Buster Mannheimer

Impact of multiple inhibitors or substrates of cytochrome P450 2D6 on plasma risperidone levels in patients on polypharmacy.

Studies that focus on multidrug interactions in natural settings are sparse. In this investigation, data from therapeutic drug monitoring (TDM) were used to study the impact of multiple cytochrome P450 enzyme (CYP) 2D6 substrates and inhibitors on plasma risperidone levels. CYP2D6 catalyzes the conversion of risperidone to the active metabolite 9-OH-risperidone. The question whether CYP2D6 activity is important for the level of the “active moiety” (ie, the sum of risperidone and 9-OH-risperidone) is controversial. Concentration-to-dose (C:D) ratios of risperidone and 9-OH-risperidone in 218 patients were associated with the number of concomitantly used substrates or inhibitors of CYP2D6. The C:D ratios of risperidone in patients with 0, 1, and >1 numbers of CYP2D6 inhibitors were 2.6, 8.5, and 17 nmol L−1 mg−1, respectively. Differences between the groups were highly significant (P < 0.001). All patients with >1 CYP2D6 inhibitors were administered at least 1 potent CYP2D6 inhibitor, that is fluoxetine, paroxetine, thioridazine, and/or levomepromazine. The C:D ratios of the active moiety (risperidone + 9-OH-risperidone) in patients with 0, 1, and >1 numbers of concomitant CYP2D6 inhibitors were 17, 24, and 30 nmol L−1 mg−1, respectively (P = 0.001), which was explained by higher levels of risperidone without any change in the levels of 9-OH-risperidone. Concomitant use of 1 or several drugs recognized as substrates for CYP2D6, without any proven inhibitory effect, had no apparent influence on the levels of risperidone or 9-OH-risperidone, suggesting that the risk of drug-drug interactions between different substrates of CYP2D6 is low when used in therapeutic doses. In conclusion, the results suggest that an increase in the number of concomitant inhibitors may be associated with a lower CYP2D6 activity, although the type of inhibitor is probably more important. Drug-dependent inhibition of CYP2D6 increases the active moiety of risperidone. An indication for risperidone TDM should therefore include concomitant medication with established CYP inhibitors.

Nationwide drug-dispensing data reveal important differences in adherence to drug label recommendations on CYP2D6-dependent drug interactions.

AIMS The study aimed to investigate the clinical adherence to drug label recommendations on important drug-drug interactions (DDIs). Dispensing data on drug combinations involving selective serotonin reuptake inhibitor (SSRI) antidepressants could help to identify areas for intensified medical education. METHODS This was a retrospective, cross-sectional analysis of individual dispensing data regarding all individuals > or =15 years old in Sweden. The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Odds were calculated between each CYP2D6 drug and the corresponding comparator drug in patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline, respectively. The odds ratio (OR) was calculated by dividing the obtained odds in patients on fluoxetine/paroxetine by the corresponding odds in patients on citalopram/escitalopram/sertraline. RESULTS Compared with patients that were dispensed citalopram/escitalopram/sertraline, patients dispensed fluoxetine/paroxetine had lower prescribing rates of metoprolol (adjusted OR 0.80; 95% confidence interval 0.76, 0.85), donepezil (0.65; 0.49, 0.86) and galantamine (0.58; 0.41, 0.81). In contrast, the use of prodrugs codeine (compared woth propoxyphene) or tamoxifen (compared with anastrozole) was similar among patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline (adjusted OR 1.03; 0.94, 1.12 and 1.29; 0.96, 1.73, respectively). CONCLUSIONS Clinically important DDIs that are associated with impaired bioactivation of prodrugs might be more easily neglected in clinical practice compared with DDIs that cause drug accumulation and symptomatic adverse drug reactions.

No Effect of High-Dose Vitamin D Treatment on β-Cell Function, Insulin Sensitivity, or Glucose Homeostasis in Subjects With Abnormal Glucose Tolerance: A Randomized Clinical Trial

OBJECTIVE There has been conflicting evidence regarding the potential role of vitamin D in glucose homeostasis. This study was designed to investigate the effect of high-dose vitamin D3 treatment on β-cell function, insulin sensitivity, and glucose tolerance in subjects with prediabetes or diet-treated type 2 diabetes. RESEARCH DESIGN AND METHODS Subjects (n = 44) were randomized to 30,000 IU vitamin D3 once weekly or placebo for 8 weeks. Hyperglycemic clamp assessed first-phase (0–12 min) and second-phase (12–120 min) insulin response, insulin sensitivity, and disposition index (DI). An oral glucose tolerance test assessed glucose tolerance and glycosylated hemoglobin assessed glycemic control. RESULTS A total of 21 (vitamin D) and 22 (placebo) subjects completed the study, respectively. Season-adjusted 25-OH-vitamin D [25(OH)D] levels were doubled in the active treated group (43–82 nmol/L). No effect of vitamin D treatment, compared with placebo, was seen on first-phase or second-phase insulin secretion. There were no group differences in insulin sensitivity, DI, or any measures of glycemic control. No hypercalcemia or other adverse effects of vitamin D treatment were seen compared with placebo. Subgroup analyses of those with the lowest basal and greatest increase in 25(OH)D levels did not change these results. CONCLUSIONS This study gives no support for any substantial effect of high-dose vitamin D treatment for 8 weeks in prediabetes or diet-treated type 2 diabetes on β-cell function, insulin sensitivity, or glycemic control.

Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype.

Purpose: To investigate the predictive value of the risperidone and venlafaxine metabolic ratios and CYP2D6 genotype. Methods: The determination of risperidone, 9-hydroxyrisperidone, and venlafaxine, O-desmethylvenlafaxine, N-desmethylvenlafaxine and CYP2D6 genotype was performed in 425 and 491 patients, respectively. The receiver operator characteristic method and the area under the receiver operator characteristic curve were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. To evaluate the proposed cutoff levels of >1 to identify individuals with a poor CYP2D6 genotype, the sensitivity, specificity, positive predictive values, and negative predictive values were calculated. Results: Area under the receiver operator characteristic curve to predict poor metabolizers for risperidone/9-hydroxyrisperidone and N-desmethylvenlafaxine/O-desmethylvenlafaxine ratios was 93% and 99%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value (confidence interval) of a risperidone/9-hydroxyrisperidone ratio >1 to predict a CYP2D6 poor metabolizer genotype were 91% (76%–97%), 86% (83%–89%), 35% (26%–46%), and 99% (97%–100%), respectively. The corresponding measures for N-desmethylvenlafaxine/O-desmethylvenlafaxine were 93% (76%–97%), 87% (83%–89%), 40% (32%–51%), and 99% (98%–100%). Conclusions: Risperidone/9-hydroxyrisperidone and N-desmethylvenlafaxine/O-desmethylvenlafaxine metabolic ratios >1 strongly predict individuals with poor metabolizer genotype, which could guide psychotropic drug treatment to avoid adverse drug reactions and to increase their therapeutic efficacy in patients prescribed these drugs.

Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy--a nationwide register study.

Purpose To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased. Methods Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin) was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed. Results OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60–1.25 and 0.92; 95% CI 0.69–1.23). Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56–0.68 and low dose 0.63; CI 0.58–0.68). Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55–0.76 and low dose 0.70; CI 0.63–0.78). Mean DDD (SD) for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149) compared to patients on statin monotherapy 127 (93), (p<0.001). Conclusions Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co-prescriptions of statins and antibiotics with an increased risk of statin-induced adverse drug reactions. Co-prescription of statins and gemfibrozil is paradoxically associated with a marked increased statin dose, further aggravating the risk for severe myopathy.

A clinical evaluation of the Janus Web Application, a software screening tool for drug-drug interactions

PurposeTo evaluate the clinical relevance of the Janus Web Application (JWA) in screening for potential drug-drug interactions (DDIs).MethodsOne hundred and fifty patients taking two drugs or more were studied. Potential DDIs were identified by the JWA. Interviewing the patient and looking into his/her medical records provided complementing information. A clinical pharmacologist judged which potential DDIs were clinically relevant. Potentially relevant DDIs identified by the JWA were then correlated with clinically relevant DDIs.ResultsA total of 150 significant potential DDIs were found. Sixteen percent (24/150) were judged to be clinically relevant.ConclusionsA very small proportion of DDIs was considered clinically relevant in the specific clinical context. To optimise the software’s user-friendliness, the following points need to be considered: the possibility of eliminating trivial potential DDIs, individualising drug alerts, and providing written information, accessible via a hyperlink.

The impact of interacting drugs on dispensed doses of warfarin in the Swedish population: A novel use of population based drug registers

To investigate the impact of interacting drugs on the dispensed doses of warfarin in the Swedish population. This was a retrospective, cross‐sectional population based register study of patients being dispensed warfarin. Warfarin doses were estimated in different age groups, in men and women, and in patients using interacting drugs. The influence of interacting drugs on the dispensed warfarin dose was analyzed using multiple regression. All 143,729 patients dispensed warfarin were analyzed. The dispensed dose of warfarin was highest in patients 30–39 years old and decreased with age. Co‐medication with carbamazepine, simvastatin, paracetamol, amiodarone, fluconazole, lactulose, or bezafibrate was associated with significant changes in dispensed warfarin doses, by +40%, −3.4%, −7.3%, −8.2%, −8.8%, −9.0%, and −9.7%, respectively. After adjustment for age and gender, sulfamethoxazole was also found to significantly alter the dispensed warfarin dose (−6.1%). We provide new support for the previous scarce evidence of interactions between warfarin and carbamazepine, bezafibrate, and lactulose. Initiation or discontinuation of bezafibrate or lactulose in a patient on warfarin should warrant close clinical monitoring. The marked increased warfarin requirement associated with carbamazepine use supports moving from a more conservative reactive towards a proactive strategy including preventive warfarin dose adjustments to avoid potential adverse effects.

Limited value of long-term biochemical follow-up in patients with adrenal incidentalomas-a retrospective cohort study

BackgroundThe prevailing view that advocates long-term hormonal follow-up of adrenal incidentalomas is currently under debate. The purpose of the present study was to examine all adrenal incidentalomas presented during five years to a single centre. We hypothesized that 24-month biochemical follow-up in patients with an initial normal screening would fail to increase the sensitivity in finding hormone producing tumours.MethodsThe present study is a retrospective register based cohort study of 194 patients referred to the Department of Endocrinology at Södersjukhuset between the years 2006–2010. Computerized medical records were used to find and extract information on patients with newly discovered adrenal incidentalomas. The sensitivity, specificity, positive predictive value and negative predictive value were calculated to evaluate the validity of an initial normal screening when used to identify individuals with hormone producing tumours.ResultsOf the incidentalomas 94% consisted of benign, non-functioning tumours. Three patients were diagnosed with cortisol hypersecretion and one with pheochromocytoma. The sensitivity, specificity, positive predictive value and negative predictive value of an initial complete negative screening to predict a hormone producing tumour were 100%, 63%, 12% and 100%, respectively.ConclusionPatients with an initially normal hormonal screening may not need further biochemical follow-up.

Adherence to Guidelines for Avoiding Drug Interactions Associated with Warfarin - A Nationwide Swedish Register Study

Purpose To investigate the extent to which clinicians avoid well-established drug-drug interactions associated with warfarin. We hypothesised that clinicians would avoid combining non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and sulfamethoxazole with warfarin. Methods A cross-sectional analysis of nationwide dispensing data was performed in Swedish individuals 18 years or older (n =  7 563 649). Odds ratios of interacting NSAIDs, tramadol and sulfamethoxazole versus respective prevalence of comparator drugs codeine, and ciprofloxacin in patients co-dispensed interacting warfarin versus patients unexposed was calculated. Results The odds of receiving an interacting NSAID versus the comparator codeine was markedly lower in patients with warfarin than in the remaining population (adjusted OR 0.21; 95% CI 0.20 – 0.22). Also, the interacting drugs tramadol and sulfamethoxazole were less common among patients dispensed warfarin as compared to the remaining population, although the decrease was much more modest (adjusted OR 0.83; CI 0.80–0.87 and 0.81; CI 0.73 – 0.90). Conclusions In conclusion, Swedish doctors in the vast majority of cases refrain from prescribing NSAIDs to patients already on warfarin. Tramadol and sulfamethoxazole are however rarely avoided.

The effect of carbamazepine on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population.

Essentials The clinical impact of the carbamazepine‐warfarin drug interaction is largely unknown. We studied the interaction in 166 patients, using data from three nationwide registries. Co‐treatment with carbamazepine increased warfarin dose requirements by 49%. International normalized ratio remained reduced for months, indicating poor control.