Evaluation of the pharmacokinetics of pemigatinib in patients with impaired hepatic or renal function.

AIMS: Pemigatinib, an inhibitor of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases, is approved for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma. Pemigatinib is predominantly metabolized by CYP3A4 with minimal renal elimination. METHODS: Separate hepatic and renal impairment studies were conducted to evaluate the effect of these impairments on pemigatinib pharmacokinetics (PK). Each study was of open-label, parallel-group design, conducted in participants with normal organ function and with hepatic or renal impairment. Plasma concentrations of pemigatinib were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS) and pemigatinib PK parameters were derived by noncompartmental analysis. Geometric mean ratios and two-sided 90% confidence intervals of Cmax , AUC0-t , and AUC0-∞ were compared by analysis of variance (ANOVA). RESULTS: Compared with healthy matched participants: Cmax and AUC0-∞ ratio (90% confidence interval) in participants with moderate hepatic impairment were 96.7% (59.4%, 157%) and 146% (100%, 212%), respectively; Cmax and AUC0-∞ ratio in participants with severe hepatic impairment were 94.2% (68.9%, 129%) and 174% (116%, 261%), respectively; Cmax and AUC0-∞ ratio in participants with severe renal impairment were 64.6% (44.1%, 94.4%) and 159% (95.4%, 264%), respectively; Cmax and AUC0-∞ ratio in participants with end-stage renal disease (ESRD) before haemodialysis (HD) were 77.5% (51.2%, 118%) and 76.8% (54.0%, 109%), respectively; Cmax and AUC0-∞ ratio in participants with ESRD after HD were 90.0% (59.3%, 137%) and 91.3% (64.1%, 130%), respectively. CONCLUSION: Pemigatinib dose should be reduced for patients with severe hepatic or renal impairment, and no dose adjustment is required for patients with moderate hepatic impairment or in ESRD patients undergoing HD.

Evaluation of drug-drug interactions of pemigatinib in healthy participants.

PURPOSE: Pemigatinib (INCB054828), a potent and selective oral fibroblast growth factor receptor 1-3 inhibitor, is a Biopharmaceutical Classification System class II compound with good permeability and pH-dependent solubility that is predominantly metabolized by cytochrome P450 (CYP) 3A. Two drug-drug interaction studies, one with acid-reducing agents, esomeprazole (proton pump inhibitor [PPI]) and ranitidine (histamine-2 [H2] antagonist), and the other with potent CYP3A-modulating agents, itraconazole (CYP3A inhibitor) and rifampin (CYP3A inducer), were performed. METHODS: Both were open-label, fixed-sequence studies conducted in up to 36 healthy participants each, enrolled into two cohorts (n = 18 each). Pemigatinib plasma concentration was measured, and pharmacokinetic parameters were derived by non-compartmental analysis. RESULTS: There was an 88% and 17% increase in pemigatinib area under the plasma drug concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), respectively, with itraconazole, and an 85% and 62% decrease in pemigatinib AUC and Cmax with rifampin coadministration. There was a 35% and 8% decrease in pemigatinib AUC and Cmax, respectively, with esomeprazole, and a 2% decrease in Cmax and 3% increase in AUC with ranitidine coadministration. In both studies, all adverse events reported were grade ≤ 2. CONCLUSION: Coadministration with itraconazole or rifampin resulted in a clinically significant change in pemigatinib exposure. Therefore, coadministration of strong CYP3A inducers with pemigatinib should be avoided, and the dose of pemigatinib should be reduced if coadministration with strong CYP3A inhibitors cannot be avoided. The effect of PPIs/H2 antagonists on pemigatinib exposure was modest, and pemigatinib can be administered without regard to coadministration of PPIs/H2 antagonists.

Substantial effect of efavirenz monotherapy on bilirubin levels in healthy volunteers.

BACKGROUND: Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs. OBJECTIVES: To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers. METHODS: Men and women (aged 18-49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported. RESULTS: Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin. CONCLUSIONS: Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.

Using the ALSFRS-R in multicentre clinical trials for amyotrophic lateral sclerosis: potential limitations in current standard operating procedures.

Objective: Uniform data collection is fundamental for multicentre clinical trials. We aim to determine the variability, between ALS trial centers, in the prevalence of unexpected or implausible improvements in the revised ALS functional rating scale (ALSFRS-R) score, and its associations with individual patient and item characteristics.Methods: We used data from two multicentre studies to estimate the prevalence of an unexpected increase or implausible improvement in the ALSFRS-R score, defined as an increase of 5 points or more between two consecutive, monthly visits. For each patient with a 5-point or more increase, we evaluated the individual contribution of each ALSFRS-R item.Results: Longitudinal ALSFRS-R scores, originating from 114 trial centers enrolling a total of 1,240 patients, were analyzed. A 5-point or more increase in ALSFRS-R total score was found in 151 (12.2%) patients, with prevalence per study center ranging from 0% to 83%. Bulbar onset, faster disease progression at enrollment, and a lower ALSFRS-R score at baseline were associated with a sudden 5-point or more increase in the ALSFRS-R total score. ALSFRS-R items 2 (saliva), 9 (stairs), 10 (dyspnea), and 11 (orthopnea) were the primary drivers when a 5-point or more increase occurred.Conclusions: Sudden 5-point or more increases in ALSFRS-R total scores between two consecutive visits are relatively common. These sudden increases were not found to occur with equal frequency in trial centers; which underscores the need for amending existing standard operating procedures toward a universal version and monitoring of data quality during the study, in multicentre research.

Effect of Hepatic Impairment on the Pharmacokinetics of Itacitinib.

Itacitinib is a potent, selective JAK-1 inhibitor currently in development for the treatment of chronic graft-vs-host-disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open-label study was to investigate the effect of hepatic impairment, as determined by Child-Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300-mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination. Participants with moderate hepatic impairment (N = 8) had an approximate 2.5-fold increase in total exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) and an approximate 2-fold increase in maximal exposure (Cmax ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC0-∞ and 1.95 [90%CI, 1.14-3.35] for Cmax ). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC0-∞ ) and an approximate 3.5-fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41-6.89] for AUC0-∞ and 3.48 [90%CI, 1.94-6.23] for Cmax ). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment-related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations.

Innovating Clinical Trials for Amyotrophic Lateral Sclerosis: Challenging the Established Order.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.

An Open-Label Study to Assess the Effect of Itraconazole and Rifampin on Parsaclisib Pharmacokinetics When Administered Orally in Healthy Participants.

Parsaclisib, a selective, potent phosphatidylinositol 3-kinase delta inhibitor being developed for the treatment of cancer and autoimmune diseases, is primarily metabolized by cytochrome P450 (CYP) 3A4. This study assessed the pharmacokinetics (PK) and safety of parsaclisib alone or combined with itraconazole (potent CYP3A inhibitor) or rifampin (potent CYP3A4 inducer) in healthy participants. In this open-label, fixed-sequence study, cohort 1 received oral parsaclisib 10 mg once daily on days 1 and 8 and oral itraconazole 200 mg once daily on days 4-11; cohort 2 received oral parsaclisib 20 mg once daily on days 1 and 11 and oral rifampin 600 mg once daily on days 4-12. Parsaclisib plasma concentration was tested and PK parameters calculated by noncompartmental analysis. Geometric mean ratios (GMRs) and 2-sided 90% confidence intervals (CIs) were estimated by 2-factor analysis of variance. Thirty-six healthy participants were enrolled (18 per cohort). Parsaclisib maximum plasma drug concentration (Cmax ) and area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) were increased by 21% and 107% with concomitant itraconazole versus parsaclisib alone (GMR, 1.21; 90%CI, 1.14-1.29; and 2.07; 90%CI, 1.97-2.17, respectively). Parsaclisib Cmax and AUC were reduced by 43% and 77%, respectively, with concomitant rifampin versus parsaclisib alone (GMR, 0.57; 90%CI, 0.53-0.60; and 0.23; 90%CI, 0.21-0.24, respectively). Headache was the most common adverse event, reported by 13.9% of participants (all in cohort 2). Single-dose parsaclisib alone or combined with itraconazole or rifampin appeared safe and well tolerated in healthy participants. Parsaclisib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors or inducers.

Evaluation of Clinical Cardiac Safety of Itacitinib, a JAK1 Inhibitor, in Healthy Participants.

Itacitinib is a JAK1-selective inhibitor in phase 3 development in graft-versus-host disease. A post hoc electrocardiogram (ECG) analysis and a plasma concentration-QTc (C-QTc) analysis were performed to assess cardiac safety using data from the first-in-human itacitinib study. The study included 2 cohorts of 12 healthy participants each in an interleaving dosing design with single doses of 10-300 mg or placebo; 500 and 1000 mg doses were subsequently added with 12 participants randomized to itacitinib or placebo. Continuous Holter recordings were collected from 1 hour predose to 8 hours postdose on each dosing day, and ECG intervals were blindly extracted to match timed pharmacokinetic samples. Data showed no hysteresis, and a prespecified linear mixed-effects C-QTc model was used with change-from-baseline QTcF (QT interval corrected for heart rate by Fridericia's method) as the dependent variable, plasma itacitinib concentrations and centered baseline QTcF as continuous covariates, treatment and time as categorical factors, and a random intercept per participant. The estimated slope of the C-QTc relationship was not significantly different from zero: 0.0002 milliseconds per nM (90%CI, -0.00019 to 0.00054 milliseconds). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. A QTc effect exceeding the threshold of concern (10 milliseconds) can be excluded for itacitinib plasma concentrations up to ∼13 000 nM (∼7200 ng/mL), which is well above the maximum concentration expected with the highest proposed therapeutic dose of itacitinib either with concomitant use of cytochrome P450 3A4 inhibitors or in patients with impaired hepatic function.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Itacitinib.

Itacitinib is a novel, selective, Janus kinase 1 inhibitor in development for treatment of graft-versus-host disease. The objective of this study was to assess pharmacokinetics and safety of 300-mg itacitinib dosed in participants with normal renal function (n = 10), severe renal impairment (n = 8), and end-stage renal disease (ESRD) on hemodialysis (n = 8). Serial plasma and urine samples (urine from normal and severe groups only) were collected before dosing until 72 hours after dosing. In the ESRD group, itacitinib was evaluated in 2 periods, when dosed before (period 1) and after (period 2) a hemodialysis session. Geometric mean ratios (90% confidence interval) in participants with severe renal impairment, ESRD period 1 and ESRD period 2 relative to participants with normal renal function were 1.65 (1.13-2.39), 0.71 (0.49-1.03), and 0.83 (0.57-1.20) for maximum plasma drug concentration and 2.23 (1.56-3.18), 0.81 (0.57-1.16), and 0.95 (0.66-1.35) for area under the plasma concentration-time curve from time zero to infinity. Itacitinib was well tolerated, and 3 grade 1 treatment-emergent adverse events were reported over the course of the study. Given the magnitude of exposure changes in participants with severe renal impairment or ESRD and the historic risk-benefit profile, no dose adjustment is recommended for itacitinib in patients with impaired renal function, although the final dosage recommendation will be based on cumulative pharmacokinetics and safety from this study and from the pivotal graft-versus-host disease trial. Additionally, itacitinib may be administered to patients undergoing dialysis regardless of the time of dialysis.

Effect of Itraconazole or Rifampin on Itacitinib Pharmacokinetics When Administered Orally in Healthy Subjects.

Itacitinib is a potent, selective JAK-1 inhibitor currently in phase 3 development for the treatment of acute and chronic graft-versus-host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily eliminated via metabolism by cytochrome P-450 (CYP)3A4 with minimal renal elimination. A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole or the strong CYP3A4 inducer rifampin on the pharmacokinetics of itacitinib in healthy volunteers. In cohort 1, subjects received 200 mg sustained release (SR) tablets of itacitinib on days 1 and 6 and 200 mg itraconazole on days 2-7. In cohort 2, subjects received 200 mg SR itacitinib on days 1 and 9 and 600 mg rifampin on days 2-9. Thirty-six subjects were enrolled, 18 in each cohort with 17 completing itacitinib dosing in cohort 1 and 15 completing itacitinib dosing in cohort 2. Coadministration of itraconazole with itacitinib resulted in a nearly 5-fold increase in area under the concentration-time curve (AUC0-∞ ) (geometric mean ratio [GMR] 4.88, 90%Cl 4.17-5.72) and an ∼3-fold increase in peak concentration (Cmax ) (GMR 3.15, 90%Cl 2.58-3.54). Coadministration of rifampin with itacitinib resulted in a nearly 80% decrease in AUC0-∞ (GMR 0.208, 90%Cl 0.173, 0.249) and Cmax (GMR 0.231, 90%Cl 0.195, 0.274). Results of this study informed the study design of the phase 3 GVHD protocols with regard to coadministration of strong CYP3A inhibitors and CYP3A4 inducers. These data combined with phase 3 data will inform final dosing recommendations.

Visit-to-visit systolic blood pressure variability and microvascular complications among patients with diabetes.

AIMS: To examine the relationship between systolic blood pressure (SBP) variability and the risk of microvascular complications in a non-elderly diabetic population. METHODS: This is a retrospective cohort study of individuals aged ≤60years treated for diabetes in 2003 in the US Department of Veterans Affairs healthcare system. Individuals were followed for five years for any new diagnosis of diabetic nephropathy, retinopathy, or neuropathy. In each year of follow-up, individuals were classified into quartiles based on their SBP variability. RESULTS: We identified 208,338 patients with diabetes without diabetic nephropathy, retinopathy, or neuropathy at baseline. Compared to individuals with the least SBP variability (Quartile 1), those with most variability (Quartile 4) had 81% (OR=1.81; 95% CI, 1.72-1.91), 17% (OR=1.17; 95% CI, 1.13-1.21), 30% (OR=1.30; 95% CI, 1.25-1.35), and 19% (OR=1.19; 95% CI, 1.15-1.23) higher incidence of nephropathy, retinopathy, neuropathy, and any complication, respectively, after adjusting for mean SBP, demographic and clinical factors. CONCLUSIONS: We found a significant graded relationship between SBP variability and the incidence of each complication and of any combined endpoint. This is the first study showing a significant association between SBP variability and the risk of diabetic retinopathy and neuropathy.

Systolic blood pressure variability and lower extremity amputation in a non-elderly population with diabetes.

OBJECTIVE: Systolic blood pressure (SBP) variability is emerging as a new risk factor for cardiovascular diseases, diabetic nephropathy, and other atherosclerotic conditions. Our objective is to examine whether it has any prognostic value for lower-extremity amputations. RESEARCH DESIGN AND METHODS: This is a nested case-control study of a cohort of patients with diabetes aged<60 years and treated in the US Department of Veterans Healthcare system in 2003. They were followed over five years for any above-ankle (major) amputations. For each case with a major amputation (event), we randomly selected up to five matched controls based on age, sex, race/ethnicity, and calendar time. SBP variability was computed using three or more blood pressure measures taken during the one-year period before the event. Patients were classified into quartiles according to their SBP variability. RESULTS: The study sample included 1038 cases and 2932 controls. Compared to Quartile 1 (lowest variability), Quartile 2 had 1.4 times (OR=1.44, 95% CI=1.00-2.07) and Quartiles 3 and 4 (highest) had 2.5 times (OR for Quartile 3=2.62, 95% CI=1.85-3.72; OR for Quartile 4=2.50, 95% CI=1.74-3.59) higher risk of major amputation (P for trend<0.001). This gradient relationship held in both normotensive and hypertensive groups as well as for individuals without prior peripheral vascular disease. CONCLUSIONS: This is the first study to show a significant graded relationship between SBP variability and risk of major amputation among non-elderly persons with diabetes.

Medication for Alzheimer's disease and associated fall hazard: a retrospective cohort study from the Alzheimer's Disease Neuroimaging Initiative.

BACKGROUND: Falls are common in the elderly, especially in those with cognitive impairment. The elderly are often treated with several medications, which may have both beneficial and deleterious effects. The use and type of medication in Alzheimer's disease (AD) patients and association with falls is limited. OBJECTIVE: We examined the association between falls and medication use in the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Diagnosis, demographics, medication use, apolipoprotein E4 allele status and functional activity level at baseline were gathered for 810 participants enrolled in the ADNI, including healthy controls and subjects with mild cognitive impairment or Alzheimer's. Reports detailing adverse event falls were tabulated. Baseline characteristics were compared between subjects with and without one or more falls. Cox proportional hazards models were conducted to evaluate the association between subject characteristics and hazard of the first fall. RESULTS: Age (p < 0.0001), Functional Activities Questionnaire (p = 0.035), Beers List (p = 0.0477) and medications for treating cognitive symptoms of Alzheimer's (p = 0.0019) were associated with hazard of fall in the univariate model. In the final multivariate model, after adjusting for covariates, Alzheimer's medication use (p = 0.0005) was associated with hazard of fall. Medication was changed by the clinician after an adverse fall event in 9% of the falls. About 7% of the falls were reported as serious adverse events and 6% were reported to be severe. CONCLUSION: We found a significant association between the use of symptomatic medication treating cognitive symptoms in AD and hazard of fall after adjusting for age and Beers List medication use. Additional pharmacovigilance of the association between falls and Alzheimer's medication use is warranted.

Cognitive dysfunction and greater visit-to-visit systolic blood pressure variability.

OBJECTIVES: To determine whether variability in blood pressure (BP) is negatively associated with performance on cognitive testing. DESIGN: Multinational, longitudinal, observational cohort study. SETTING: The Alzheimer's Disease Neuroimaging Initiative study. PARTICIPANTS: Individuals with a screening diagnosis of mild cognitive impairment or normal cognition (N=626). MEASUREMENTS: Mean, variance, and maximum BP were calculated based on measures collected from screening to 36 months. Analysis of covariance models were used to determine the association between BP measures and cognitive scores at 36 months after adjusting for covariates. RESULTS: Greater variability in systolic (P<.05) but not diastolic (P>.18) BP was associated with worse global (Modified Alzheimer's Disease Assessment Scale Cognitive Component and Clinical Dementia Rating sum of boxes) and executive (Trail-Making Test Part B, Animal Fluency, and Vegetable Fluency) function and episodic memory (Rey Auditory Verbal Learning Test Total Score). CONCLUSION: There is a clinically significant association between greater systolic BP variability and greater cognitive dysfunction. These results should be verified in other well-characterized cohorts, and the neuroanatomical pathophysiology underlying the observed greater cognitive impairment should be further explored.

Vascular risk factors and cardiovascular outcomes in the Alzheimer's disease neuroimaging initiative.

BACKGROUND: Vascular disease and medical factors are associated with cognitive decline and cardiovascular events. We examined the association between vascular risk factors and events in the Alzheimer's Disease Neuroimaging Initiative cohort. METHODS: The association between vascular risk factors and cardiovascular events in a cohort of 810 participants, including 400 with mild cognitive impairment, 184 with Alzheimer's, and 226 controls was investigated using a longitudinal hazard model. RESULTS: There were 31 events including 11 strokes, 7 myocardial infarctions, 5 revascularizations, and 8 deaths during an average follow-up of 31 months. Longitudinal cardiovascular event rates were low and similar between diagnostic groups. CONCLUSIONS: All baseline vascular risk factors that were expected to be associated with longitudinal cardiovascular events were, or were trending toward, associating with cardiovascular events except atrial fibrillation, depression, and apolipoprotein E genotype. Despite differences in baseline vascular risk factors, longitudinal cardiovascular event rates were similar between diagnostic groups.

Differences in medication use in the Alzheimer's disease neuroimaging initiative: analysis of baseline characteristics.

INTRODUCTION: The ADNI (Alzheimer's Disease Neuroimaging Initiative) is a large longitudinal study of patients with probable Alzheimer's disease (AD), patients with mild cognitive impairment (MCI) and healthy elderly controls followed for at least 2-3 years. Many participants in the ADNI are being treated with medications, and these may have beneficial or deleterious effects. OBJECTIVE: The goal of the study was to characterize baseline medication use in the ADNI. METHODS: Diagnosis, demographics, medication status, psychometric data and MRI measures of hippocampal volume and entorhinal cortex thickness were obtained for 818 participants from the ADNI cohort. Total number of medications, Beers list (potentially dangerous) medications and AD treatments were also tabulated. ANOVA and logistic regression were used to assess associations between baseline pharmacotherapy and diagnosis, demographics, and selected clinical and MRI variables. RESULTS: Of the 818 enrolled ADNI participants, 809 were available for analysis in the present study, including 184 patients with AD, 399 patients with MCI and 226 healthy elderly controls. Significant gender differences in recruitment were observed in the MCI group. The average number of medications per participant was 8 (SD 4) and 22% reported treatment with one or more Beers list medications. For symptomatic treatment of MCI or AD, donepezil and memantine were the most commonly reported drugs. As expected, MCI and AD patients with more severe impairment were more likely to be treated. Men received treatment more frequently than women. Older subjects and those with less education were less likely to receive treatment. CONCLUSIONS: AD and MCI participants from the ADNI cohort were being treated with polypharmacy and many were also taking one or more medications with the potential for adverse effects. Off-label use of cholinesterase inhibitors and/or memantine for MCI was common, with more severely affected patients most likely to receive treatment. Differences in the frequency of symptomatic treatment were also observed as a function of age, years of education, gender and disease severity.