Predictors of increased melphalan exposure correlate with overall survival, nonrelapse mortality, and toxicities in patients undergoing reduced-intensity allogeneic stem cell transplantation with fludarabine and melphalan.

The reduced-intensity conditioning regimen, fludarabine and melphalan 140 mg/m2 (FM140), is widely adopted in practice. Pharmacokinetic studies report 10-fold interpatient variability in melphalan exposure. We identified low hemoglobin (Hb) and/or creatinine clearance (CrCl), determinants of melphalan pharmacokinetic, as strong predictors of outcomes after high-dose melphalan and autologous transplant. We hypothesized that these variables could predict for outcomes after FM140. Overall survival was shorter in patients with a lower Hb (113 vs. 2536 days; p = 0.004), due to an increased rate of nonrelapse mortality (NRM) (p = 0.0005). Overall survival was also worse in patients with lower CrCl (75 vs. 317 days; p = 0.003), with a significantly worse nonrelapse mortality (p = 0.0023). In a multivariate analysis, a higher Hb and CrCl predicted for better overall survival (p = 0.017). In patients with a lower Hb, the median duration of hospitalization (p = 0.02) and the mean duration of diarrhea (p = 0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization (p = 0.06) and the mean duration of diarrhea (p = 0.0009) longer, and the rate of infection was higher (p = 0.02). We show for the first time that Hb and CrCl represent important determinants of outcomes after FM140, suggesting that pharmacokinetic-directed dosing may be beneficial in achieving optimal outcomes.

Development of a method for clinical pharmacokinetic testing to allow for targeted Melphalan dosing in multiple myeloma patients undergoing autologous transplant.

AIMS: High dose melphalan (HDM) and autologous stem cell transplant (ASCT) is standard of care for multiple myeloma (MM), but there is significant variability in melphalan exposure (area under the plasma drug concentration-time curve, AUC) when using body surface area-based dosing. Our aim was to establish a method of pharmacokinetic (PK) testing for real-time melphalan dose adjustments. METHODS: We performed a prospective PK study of melphalan 140 or 200 mg/m2 in MM patients undergoing ASCT. Twenty MM patients were administered HDM on days -2 and - 1, with PK sampling at 8-10 time points. PK testing was performed on day -2 in all patients, and on day -1 in 5 patients. RESULTS: Less than 20% interpatient variation in the day -2 and - 1 AUC was observed. The day -2 range in AUC (4.95-11.28 mg h/L) confirmed significant interpatient variability. The hypothetical total dose ranged from 133-302 mg/m2 to achieve the total median AUC. A 4-time point AUC (0, 30, 150 and 240 min) highly correlated with the AUC from the 8-time point schedule. A higher AUC correlated with increased risk of febrile neutropenia (P = .05). CONCLUSION: Here we outline the methods to establish novel melphalan dosing using PK testing in MM patients undergoing ASCT to target a desired melphalan AUC.

Prevalence of Cardiac Risk Factors in Patients Prescribed Azithromycin before and after the 2012 FDA Warning on the Risk of Potentially Fatal Heart Rhythms.

STUDY OBJECTIVE: To measure the prevalence of cardiac risk factors among patients prescribed azithromycin before and after the United States Food and Drug Administration (FDA) issued a warning on May 17, 2012, on the risk of potentially fatal heart rhythms associated with the drug. DESIGN: Retrospective cohort study using administrative claims data. DATA SOURCE: Truven Health Analytics MarketScan database. PATIENTS: A total of 12,971,078 unique patients with 23,749,652 azithromycin prescriptions dispensed between January 2009 and June 2015 were included. Patients had to be continuously enrolled in a health plan for at least 365 days (baseline) before the date of azithromycin dispensing (index date). Cohorts were assigned based on the index dates of the azithromycin prescriptions, either before (January 1, 2009-May 1, 2012) or after (June 1, 2012-June 30, 2015) the FDA warning was issued. MEASUREMENTS AND MAIN RESULTS: A cardiac risk factor included either a cardiac condition (heart failure or dysrhythmias) or concurrent use of drugs that prolong the QT interval. The unit of analysis was each prescription of azithromycin. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of cardiac risk factors. Mean age of the patients was 40.1 ± 21.3 years old, with 60.8% females. Prior to the FDA warning, 11,596,022 (48.8%) azithromycin prescriptions were identified, and 12,153,630 (51.2%) were identified after the warning. The prevalence of a preexisting cardiac condition was 7.3% versus 7.9% (p<0.0001) before and after the FDA warning, respectively. Concurrent use of a QT-interval-prolonging drug was 23.3% versus 24.2% (p<0.0001) before and after the FDA warning, respectively. After controlling for confounders, the odds of having a cardiac risk factor after the FDA warning were significantly lower (odds ratio 0.938, 95% CI 0.936-0.940) compared with before the FDA warning. CONCLUSION: Despite the 2012 FDA warning, a nontrivial number of azithromycin prescriptions was prescribed concurrently in patients with preexisting a cardiac condition (1 of 12 azithromycin prescriptions) and in those using a QT-interval-prolonging drug (1 of 5 azithromycin prescriptions). After adjusting for confounders, the odds of cardiac risk factors being present in patients prescribed azithromycin were modestly lower after the warning; however, the prevalence remained essentially unchanged before and after the FDA warning was issued.