Influence of allopurinol on thiopurine associated toxicity: A retrospective population-based cohort study.

AIMS: Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol. METHODS: A retrospective population-based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co-use of allopurinol was compared to non-use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time-dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log-rank statistics. RESULTS: Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30-0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89-1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01-8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co-users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001). CONCLUSION: In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy.

A semi-mechanistic model based on glutathione depletion to describe intra-individual reduction in busulfan clearance.

AIM: To develop a semi-mechanistic model, based on glutathione depletion and predict a previously identified intra-individual reduction in busulfan clearance to aid in more precise dosing. METHODS: Busulfan concentration data, measured as part of regular care for allogeneic hematopoietic cell transplantation (HCT) patients, were used to develop a semi-mechanistic model and compare it to a previously developed empirical model. The latter included an empirically estimated time effect, where the semi-mechanistic model included theoretical glutathione depletion. As older age has been related to lower glutathione levels, this was tested as a covariate in the semi-mechanistic model. Lastly, a therapeutic drug monitoring (TDM) simulation was performed comparing the two models in target attainment. RESULTS: In both models, a similar clearance decrease of 7% (range -82% to 44%), with a proportionality to busulfan metabolism, was found. After 40 years of age, the time effect increased with 4% per year of age (0.6-8%, P = 0.009), causing the effect to increase more than a 2-fold over the observed age-range (0-73 years). Compared to the empirical model, the final semi-mechanistic model increased target attainment from 74% to 76%, mainly through better predictions for adult patients. CONCLUSION: These results suggest that the time-dependent decrease in busulfan clearance may be related to gluthathione depletion. This effect increased with older age (>40 years) and was proportional to busulfan metabolism. The newly constructed semi-mechanistic model could be used to further improve TDM-guided exposure target attainment of busulfan in patients undergoing HCT.

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.

BACKGROUND: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. METHODS: In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses. FINDINGS: 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37). INTERPRETATION: Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications. FUNDING: Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.

Bridging differences in outcomes of pharmacoepidemiological studies: design and first results of the PROTECT project.

BACKGROUND: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. PURPOSE: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. METHODS: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. RESULTS: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. CONCLUSION: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.

Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing.

BACKGROUND AND OBJECTIVES: The wide variability in pharmacokinetics of busulfan in children is one factor influencing outcomes such as toxicity and event-free survival. A meta-analysis was conducted to describe the pharmacokinetics of busulfan in patients from 0.1 to 26 years of age, elucidate patient characteristics that explain the variability in exposure between patients and optimize dosing accordingly. PATIENTS AND METHODS: Data were collected from 245 consecutive patients (from 3 to 100 kg) who underwent haematopoietic stem cell transplantation (HSCT) in four participating centres. The inter-patient, inter-occasion and residual variability in the pharmacokinetics of busulfan were estimated with a population analysis using the nonlinear mixed-effects modelling software NONMEM VI. Covariates were selected on the basis of their known or theoretical relationships with busulfan pharmacokinetics and were plotted independently against the individual pharmacokinetic parameters and the weighted residuals of the model without covariates to visualize relations. Potential covariates were formally tested in the model. RESULTS: In a two-compartment model, body weight was the most predictive covariate for clearance, volume of distribution and inter-compartmental clearance and explained 65%, 75% and 40% of the observed variability, respectively. The relationship between body weight and clearance was characterized best using an allometric equation with a scaling exponent that changed with body weight from 1.2 in neonates to 0.55 in young adults. This implies that an increase in body weight in neonates results in a larger increase in busulfan clearance than an increase in body weight in older children or adults. Clearance on the first day was 12% higher than that of subsequent days (p < 0.001). Inter-occasion variability on clearance was 15% between the 4 days. Based on the final pharmacokinetic-model, an individualized dosing nomogram was developed. CONCLUSIONS: The model-based individual dosing nomogram is expected to result in predictive busulfan exposures in patients ranging between 3 and 65 kg and thereby to a safer and more effective conditioning regimen for HSCT in children.

Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer.

PURPOSE: The use of cytochrome P450 2D6-inhibiting drugs (CYP2D6 inhibitors) during tamoxifen treatment leads to a decrease in plasma concentration of endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6 inhibitors, such as selective serotonin reuptake inhibitors, as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in patients with breast cancer. The objectives of this study were to relate concomitant CYP2D6 inhibitor use and tamoxifen adherence to breast cancer event-free time (EFT). PATIENTS AND METHODS: Data were from PHARMO and included a community pharmacy dispensing database; PALGA, a nationwide pathology database; and the Dutch Medical Register in the Netherlands. Patients with breast cancer treated with adjuvant tamoxifen between 1994 and 2006 were included. A Cox proportional hazards model with a time-dependent definition for concomitant CYP2D6 inhibitor exposure was used. Adherence calculated over the first year after tamoxifen initiation was related to breast cancer events in the following period. RESULTS: In total, 1,962 patients with breast cancer using tamoxifen were included, among whom 150 (7.6%) frequently used a CYP2D6 inhibitor during tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use and breast cancer recurrence was observed (adjusted hazard ratio [HR], 0.87; 95% CI, 0.42 to 1.79; P = .69). Poor tamoxifen adherence was associated with lower EFT (adjusted HR, 0.987; 95% CI, 0.975 to 0.999; P = .029). CONCLUSION: This observational study did not show an association between concomitant CYP2D6 inhibitor use and breast cancer recurrence among patients treated with adjuvant tamoxifen despite the strong biologic rationale. This study shows, to the best of our knowledge for the first time, that poor tamoxifen adherence is associated with an increased risk of breast cancer events.

[Separate pharmaceutical budgets: skating on thin ice]. / Gescheiden farmaceutische budgetten: dansen over ijsschotsen.

In the Netherlands there are separate pharmaceutical budgets for hospital, nursing home and primary healthcare. This complex method of funding drug use, plus three recent developments, is putting increasing pressure on patient access to adequate pharmacotherapy. The three developments concerned are: the rapidly increasing number of expensive drugs available; the transfer of complex hospital care to primary care; and the transfer of budget responsibility from the government to health insurance companies. The so called 'postcode lottery affair' is just one example of access to expensive drugs (e.g. trastuzumab) depending on the region in which patients live. A reform of the way pharmaceutical budgets are distributed needs urgent reconsideration.

Safety-related regulatory actions for biologicals approved in the United States and the European Union.

CONTEXT: Biologicals are a relatively new class of medicines that carry specific risks (eg, immunogenicity). However, limited information is available on the nature and timing of safety problems with their use that were identified after approval. OBJECTIVE: To determine the nature, frequency, and timing of safety-related regulatory actions for biologicals following approval in the United States and/or the European Union. DESIGN AND SETTING: Follow-up of a group of biologicals approved in the United States and/or European Union between January 1995 and June 2007. Vaccines, allergenic products, and products for further manufacture and transfusion purposes were excluded. MAIN OUTCOME MEASURES: Nature, frequency, and timing of safety-related regulatory actions defined as (1) dear healthcare professional letters (United States) and direct healthcare professional communications (European Union), (2) black box warnings (United States), and (3) safety-related marketing withdrawals (United States and European Union) issued between January 1995 and June 2008. RESULTS: A total of 174 biologicals were approved (136 in the United States and 105 in the European Union, of which 67 were approved in both regions). Eighty-two safety-related regulatory actions (46 dear healthcare professional letters, 17 direct healthcare professional communications, 19 black box warnings, and no withdrawals) were issued for 41 of the 174 different biologicals (23.6%). The probability of a first safety-related regulatory action, derived from Kaplan-Meier analyses, was 14% (95% confidence interval [CI], 9%-19%) 3 years after approval and 29% (95% CI, 20%-37%) 10 years after approval. Biologicals first in class to obtain approval had a higher risk for a first safety-related regulatory action compared with later approved products in that class (12.0/1000 vs 2.9/1000 months, respectively; hazard ratio, 3.7 [95% CI, 1.5-9.5]). Warnings mostly concerned the classes general disorders and administration site conditions, infections and infestations, immune system disorders and neoplasms benign, malignant, and unspecified. CONCLUSIONS: The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effect (infections). Because the biologicals first to be approved in a class were more likely to be subjected to regulatory action, close monitoring is recommended.

Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands.

BACKGROUND: Medication-related problems that lead to hospitalization have been the subject of many studies, many of which were limited to 1 hospital or lacked patient follow-up. Furthermore, little information exists on potential risk factors associated with preventable medication-related hospitalizations. METHODS: A prospective multicenter study was conducted to determine the frequency and patient outcomes of medication-related hospital admissions. A case-control design was used to determine risk factors for potentially preventable admissions. All unplanned admissions in 21 hospitals were assessed during 40 days. Controls were patients admitted for elective surgery. Cases and controls were followed up until hospital discharge. The frequency of medication-related hospital admissions, potential preventability, and outcomes were assessed. For potentially preventable medication-related admissions, risk factors were identified in the case-control study. RESULTS: Almost 13,000 unplanned admissions were screened, of which 714 (5.6%) were medication related. Almost half (46.5%) of these admissions were potentially preventable, resulting in 332 case patients matched with 332 controls. Outcomes were favorable in most patients. The main determinants of preventable medication-related hospital admissions were impaired cognition (odds ratio, 11.9; 95% confidence interval, 3.9-36.3), 4 or more comorbidities (8.1; 3.1-21.7), dependent living situation (3.0; 1.4-6.5), impaired renal function (2.6; 1.6-4.2), nonadherence to medication regimen (2.3; 1.4-3.8), and polypharmacy (2.7; 1.6-4.4). CONCLUSIONS: Adverse drug events are an important cause of hospitalizations, and almost half are potentially preventable. The identified risk factors provide a starting point for preventing medication-related hospital admissions.

Relationship between polypharmacy and underprescribing.

AIMS: Underprescribing is increasingly recognized as an important problem. The aim of this study was to determine the relationship between polypharmacy and underprescribing. METHODS: Treatment of current medical problems in geriatric patients was compared with general practitioner and national guidelines. Underprescription was defined as lack of an indicated drug, while no reason could be found for not prescribing it. Polypharmacy was defined as five or more drugs. RESULTS: Polypharmacy was present in 61% of 150 patients. Underprescription was found in 47 (31%). Of patients with polypharmacy 42.9% were undertreated, in contrast to 13.5% of patients using four medicines or less (OR 4.8, 95% CI 2.0, 11.2). The estimated probability of underprescription increased significantly with the number of drugs. CONCLUSIONS: We found a clear relationship between polypharmacy and underprescribing.

Compliance with national guidelines for the management of drug-drug interactions in Dutch community pharmacies.

BACKGROUND: Pharmacists contribute to the detection and prevention of drug therapy-related problems, including drug-drug interactions. Little is known about compliance with pharmacy practice guidelines for the management of drug-drug interaction alerts. OBJECTIVE: To measure the compliance of community pharmacists with Dutch guidelines for the management of drug-drug interactions and to determine patient- and prescriber-related determinants for noncompliance. METHODS: Sixteen clinically relevant drug-drug interactions were included in the study based on certain described criteria. From June to August 2005, Dutch pharmacists (N = 149) collected alerts occurring in daily patient care for these interactions as well as information related to the patient, the alert itself, the prescriber, and the management of the alert. Noncompliance was measured by comparing the management executed by the pharmacy with the national guidelines. RESULTS: Overall compliance with the guidelines was 69.3% (n = 423), with large differences between the various drug-drug interactions. Male sex (OR 2.25; 95% CI 1.52 to 3.31), oldest age (>75 y; OR 1.97; 95% CI 1.03 to 3.75), and polypharmacy (>7 medications; OR 2.35; 95% CI 1.46 to 3.80) were associated with a higher probability for noncompliance with the guidelines. Prescriber-related variables had no significant influence on guideline compliance. Substitution of one of the involved agents, recommended for most of the drug-drug interactions, was executed in a small minority of cases. The outcome of interaction management, such as substitution, dose reduction, or temporary stop of one of the agents, was frequently inconsistent with the guidelines. Compliance rates were partly influenced by the ultimate decision made by the prescriber. In that way, pharmacies' compliance was not solely assessed. However, in only 22.5% of the cases was the drug-drug interaction presented to the prescriber. CONCLUSIONS: Noncompliance with Dutch guidelines for the management of drug-drug interaction alerts is common in community pharmacies. Further research into underlying reasons for noncompliance is warranted, such as the relation between pharmacist and prescriber in this context.

Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration.

Lithium is the drug that is most frequently associated with acquired nephrogenic diabetes insipidus (NDI). The exact mechanism of lithium-induced NDI in man is unknown. The aim of the present study was to investigate the kidney response to minimal and maximal stimulation of the kidney urine concentrating mechanism by measuring urine osmolality, and urine levels of cAMP and AQP-2 in urine of patients under long-term lithium treatment. Twenty patients under long-term lithium treatment were included. The kidney urinary 3',5'-cyclic adenosine monophosphate (cyclic AMP), aquaporin-2 levels and urine osmolality were determined during a situation of minimal kidney urine concentrating activity (induced by water loading) and during a situation following maximal stimulation of kidney urine concentrating activity (induced by 1-desamino-8-D-arginine-vasopressin). Patients were classified as NDI, partial NDI and non-NDI based on maximal reached urine osmolality. The partial correlation (r) between urinary cyclic AMP levels (mol/l) and urine osmolality was 0.94 (P<0.001). No significant correlation was observed between urinary aquaporin-2 levels (mol/mol creatinine) and osmolality nor between urinary cyclic AMP and aquaporin-2 levels. The rise in urinary cyclic AMP but not aquaporin-2 levels upon 1-desamino-8-D-arginine-vasopressin administration after water loading significantly differed between the three categories, decreasing with increasing NDI category. In conclusion we found that in lithium-induced kidney urine concentrating deficit in man, the cyclic AMP generation in response to 1-desamino-8-D-arginine-vasopressin administration after water loading, is impaired. It remains to be elucidated whether principal cells, G-proteins or adenylate cyclase e.g. are the major targets for the mechanism underlying lithium-induced NDI in man.

The risk of cancer in users of statins.

PURPOSE: Several preclinical studies suggested a role for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of cancer. The objective of this study was to compare the risk of incident cancer between users of statins and users of other cardiovascular medication. METHODS: Data were used from the PHARMO database, containing drug dispensing records from community pharmacies and linked hospital discharge records for residents of eight Dutch cities. The study base included all patients with one or more prescriptions for cardiovascular drugs in the period between January 1, 1985 and December 31, 1998. Cases were identified as patients in the study base with a diagnosis of incident cancer and matched with four to six controls on sex, year of birth, geographic region, duration of follow-up, and index date. The analysis was adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers, nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug therapies. RESULTS: In the study base, 3129 patients were identified and matched to 16976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91). CONCLUSION: This observational study suggests that statins may have a protective effect against cancer.

Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients.

BACKGROUND: Several reports of various bleeding problems associated with the use of serotonergic antidepressants have been published. However, no information concerning the effect of these drugs on perioperative blood loss and blood transfusion requirements during orthopedic surgery is available. The objective of this study was to determine the association between use of serotonergic antidepressants and perioperative blood loss and transfusion in orthopedic surgical patients. METHODS: A retrospective follow-up study, using routinely collected hospital and pharmacy data, was conducted among all orthopedic patients undergoing surgery from January 1, 1999, through December 31, 2000. The actual blood transfusion requirements and blood loss during surgery were assessed. Patients were divided into 3 groups for comparison: users of serotonergic antidepressants, users of nonserotonergic antidepressants, and nonusers of antidepressants. The Medical Ethics Committee approved the study protocol, and informed consent was obtained from all patients or their legal relatives. RESULTS: A total of 520 subjects with evaluable data participated in the study. The risk of blood transfusion almost quadrupled for the serotonergic antidepressant group as compared with the nonusers (adjusted odds ratio, 3.71; 95% confidence interval, 1.35-10.18). Patients using nonserotonergic antidepressants had no increased risk (odds ratio, 0.74; 95% confidence interval, 0.10-5.95). CONCLUSIONS: Use of serotonergic antidepressants is associated with an increased risk of bleeding and subsequent need for blood transfusion during orthopedic surgery. The bleeding could be attributed to inhibition of serotonin-mediated platelet activation.