONCLUSION: The present findings suggest that the provision of pharmaceutical care in community pharmacy is still limited within Europe. Pharmacists were routinely engaged in general activities such as patient record screening but were infrequently involved in patient centred professional activities such as the implementation of therapeutic objectives and monitoring plans, or in self-evaluation of performance.

Hematocrit, blood volume, and surface area of dried blood spots - a quantitative model.

The use of the dried blood spot (DBS) sampling technique has extended the scope of clinical research, particularly in children. The effects of different hematocrit levels (25-55%) and different blood volumes (7.5-30 µL) on the surface area of the blood spots were investigated using ImageJ® software. Variation in hematocrit levels between patients and inaccuracies in blood volumes applied to Guthrie cards can have a marked effect on analyte concentrations measured in DBS samples. The current study presents a validated model that links blood volume and hematocrit to the surface area of the blood spot. The final model showed that both factors affect the blood spot surface area, however, the positive effect of blood volume is higher than the negative effect of hematocrit. The measurement of surface area could be added as an additional quality control step in clinical studies that have adopted fixed volume DBS sampling for the quantification of the analytes. This approach can be used in estimating the hematocrit if this is not known for a patient or estimating the volume in spots that are visually different in size from the norm, i.e. technical error.

Determination of azathioprine/6-mercaptopurine metabolites in dried blood spots: Correlation with RBC concentrations.

The analysis of 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-mMP) in biological samples is not straight forward and requires pre-treatment of samples. There are no validated published methods for the analysis of azathioprine/6-mercaptopurine (AZA/6-MP) metabolites in dried blood spot (DBS) samples that study the correlation with red blood cells (RBC) concentrations. DBS was prepared by applying fifteen microliters of blood [spiked with analytes or samples obtained from patients] to a Guthrie card which was then dried at room temperature overnight. The sample treatment procedure used protein precipitation followed by a hydrolysis step in which, 6-mMP was converted into 4-amino-5-(methylthio)carbonyl imidazole (AMTCI) then analytes were transferred to a solid phase extraction cartridge. The extracted sample was chromatographed using a reversed phase system (C18) column preceded by a guard column of matching chemistry. The method gave a linear calibration over the range 0.5-15 µmol/L and 3.75-175 µmol/L for 6-TG and 6-mMP, respectively. The method has been applied successfully to the determination of 6-TG and 6-mMP concentrations in DBS finger-prick samples from 27 paediatric patients with IBD who were receiving (AZA/6-MP). Patient 6-TG and 6-mMP RBC concentrations, calculated from whole blood finger prick DBS samples and those measured in RBCs derived from matched venous samples (analyzed using conventional HPLC-UV technique) showed good agreement using the Bland-Altman test. This is the first published method for determining 6-TG and 6-mMP in DBS that studies their correlation with RBCs concentrations. It is applicable to a range of clinical studies such as adherence and pharmacokinetic studies involving AZA/6-MP.

Adherence to Azathioprine/6-Mercaptopurine in Children and Adolescents with Inflammatory Bowel Diseases: A Multimethod Study.

Background: Measurement of the degree of adherence is a key element for the evaluation of treatment efficacy and safety; thus, adherence plays an important role in clinical research and practice. The aim of this study was to investigate medication adherence in children with inflammatory bowel disease (IBD) utilizing a multimethod assessment approach. A further aim was to examine factors that can influence adherence within this population. Methods: Medication adherence in 47 children (age range 3 to 17 years) with IBD in three centers in Northern Ireland and Jordan was assessed via subjective (parent and child versions of the Medication Adherence Report Scale (MARS) specific questionnaire) and objective methods, that is, high-performance liquid chromatography (HPLC) determination of the 6-mercaptopurine (6-MP) and azathioprine (AZA) metabolites in packed red blood cell samples taken during a clinic visit. Beliefs about prescribed medicines were also assessed in parents/guardians using the Beliefs about Medicines Questionnaire (BMQ). Results: An overall nonadherence to AZA/6-MP therapy in children with IBD was found to be 36.17% (17 out of 47 patients were classified as nonadherent using at least one of the assessment methods). A total of 41 patients (91.1%) were classified as adherent to AZA or 6-MP using the blood sampling, while adherence rates using the MARS questionnaire completed by children and parents/guardians were 60.6% and 72.7%, respectively. The latter provides a more longitudinal measure of adherence. Child self-reported nonadherence rates were significantly higher than parent/guardian reported rates (p=0.013). Binary logistic regression analysis identified age to be independently predictive of adherence, with adolescents (children aged ≥ 13 years old) more likely to be classified as nonadherent. Regarding the BMQ, when parental/guardian necessity beliefs outweighed concerns, that is, higher scores in the necessity-concern differential (NCD), adolescents were more likely to be classified as adherent. Conclusion: Results provide evidence for ongoing adherence challenges in the paediatric population with IBD. It is recommended that parents/guardians (particularly of older children) and older children themselves, should receive enhanced counselling and education about their prescribed medicines.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant.

AIMS: The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation. METHODS: Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes. RESULTS: The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (> or =30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677->T variant allele also had a significant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were significantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation. CONCLUSIONS: These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post-transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety.