Population pharmacokinetics of total and unbound concentrations of intravenous posaconazole in adult critically ill patients.

BACKGROUND: The population pharmacokinetics of total and unbound posaconazole following intravenous administration has not yet been described for the critically ill patient population. The aim of this work was, therefore, to describe the total and unbound population pharmacokinetics of intravenous posaconazole in critically ill patients and identify optimal dosing regimens. METHODS: This was a prospective observational population pharmacokinetic study in critically ill adult patients with presumed/confirmed invasive fungal infection. A single dose of 300 mg posaconazole was administered intravenously as an add-on to standard antifungal therapy, and serial plasma samples were collected over 48 h. Total and unbound posaconazole concentrations, measured by chromatographic method, were used to develop a population pharmacokinetic model and perform dosing simulations in R using Pmetrics. RESULTS: From eight patients, 93 pairs of total and unbound concentrations were measured. A two-compartment linear model with capacity-limited plasma protein binding best described the concentration-time data. Albumin and body mass index (BMI) were included as covariates in the final model. Mean (SD) parameter estimates for the volume of the central compartment (V) and the elimination rate constant were 72 (43) L and 42.1 (23.7) h-1, respectively. Dosing simulations showed that high BMI was associated with a reduced probability of achieving target total and unbound posaconazole concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound posaconazole concentrations. CONCLUSIONS: An important clinical message of this study is that critically ill patients with increased BMI may require larger than approved loading doses of intravenous posaconazole when considering currently recommended dosing targets. Variability in plasma albumin concentration appears unlikely to affect dosing requirements when the assessment is based on unbound concentrations. Where available, therapeutic drug monitoring of unbound concentrations may be useful.

Impact of drug burden index on adverse health outcomes in Irish community-dwelling older people: a cohort study.

BACKGROUND: The Drug Burden Index (DBI) quantifies exposure to medications with anticholinergic and/or sedative effects. A consensus list of DBI medications available in Ireland was recently developed for use as a DBI tool. The aim of this study was to validate this DBI tool by examining the association of DBI score with important health outcomes in Irish community-dwelling older people. METHODS: This was a cohort study using data from The Irish Longitudinal Study on Ageing (TILDA) with linked pharmacy claims data. Individuals aged ≥65 years participating in TILDA and enrolled in the General Medical Services scheme were eligible for inclusion. DBI score was determined by applying the DBI tool to participants' medication dispensing data in the year prior to outcome assessment. DBI score was recoded into a categorical variable [none (0), low (> 0 and < 1), and high (≥1)]. Outcome measures included any Activities of Daily Living (ADL) impairment, any Instrumental Activities of Daily Living (IADL) impairment, any self-reported fall in the previous 12 months, any frailty criterion met (Fried Phenotype measure), quality of life (QoL) score (CASP-19 [Control Autonomy Self-realisation Pleasure] measure), and healthcare utilisation (any hospital admission and any emergency department (ED) visit) in the previous 12 months. Statistical analyses included multivariate logistic and linear regression models controlling for potential confounders. RESULTS: 61.3% (n = 1946) of participants received at least one DBI prescription in the year before their outcome assessment. High DBI exposure (DBI score ≥ 1) vs none was significantly associated with impaired function (ADL impairment adjusted OR 1.89, 95% CI 1.25, 2.88; IADL impairment adjusted OR 2.97, 95% CI 1.91, 4.61), self-reported falls (adjusted OR 1.50, 95%CI 1.03, 2.18), frailty (adjusted OR 1.74, 95% CI 1.14, 2.67), and reduced QoL (ß = - 1.84, 95%CI -3.14, - 0.54). There was no significant association between DBI exposure and healthcare utilisation. CONCLUSIONS: The findings validate the use of the DBI tool for predicting risk of functional impairment, falls, frailty and reduced QoL in older people in Ireland, and may be extended to other European countries. Integration of this tool into routine practice may be an appropriate step forward to improve outcomes in older people.

Anticholinergic and sedative drug burden in community-dwelling older people: a national database study.

OBJECTIVES: The Drug Burden Index (DBI) tool quantifies individual exposure to anticholinergic and sedative medications. The DBI has been internationally validated against adverse health outcomes in older people. DBI exposure has not been reported in the Irish older population. This study aimed to: (1) develop a list of drugs with clinically significant anticholinergic and/or sedative effects (DBI medications) relevant to Ireland; (2) examine, using the DBI formula, the prevalence of exposure to DBI medications in Irish older people and (3) explore patient factors associated DBI exposure. DESIGN: A cross-sectional national pharmacy claims database study. SETTING: Community setting using the General Medical Services (GMS) scheme pharmacy claims database maintained by the Health Service Executive Primary Care Reimbursement Services. PARTICIPANTS: Irish older individuals (aged ≥65 years) enrolled in the GMS scheme and dispensed at least one prescription item in 2016 (n=428 516). MAIN OUTCOME MEASURES: Prevalence of exposure to DBI medications and patient factors associated with DBI exposure. RESULTS: 282 874 (66%) of the GMS population aged ≥65 years were exposed to at least one DBI medication in 2016. Prevalence of exposure to DBI medications was significantly higher in females than males (females 71.6% vs males 58.7%, adjusted OR 1.65, 95% CI 1.63 to 1.68). Prevalence of DBI exposure increased progressively with the number of chronic drugs used, rising from 42.7% of those prescribed 0-4 chronic drugs to 95.4% of those on ≥12 chronic drugs (adjusted OR 27.8, 95% CI 26.7 to 29.0). The most frequently used DBI medications were codeine/paracetamol combination products (20.1% of patients), tramadol (11.5%), zopiclone (9.5%), zolpidem (8.5%), pregabalin (7.9%) and alprazolam (7.8%). CONCLUSIONS: The majority of older people in Ireland are exposed to medications with anticholinergic and/or sedative effects, particularly females and those with multiple comorbidities. The high use of low-dose codeine/paracetamol combination products, Z-drugs and benzodiazepines, suggests there are opportunities for deprescribing.

Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy.

Objectives: To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively. Results: Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions: Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.

High-risk prescribing in an Irish primary care population: trends and variation.

AIMS: The aims of the present study were to examine the prevalence of high-risk prescribing (HRP) in community-dwelling adults in Ireland from 2011-2015 using consensus-validated indicators, factors associated with HRP, and the variation in HRP between general practitioners (GPs) and in the dispensing of high-risk prescriptions between pharmacies. METHODS: A repeated cross-sectional national pharmacy claims database study was conducted. Prescribing indicators were based on those developed in formal consensus studies and applicable to pharmacy claims data. Multilevel logistic regression was used to examine factors associated with HRP and dispensing. RESULTS: There were significant reductions in the rates of most indicators over time (P < 0.001). A total of 66 022 of 300 906 patients at risk in 2011 [21.9%, 95% confidence interval (CI) 21.8, 22.1%], and 42 109 of 278 469 in 2015 (15.1%, 95% CI 15.0, 15.3%), received ≥1 high-risk prescription (P < 0.001). In 2015, indicators with the highest rates of HRP were prescription of a nonsteroidal anti-inflammatory drug (NSAID) without gastroprotection in those ≥75 years (37.2% of those on NSAIDs), coprescription of warfarin and an antiplatelet agent or high-risk antibiotic (19.5% and 16.2% of those on warfarin, respectively) and prescription of digoxin ≥250 µg day-1 in those ≥65 years (14.0% of those on digoxin). Any HRP increased significantly with age and number of chronic medications (P < 0.001). a) After controlling for patient variables, the variation in the rate of HRP between GPs was significant (P < 0.05); and b) after controlling for patient variables and the prescribing GP, the variation in the rate of dispensing of high-risk prescriptions between pharmacies was significant (P < 0.05). CONCLUSIONS: HRP in Ireland has declined over time, although some indicators persist. The variation between GPs and pharmacies suggests the potential for improvement in safe medicines use in community care, particularly in vulnerable older populations.

Variability in Trough Total and Unbound Teicoplanin Concentrations and Achievement of Therapeutic Drug Monitoring Targets in Adult Patients with Hematological Malignancy.

The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).

Teicoplanin use in adult patients with haematological malignancy: Exploring relationships between dose, trough concentrations, efficacy and nephrotoxicity.

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P<0.05). Results suggested a positive relationship between trough concentration and the likelihood of a favourable outcome for coagulase-negative staphylococcal central line-associated bloodstream infections. Elucidation of a specific target concentration requires further investigation. Teicoplanin was well tolerated renally. Findings suggest a risk of underexposure if conventional teicoplanin doses are used in haematological malignancy patients. Given the variability in trough concentrations observed, the identified factors affecting trough concentrations attained and the suggested link with clinical outcome, individualised initial dosing followed by therapeutic drug monitoring is recommended to ensure early adequate exposure in this vulnerable patient group.