Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African American kidney transplant recipients

BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. STUDY DESIGN: Randomized prospective crossover study. SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing. INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. OUTCOMES: Tacrolimus 24-hour AUC (AUC MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. RESULTS: ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922

Predicting Future Years of Life, Health, and Functional Ability: A Healthy Life Calculator for Older Adults

Introduction Planning for the future would be easier if we knew how long we will live and, more importantly, how many years we will be healthy and able to enjoy it. There are few well-documented aids for predicting our future health. We attempted to meet this need for persons 65 years of age and older. Methods Data came from the Cardiovascular Health Study, a large longitudinal study of older adults that began in 1990. Years of life (YOL) were defined by measuring time to death. Years of healthy life (YHL) were defined by an annual question about self-rated health, and years of able life (YABL) by questions about activities of daily living. Years of healthy and able life (YHABL) were the number of years the person was both Healthy and Able. We created prediction equations for YOL, YHL, YABL, and YHABL based on the demographic and health characteristics that best predicted outcomes. Internal and external validity were assessed. The resulting CHS Healthy Life Calculator (CHSHLC) was created and underwent three waves of beta testing. Findings A regression equation based on 11 variables accounted for about 40% of the variability for each outcome. Internal validity was excellent, and external validity was satisfactory. As an example, a very healthy 70-year-old woman might expect an additional 20 YOL, 16.8 YHL, 16.5 YABL, and 14.2 YHABL. The CHSHLC also provides the percent in the sample who differed by more than 5 years from the estimate, to remind the user of variability. Discussion The CHSHLC is currently the only available calculator for YHL, YABL, and YHABL. It may have limitations if today’s users have better prospects for health than persons in 1990. But the external validity results were encouraging. The remaining variability is substantial, but this is one of the few calculators that describes the possible accuracy of the estimates. Conclusion The CHSHLC, currently at http://diehr.com/paula/healthspan, meets the need for a straightforward and well-documented estimate of future years of healthy and able life that older adults can use in planning for the future

Suicidality in primary care patients who present with sadness and anhedonia: a prospective European study

Background: Sadness and anhedonia (loss of interest in activities) are central symptoms of major depression. However, not all people with these symptoms meet diagnostic criteria for major depression. We aimed to assess the importance of suicidality in the outcomes for primary care patients who present with sadness and anhedonia. Method: Cohort study of 2,599 unselected primary care attenders in six European countries followed up at 6 and 12 months. Results: 1) In patients with sadness and/or anhedonia who were not depressed at entry to the study, suicide plans (OR = 3.05; 95 % CI = 1.50–6.24; p = 0.0022) and suicide attempts (OR = 9.08; 95 % CI = 2.57–32.03; p = 0.0006) were significant predictors of developing new onset depression at 6 or 12 months. 2) In patients with sadness and/or anhedonia who met CIDI criteria for major depression at entry, suicidal ideation (OR = 2.93; 95 % CI = 1.70–5.07; p = 0.0001), suicide plans (OR = 3.70; 95 % CI = 2.08–6.57; p < 0.0001), and suicide attempts (OR = 3.33; 95 % CI = 1.47–7.54; p = 0.0040) were significant predictors of persistent depression at 6 or 12 months. Conclusions: Three questions on suicidality could help primary care professionals to assess such patients more closely without necessarily establishing whether they meet criteria for major depression.This research was funded by a grant from The European Commission, referencePREDICT-QL4-CT2002-00683. We are also grateful for part support in Europe from: the Estonian Scientific Foundation (grant number 5696); the Slovenian Ministry for Research (grant No.4369-1027); the Spanish Ministry of Health (grant FIS references: PI041980, PI041771, PI042450) and the Spanish Network of Primary Care Research, redIAPP (ISCIII-RETICS RD06/0018) and SAMSERAP group; and the UK NHS Research and Development office for providing service support costs in the UK. We are also grateful for the support from the University of Malaga (Spain) and to Carlos García from Loyola Andalucía University (Spain)