Evaluation of Bayesian Forecasting Methods for Prediction of Tacrolimus Exposure Using Samples Taken on Two Occasions in Adult Kidney Transplant Recipients.

BACKGROUND: Bayesian forecasting-based limited sampling strategies (LSSs) for tacrolimus have not been evaluated for the prediction of subsequent tacrolimus exposure. This study examined the predictive performance of Bayesian forecasting programs/services for the estimation of future tacrolimus area under the curve (AUC) from 0 to 12 hours (AUC0-12) in kidney transplant recipients. METHODS: Tacrolimus concentrations were measured in 20 adult kidney transplant recipients, 1 month post-transplant, on 2 occasions one week apart. Twelve samples were taken predose and 13 samples were taken postdose at the specified times on the first and second sampling occasions, respectively. The predicted AUC0-12 (AUCpredicted) was estimated using Bayesian forecasting programs/services and data from both sampling occasions for each patient and compared with the fully measured AUC0-12 (AUCmeasured) calculated using the linear trapezoidal rule on the second sampling occasion. The bias (median percentage prediction error [MPPE]) and imprecision (median absolute prediction error [MAPE]) were determined. RESULTS: Three programs/services were evaluated using different LSSs (C0; C0, C1, C3; C0, C1, C2, C4; and all available concentrations). MPPE and MAPE for the prediction of fully measured AUC0-12 were <15% for each program/service (with the exclusion of when only C0 was used), when using estimated AUC from data on the same (second) occasion. The MPPE and MAPE for the prediction of a future fully measured AUC0-12 were <15% for 2 programs/services (and for the third when participants who had a tacrolimus dose change between sampling days were excluded), when the occasion 1-AUCpredicted, using C0, C1, and C3, was compared with the occasion 2-AUCmeasured. CONCLUSIONS: All 3 Bayesian forecasting programs/services evaluated had acceptable bias and imprecision for predicting a future AUC0-12, using tacrolimus concentrations at C0, C1, and C3, and could be used for the accurate prediction of tacrolimus exposure in adult kidney transplant recipients.

Investigation of the Association Between Total and Free Plasma and Saliva Mycophenolic Acid Concentrations Following Administration of Enteric-Coated Mycophenolate Sodium in Adult Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Mycophenolic acid (MPA) is commonly used following renal transplant. Saliva MPA concentrations may reflect the pharmacologically active form of MPA in plasma. Therapeutic drug monitoring using saliva is convenient and non-invasive. This study examined the correlation between total and free plasma and saliva MPA concentrations following enteric-coated mycophenolate sodium (EC-MS) administration in renal transplant recipients. METHODS: Total and free plasma and saliva MPA concentrations were measured simultaneously in 20 adult renal transplant recipients 1-2 months' post-transplant. Thirteen samples were taken pre-dose and at specified time points up until 12 h post-dose. RESULTS: When considering all time points, correlation between total plasma and saliva MPA was r2 = 0.51 and between free plasma and saliva MPA concentrations r2 = 0.41. The correlation between total plasma MPA area under the concentration-time curve (AUC) or free plasma AUC and saliva MPA AUC was r2 = 0.25 and r2 = 0.13, respectively. The correlation between total plasma MPA AUC and total plasma MPA trough (C0) concentrations was r2 = 0.51, and between total plasma MPA AUC and saliva MPA trough concentrations, r2 = 0.03. CONCLUSIONS: Measurement of MPA concentration in saliva cannot currently replace plasma measurement for therapeutic drug monitoring of MPA following EC-MS administration. Additional studies are required to examine the relationship between MPA saliva concentrations and patient outcomes.

Prednisolone Concentrations in Plasma (Total and Unbound) and Saliva of Adult Kidney Transplant Recipients.

BACKGROUND: Prednisolone displays significant pharmacokinetic variability and exposure-outcome relationships in renal transplant recipients, suggesting a role for drug monitoring in some scenarios. It is highly protein-bound, and the free form is pharmacologically active but cumbersome to measure. Saliva concentrations might reflect free plasma prednisolone and present an alternative measurement. The aim of this study was to examine the correlation between total and free plasma and saliva prednisolone in adult renal transplant recipients. METHODS: Total and free plasma and saliva prednisolone concentrations were measured in 20 patients receiving oral prednisolone 1-2 months after transplant, between pre-dose and 12 hours post-dose. Prednisolone was determined using high-performance liquid chromatography mass spectrometric detection. The Pearson coefficient was used to assess the association between plasma and salivary prednisolone concentrations and area under the concentration-time curves (AUC0-12). RESULTS: When considering all time points, the total and free plasma prednisolone concentrations correlated well (r = 0.81), but there was poor correlation between saliva and free (r = 0.003) and total (r = 0.01) plasma concentrations. When concentrations before the maximum free prednisolone plasma value were excluded, the correlation between free plasma and saliva concentrations improved (r = 0.57). There was a moderate correlation between free and total plasma prednisolone AUC0-12 (r = 0.62) using all time points, but a poor correlation between free and total plasma prednisolone AUC0-12 and saliva AUC0-12 (r = 0.07; r = 0.17). CONCLUSIONS: Total and free plasma prednisolone measurements correlated poorly with saliva measurements; however, correlation improved when concentrations early in the dosing interval were excluded.

Is Conversion from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium Justifiable for Gastrointestinal Quality of Life?

BACKGROUND: Globally, enteric-coated mycophenolate sodium (EC-MPS) is replacing mycophenolate mofetil (MMF) in maintenance immunosuppressant regimens. The predominant reason for conversion is the purported improvement in gastrointestinal (GI) quality of life. This paper considers the level of bias associated with studies comparing EC-MPS and MMF for GI-related improvement and provides insight into whether conversion is supported by evidence. METHODS: Using a pre-determined protocol, a literature search was conducted. Full-text review, data extraction and risk of bias analysis was conducted by two independent authors using the Cochrane domain-based evaluation of risk of bias. The review was reported according to the preferred reporting items for systematic reviews and meta-analyses. RESULTS: Twenty-nine studies were included in risk of bias analysis. Of these, only three were deemed a low risk of bias. Across these three studies, there were no statistically significant differences in the proportion of GI-related adverse events nor was there a significant difference in the GI-related quality of life between EC-MPS- and MMF-treated patients in these data. CONCLUSION: There was a high risk of bias across the 29 studies investigating conversion from MMF to EC-MPS for potential improvement in GI-related quality of life. The consolidated results of the three studies with low risk of bias suggest no evidence to convert patients stabilised on MMF. If a patient experiences GI-related adverse events whilst taking MMF, other methods should be explored before conversion to EC-MPS.

Psychiatric adverse events in oseltamivir prophylaxis trials: Novel comparative analysis using data obtained from clinical study reports.

PURPOSE: Estimating the rate of adverse events (AEs) caused by a treatment in clinical trials typically involves comparing the proportions of patients experiencing AEs in intervention and control groups. However, potentially important information, including duration, recurrence, and intensity of events, is lost. In this study, we illustrate how the additional information can be obtained and incorporated into analyses of AEs. METHODS: Data on psychiatric AEs were extracted from clinical study reports (CSRs) provided by the manufacturer of oseltamivir in 4 prophylaxis randomised trials in adults and adolescents. We analysed the incidence, recurrence, duration, and intensity of events, using logistic regression models where the outcome compared was proportion of days suffering from an event, and developed novel presentation techniques. RESULTS: Psychiatric AEs were generally more frequent, longer, and more intense in the treatment than placebo arms. Logistic regression models confirm the apparent association overall (odds ratio [OR] 3.46, 95% confidence interval [CI] 1.28 to 9.32), particularly for events classified as severe (OR 34.5, 95% CI 3.66 to 325). However, the absolute difference in proportion of days suffering from severe psychiatric AEs between groups was small. CONCLUSIONS: This example analysis shows evidence of a causal effect of oseltamivir on psychiatric AEs, not apparent in the published versions of the same trials and a Cochrane review which showed a nonsignificant 81% increased odds of experiencing a psychiatric event. This unique and important finding was dependent on obtaining previously unavailable data from clinical study reports and using novel analyses and presentation methods.

Evaluation of Multiple Linear Regression-Based Limited Sampling Strategies for Enteric-Coated Mycophenolate Sodium in Adult Kidney Transplant Recipients.

BACKGROUND: Although multiple linear regression-based limited sampling strategies (LSSs) have been published for enteric-coated mycophenolate sodium, none have been evaluated for the prediction of subsequent mycophenolic acid (MPA) exposure. This study aimed to examine the predictive performance of the published LSS for the estimation of future MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12) in renal transplant recipients. METHODS: Total MPA plasma concentrations were measured in 20 adult renal transplant patients on 2 occasions a week apart. All subjects received concomitant tacrolimus and were approximately 1 month after transplant. Samples were taken at 0, 0.33, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours and 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 hours after dose on the first and second sampling occasion, respectively. Predicted MPA AUC0-12 was calculated using 19 published LSSs and data from the first or second sampling occasion for each patient and compared with the second occasion full MPA AUC0-12 calculated using the linear trapezoidal rule. Bias (median percentage prediction error) and imprecision (median absolute prediction error) were determined. RESULTS: Median percentage prediction error and median absolute prediction error for the prediction of full MPA AUC0-12 were <15% for 4 LSSs, using the data from the same (second) occasion. One equation (1.583C1 + 0.765C2 + 0.369C2.5 + 0.748C3 + 1.518C4 + 2.158C6 + 3.292C8 + 3.6690) showed bias and imprecision <15% for the prediction of future MPA AUC0-12, where the predicted AUC0-12 from the first occasion was compared with the full AUC0-12 from the second. All LSSs with an acceptable predictive performance included concentrations taken at least 6 hours after the dose. CONCLUSIONS: Only one LSS had an acceptable bias and precision for future estimation. Accurate dosage prediction using a multiple linear regression-based LSS was not possible without concentrations up to at least 8 hours after the dose.

Development of Improved Dosing Regimens for Mycophenolate Mofetil Based on Population Pharmacokinetic Analyses in Adults with Lupus Nephritis.

BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-ß-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements. METHODS: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions. RESULTS: A total of 225 and 226 concentration-time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/F MPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration-time curve from 0 to 12 h (AUC0-12) of 45 mg·h/L. CONCLUSION: A 'tiered' dosing approach considering patient renal function and CsA co-therapy, rather than a 'one dose fits all' approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.

Associations of Guideline Recommended Medications for Acute Coronary Syndromes With Fall-Related Hospitalizations and Cardiovascular Events in Older Women With Ischemic Heart Disease.

BACKGROUND: Guidelines for acute coronary syndrome recommend statins, ß-blockers, angiotensin-converting-enzyme inhibitors or renin-angiotensin system blockers, and antiplatelet agents for the secondary prevention of cardiovascular events. The aim was to examine associations between guideline recommended medications and fall-related hospitalizations and cardiovascular events in robust and frail older women. METHODS: 2002-2011 surveys from the Australian Longitudinal Study on Women's Health linked with administrative hospital, pharmaceutical and death registry data (2003-mid-2011) were used. Eight hundred eighty-five women (82.7±2.7 years, range 76-90) had prior admission for ischemic heart disease and ≥1 claims for any of the four medication classes. Four hundred thirteen (46.7%) were robust and 472 (53.3%) were frail. Fall-related admissions; cardiovascular event-related admissions or death; and cardiovascular death were recorded. Associations between each of the exposures and outcomes were analyzed using survival analyses with noncardiovascular death as a competing risk. RESULTS: There were 192 fall-related admissions and 314 cardiovascular events including 82 deaths. Using four recommended classes (compared to using one) was associated with increased risks of fall-related admissions (hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.24-5.33), but not with cardiovascular events (HR = 1.41, CI = 0.97-2.05) or cardiovascular death (HR = 0.68, CI = 0.35-1.34). Associations for fall-related admissions were stronger in frail participants (HR = 5.46, CI = 1.34-22.30) than robust (HR = 1.37, CI = 0.48-3.95). CONCLUSIONS: In older women with ischemic heart disease, the combination of the four recommended medication classes was associated with increased risk of falls, particularly among frail women, with no statistically significant gain in cardiovascular health. The risks of falls and consequential morbidity in women over 75 needs consideration when prescribing medications after myocardial infarction.

Ezetimibe: Use, costs, and adverse events in Australia.

AIM: To analyze the subsidized use and reported adverse events of ezetimibe, used to lower cholesterol, in Australia over the 11 years following its inclusion on the Pharmaceutical Benefits Scheme (PBS) in 2004. METHODS: Pharmacoepidemiological analysis of dispensed prescriptions from Medicare Australia. Adverse event data were obtained from the Therapeutic Goods Administration. Use was measured by the defined daily dose (DDD) per 1000 population per day for each calendar year. Adverse events were counted by organ class system. RESULTS: Total ezetimibe use rose to 8.46 DDD/1000 population/d in the 11 years to 2015. Ezetimibe as a sole active ingredient was the most commonly dispensed formulation followed by the two combination products containing ezetimibe and 40 mg or 80 mg simvastatin. The average yearly increase in utilization was 19% with a 24% annual increase in costs to government (2006-2015) to $169.0 million in 2015. There were substantial differences in ezetimibe use between states, with no relationship to deaths from ischaemic heart disease (IHD) in each jurisdiction. The major reported adverse events were musculoskeletal and connective tissue disorders and gastrointestinal disorders. CONCLUSIONS: Ezetimibe use has increased rapidly in Australia since receiving public subsidy. Although the indications for subsidy are very restricted, there appears to have been widespread use, not explained by differential geographical IHD death rates. Latest guidelines still question the value of ezetimibe, so further discussion about whether the public spending on this medication for any potential improvement in population health outcomes is justified.

Associations Between Statin Use and Physical Function in Older Adults from The Netherlands and Australia: Longitudinal Aging Study Amsterdam and Australian Longitudinal Study on Women's Health.

BACKGROUND: Statin therapy may cause myopathy, but long-term effects on physical function are unclear. OBJECTIVE: We investigated whether statin use is associated with poorer physical function in two population-based cohorts of older adults. METHODS: Data were from 691 men and women (aged 69-102 years in 2005/2006) in the LASA (Longitudinal Aging Study Amsterdam) and 5912 women (aged 79-84 years in 2005) in the ALSWH (Australian Longitudinal Study on Women's Health). Statin use and dose were sourced from containers (LASA) and administrative databases (ALSWH). Physical function was assessed using performance tests, questionnaires on functional limitations and the SF-12 (LASA) and SF-36 (ALSWH) questionnaires. Cross-sectional (both studies) and 3-year prospective associations (ALSWH) were analysed for different statin dosage using linear and logistic regression. RESULTS: In total, 25 % of participants in LASA and 61 % in ALSWH used statins. In the cross-sectional models in LASA, statin users were less likely to have functional limitations (percentage of subjects with at least 1 limitation 63.9 vs. 64.2; odds ratio [OR] 0.6; 95 % confidence interval [CI] 0.3-0.9) and had better SF-12 physical component scores (mean [adjusted] 47.3 vs. 44.5; beta [B] = 2.8; 95 % CI 1.1-4.5); in ALSWH, statin users had better SF-36 physical component scores (mean [adjusted] 37.4 vs. 36.5; B = 0.9; 95 % CI 0.3-1.5) and physical functioning subscale scores (mean [adjusted] 55.1 vs. 52.6; B = 2.4; 95 % CI 1.1-3.8) than non-users. Similar associations were found for low- and high-dose users and in the prospective models. In contrast, no significant associations were found with performance tests. CONCLUSIONS: Two databases from longitudinal population studies in older adults gave comparable results, even though different outcome measures were used. In these two large cohorts, statin use was associated with better self-perceived physical function.

Population Pharmacokinetic Modelling and Bayesian Estimation of Tacrolimus Exposure: Is this Clinically Useful for Dosage Prediction Yet?

This review summarises the available data on the population pharmacokinetics of tacrolimus and use of Maximum A Posteriori (MAP) Bayesian estimation to predict tacrolimus exposure and subsequent drug dosage requirements in solid organ transplant recipients. A literature search was conducted which identified 56 studies that assessed the population pharmacokinetics of tacrolimus based on non-linear mixed effects modelling and 14 studies that assessed the predictive performance of MAP Bayesian estimation of tacrolimus area under the plasma concentration-time curve (AUC) from time zero to the end of the dosing interval. Studies were most commonly undertaken in adult kidney transplant recipients and investigated the immediate-release formulation. The pharmacokinetics of tacrolimus were described using one- and two-compartment disposition models with first-order elimination in 61 and 39 % of population pharmacokinetic studies, respectively. Variability in tacrolimus whole blood apparent clearance amongst transplant recipients was most commonly related to cytochrome P450 (CYP) 3A5 genotype (rs776746), patient haematocrit, patient weight, post-operative day and hepatic function (aspartate aminotransferase). Bias, as calculated using estimation of the mean predictive error (MPE) or mean percentage predictive error (MPPE) associated with prediction of the tacrolimus AUC, ranged from -15 to 9.95 %. Imprecision, as calculated through estimation of the root mean squared error (RMSE) or mean absolute prediction error (MAPE), was generally much poorer overall, ranging from 0.81 to 40. r 2 values ranged from 0.27 to 0.99 %. Of the Bayesian forecasting strategies that used two or more tacrolimus concentrations, 71 % showed bias of 10 % or less; however, only 39 % showed imprecision of 10 % or less. The combination of sampling times at 0, 1 and 3 h post-dose consistently showed bias and imprecision values of less than 15 %. No studies to date have examined how closely MAP Bayesian dosage predictions of tacrolimus actually achieve target AUC by comparing dosage prediction from one occasion with a future measured AUC. Further research involving larger prospective studies including more diverse transplant groups and the extended-release formulation of tacrolimus is needed. Several questions require further examination, including the following. Do Bayesian forecasting methods currently use the most appropriate population pharmacokinetic models and optimal sampling times for dosage prediction? Does Bayesian forecasting perform well when applied to make dosage predictions on a subsequent occasion? How can Bayesian forecasting be simplified for use in the clinical setting? And, are patient outcomes improved with dosage prediction based on Bayesian forecasting compared with trough concentration monitoring?

Multinational Evaluation of Mycophenolic Acid, Tacrolimus, Cyclosporin, Sirolimus, and Everolimus Utilization.

BACKGROUND: Increasing immunosuppressant utilization and expenditure is a worldwide challenge as more people successfully live with transplanted organs. Our aims were to characterize utilization of mycophenolate, tacrolimus, cyclosporin, sirolimus, and everolimus in Australian transplant recipients from 2007 to 2013; to identify specific patterns of usage; and to compare Australian utilization with Norwegian, Danish, Swedish, and the Netherlands use. MATERIAL AND METHODS: Australian utilization and expenditure data were captured through national Pharmaceutical Benefits Scheme and Highly Specialized Drug administrative databases. Norwegian, Danish, Swedish, and the Netherlands utilization were retrieved from their healthcare databases. Utilization was compared as defined daily dose per 1000 population per day (DDD/1000 population/day). Data on kidney transplant recipients, the predominant patient group prescribed these medicines, were obtained from international transplant registries. RESULTS: From 2007-2013 Australian utilization of mycophenolic acid, tacrolimus and everolimus increased 2.7-fold, 2.2-fold, and 2.3-fold, respectively. Use of cyclosporin and sirolimus decreased 20% and 30%, respectively. Australian utilization was significantly lower than European utilization (2013) but was increasing at a faster rate. Total Australian expenditure increased approximately AUD$30 million over the study period to almost AUD$100 million in 2013. Kidney transplantation rates increased across each country over this time, with Australia having the lowest rate. CONCLUSIONS: Immunosuppressant usage and subsequent expenditure are rising in Australia and Northern Europe. With increased numbers of people living with transplants, and the observed growth potential predicted from Northern European data, this class of medicines can be expected to continue consuming an increasing share of Australian pharmaceutical expenditure into the future.

Actions following adverse drug events - how do these influence uptake and utilisation of newer and/or similar medications?

BACKGROUND: Over the last decade, actions following some adverse drug events received major publicity. This study investigated changes in usage patterns of medications in Australia following two examples - rofecoxib market withdrawal (2004) and warnings about jaw necrosis following bisphosphonates (2007). METHODS: Dispensing data for COX-2 inhibitors (2000-2008) and anti-osteoporosis medications (2003-2012) were obtained from the Australian Pharmaceutical Benefits Scheme database. For bisphosphonates, data on Australian marketing expenditures were purchased from Cegedim(R). RESULTS: For COX-2 inhibitors, celecoxib dispensing halved after rofecoxib withdrawal, but meloxicam dispensing increased by 60 %. When lumiracoxib was introduced (2006) there was uptake of prescribing at a faster rate than meloxicam in 2002, its first year of use. For bisphosphonates, alendronate had highest use at the time of the warnings (8.3 DDD/1000/day), dropping to 4.9 DDD/1000/day by 2012. In contrast, risedronate use rose 2007-2012 from 4.1 to 4.9 DDD/1000/day. There was 49 % increase in reported annual expenditure on detailing for risedronate from 2007 to 2008 (to AUD$7.3 million) and only 29 % increase for alendronate (to AUD$3.1 million). CONCLUSIONS: The rapid uptake of prescribing of lumiracoxib and increased use of meloxicam flagged a concern, especially after rofecoxib withdrawal due to safety issues. Bisphosphonates are useful drugs, however the dramatic rise in expenditure on detailing, followed by a rise in utilisation of risedronate could suggest that adverse publicity triggered a marketing response. These examples highlight the importance of tracking utilisation of medication classes in real time, using different data as needed, to ensure that due caution is exercised (and quick intervention provided if needed) for medications in the same class.

The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women: A prospective cohort study.

OBJECTIVES: Proton pump inhibitors (PPIs) are among the most prescribed medications worldwide, however, there is growing concern regarding potential negative effects on bone health. The aim was to examine the effect of dose and type of PPI use on subsequent use of osteoporosis medication and fractures in older Australian women. METHODS: Data were included from 4432 participants (born 1921-26) in the 2002 survey of the Australian Longitudinal Study on Women's Health. Medication data were from the national pharmaceutical administrative database (2003-2012, inclusive). Fractures were sourced from linked hospital datasets available for four major States of Australia. Competing risk regression models used PPI exposure as a time-dependent covariate and either time to first osteoporosis medication prescription or fracture as the outcome, with death as a competing risk. RESULTS: Of the 2328 PPI users and 2104 PPI non-users, 827 (36%) and 550 (26%) became users of osteoporosis medication, respectively. PPI use was associated with an increased risk of subsequent use of osteoporosis medication (adjusted sub-hazard ratio [SHR]=1.28; 95% confidence interval [CI]=1.13-1.44) and subsequent fracture (SHR=1.29, CI=1.08-1.55). Analysis with PPI categorized according to defined daily dose (DDD), showed some evidence for a dose-response effect (osteoporosis medication: <400 DDD: SHR=1.23, CI=1.06-1.42 and ≥400 DDD: SHR=1.39, CI=1.17-1.65, compared with non-users; SHRs were in the same range for fractures). Esomeprazole was the most common PPI prescribed (22.9%). Analysis by type of PPI use showed an increased subsequent risk for: (1) use of osteoporosis medication for rabeprazole (SHR=1.51, CI=1.08-2.10) and esomeprazole (SHR=1.48, CI=1.17-1.88); and (2) fractures for rabeprazole (SHR=2.06, CI=1.37-3.10). Users of multiple types of PPI also had increased risks for use of osteoporosis medication and fractures. CONCLUSION: An appropriate benefit/risk assessment should be made when prescribing PPIs, especially for esomeprazole and rabeprazole, as osteoporosis and fracture risks were increased in this cohort of elderly females subsequent to PPI prescription.

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients.

Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf(®), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf(®) and Envarsus(®) XR) and various generic versions of Prograf(®) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf(®), Advagraf(®) and Envarsus(®) XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24 h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf(®) to Advagraf(®), while a daily dosage reduction appears necessary for conversion from Prograf(®) to Envarsus(®) XR. Prograf(®) itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further elucidated. Most pharmacokinetic comparison studies to date have involved relatively stable patients, and many have been sponsored by the pharmaceutical companies manufacturing the new formulations. Larger randomized, controlled trials are needed in different transplant populations to determine whether there are differences in efficacy and toxicity across the formulations and whether formulation conversion is worthwhile in the longer term. While it has been suggested that once-daily administration of tacrolimus may improve patient compliance, further studies are required to demonstrate this. Mistakenly interchanging different tacrolimus formulations can lead to serious patient harm. Once-daily tacrolimus is now available as an alternative to twice-daily tacrolimus and can be used de novo in solid-organ transplant recipients or as a different formulation for existing patients, with appropriate dosage modifications. Clinicians need to be fully aware of pharmacokinetic and possible outcome differences across the different formulations of tacrolimus.

Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis.

AIMS: The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis. METHODS: Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events. RESULTS: Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023). CONCLUSIONS: This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.

Is statin use associated with new joint-related symptoms, physical function, and quality of life? Results from two population-based cohorts of women.

OBJECTIVE: Previous studies have suggested that statins may prevent development of osteoarthritis and have antiinflammatory effects. Our aim was to examine the associations between statin use and patient-reported joint symptoms in 2 large cohorts of middle-aged and older women. METHODS: Data were from 6,966 middle-aged (born 1946-1951) and 4,806 older (born 1921-1926) participants in the Australian Longitudinal Study on Women's Health who completed surveys from 2001 to 2011, including questions about joint pain/stiffness, physical functioning, and self-rated health (SRH). Administrative pharmaceutical data were used to classify participants according to statin use, cumulative volume of statin use, and type of drug. Associations between statin use and newly reported symptoms were analyzed using logistic regression with generalized estimating equations to account for repeated measures. RESULTS: A total of 2,096 (31.3%) of the middle-aged women and 2,473 (51.5%) of the older women were classified as statin users. After adjustment for confounders, statin use in middle-aged women was weakly associated with poor physical functioning (odds ratio [OR] 1.29, 99% confidence interval [99% CI] 1.07-1.55) and poor SRH (OR 1.35, 99% CI 1.13-1.61), but not with new joint pain/stiffness (OR 1.09, 99% CI 0.88-1.34). No dose-response relationships were found. Pravastatin and atorvastatin were associated with poor physical functioning, while atorvastatin was also associated with poor SRH. Associations found in older women were mostly explained by confounders. CONCLUSION: This large study did not demonstrate an association between statin use and reduced onset of joint pain/stiffness. Associations between statin use and poor physical functioning and poor SRH may be explained by factors other than joint pain/stiffness, e.g., muscle pain.

Osteoporosis medication dispensing for older Australian women from 2002 to 2010: influences of publications, guidelines, marketing activities and policy.

PURPOSE: Developments in anti-osteoporosis medications (AOMs) have led to changes in guidelines and policy, which, along with media and marketing strategies, have had an impact upon the prescribing of AOM. The aim was to examine patterns of AOM dispensing in older women (aged 76-81 years at baseline) from 2002 to 2010. METHODS: Administrative claims data were used to describe AOM dispensing in 4649 participants (born in 1921-1926 and still alive in 2011) in the Australian Longitudinal Study on Women's Health. The patterns were interpreted in the context of changes in guidelines, indications for subsidy, publications (scholarly and general media), and marketing activities. RESULTS: Total use of AOM increased from 134 DDD/1000/day in 2002 to 216 DDD/1000/day in 2007 but then decreased to 184 DDD/1000/day in 2010. Alendronate was the most commonly dispensed AOM but decreased from 2007, while use of risedronate (2002 onward), strontium ranelate (2007 onward) and zoledronic acid (2008 onward) increased. Etidronate and hormone replacement therapy (HRT) prescriptions gradually decreased over time. The decline in alendronate dispensing coincided with increases of other bisphosphonates and publicity about potential adverse effects of bisphosphonates, despite relaxing indications for bone density testing and subsidy for AOM. CONCLUSIONS: Overall dispense of AOM from 2002 reached a peak in 2007 and thereafter declined despite increases in therapeutic options and improved subsidised access. The recent decline in overall AOM dispensing seems to be explained largely by negative publicity rather than specific changes in guidelines and policy.

Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update.

This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients.

How accurate and precise are limited sampling strategies in estimating exposure to mycophenolic acid in people with autoimmune disease?

Mycophenolic acid (MPA) is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. Dosing to achieve a specific target MPA area under the concentration-time curve from 0 to 12 h post-dose (AUC12) is likely to lead to better treatment outcomes in patients with autoimmune disease than a standard fixed-dose strategy. This review summarizes the available published data around concentration monitoring strategies for MPA in patients with autoimmune disease and examines the accuracy and precision of methods reported to date using limited concentration-time points to estimate MPA AUC12. A total of 13 studies were identified that assessed the correlation between single time points and MPA AUC12 and/or examined the predictive performance of limited sampling strategies in estimating MPA AUC12. The majority of studies investigated mycophenolate mofetil (MMF) rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation of MPA. Correlations between MPA trough concentrations and MPA AUC12 estimated by full concentration-time profiling ranged from 0.13 to 0.94 across ten studies, with the highest associations (r (2) = 0.90-0.94) observed in lupus nephritis patients. Correlations were generally higher in autoimmune disease patients compared with renal allograft recipients and higher after MMF compared with EC-MPS intake. Four studies investigated use of a limited sampling strategy to predict MPA AUC12 determined by full concentration-time profiling. Three studies used a limited sampling strategy consisting of a maximum combination of three sampling time points with the latest sample drawn 3-6 h after MMF intake, whereas the remaining study tested all combinations of sampling times. MPA AUC12 was best predicted when three samples were taken at pre-dose and at 1 and 3 h post-dose with a mean bias and imprecision of 0.8 and 22.6 % for multiple linear regression analysis and of -5.5 and 23.0 % for maximum a posteriori (MAP) Bayesian analysis. Although mean bias was less when data were analysed using multiple linear regression, MAP Bayesian analysis is preferable because of its flexibility with respect to sample timing. Estimation of MPA AUC12 following EC-MPS administration using a limited sampling strategy with samples drawn within 3 h post-dose resulted in biased and imprecise results, likely due to a longer time to reach a peak MPA concentration (t max) with this formulation and more variable pharmacokinetic profiles. Inclusion of later sampling time points that capture enterohepatic recirculation and t max improved the predictive performance of strategies to predict EC-MPS exposure. Given the considerable pharmacokinetic variability associated with mycophenolate therapy, limited sampling strategies may potentially help in individualizing patient dosing. However, a compromise needs to be made between the predictive performance of the strategy and its clinical feasibility. An opportunity exists to combine research efforts globally to create an open-source database for MPA (AUC, concentrations and outcomes) that can be used and prospectively evaluated for AUC target-controlled dosing of MPA in autoimmune diseases.