Incidence of cytomegalovirus DNAemia in pediatric kidney, liver, and heart transplant recipients: Efficacy and risk factors associated with failure of weight-based dosed valganciclovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality in solid organ transplant recipients (SOTR). Valganciclovir (VGC) is extensively used for prophylaxis. Optimal dosing in children, risk factors for failure, and the impact of dose adjustments on CMV DNAemia is not well established. METHODS: This retrospective cohort study of pediatric SOTR transplanted between 2010-2018 evaluated the epidemiology of CMV DNAemia and used Cox-regression to assess the risk factors for CMV DNAemia within one-year following SOTR. RESULTS: In 393 pediatric SOTR (heart [96, 24.4%], kidney [180, 45.6%], liver [117, 29.8%]; median age 9.5 ± 0.3 years), overall CMV DNAemia incidence was 6.6/10 000 days (95%CI 5.1/10 000-7.9/10 000) and varied by organ groups: heart 8.2/10 000 days (95%CI 4.9/10 000-11.4/10 000), kidney 5.8/10 000 days (95%CI 3.9/10 000-7.8/10 000), liver 6.2/10 000 days (95%CI 3.7/10 000-8.7/10 000). CMV DNAemia was detected in 75 of 275 (27.2%) patients who received prophylaxis (40 cases occurred during prophylaxis and 35 occurred after completion of prophylaxis). The median VGC dose given according to institutional weight-based algorithm was approximately 1.5-fold lower than the manufacturer-recommended dose. This discordance was more prominent at younger age groups (3.2-fold lower in <2-year-old [100 mg versus 325 mg], 2.5-fold lower in <6-year-old [200 mg versus 447 mg]). Dose reduction due to adverse events was an independent risk factor for breakthrough CMV DNAemia (hazard ratio 2.2, 95%CI 1.2-3.8) among patients with similar age, CMV risk stratification, starting VGC dose, immunosuppressive therapy, and organ group. CONCLUSION: CMV events occurred while on VGC prophylaxis. Weight-based VGC may prevent supratherapeutic VGC exposure especially in younger children. Dose reduction of VGC prophylaxis for adverse event management places patients at an increased risk for CMV DNAemia suggesting other agents with fewer adverse effects should be considered and need to be studied in children.

In vitro inhibitory effects of herbal supplements on tamoxifen and irinotecan metabolism.

BACKGROUND: As the use of herbal supplements continues to rise throughout the world, the potential for drug-herbal interactions also increases. For chemotherapeutic prodrugs, this interaction could prevent the metabolic conversion of the prodrug to its active metabolite(s), thereby potentially resulting in subtherapeutic systemic exposure of the drug and reduced efficacy of the therapy. METHODS: In this study, in vitro metabolism with human liver microsomes is used to measure the impact of ten commonly used herbal supplements on the biotransformation of the chemotherapeutic prodrugs tamoxifen (TAM) and irinotecan (IR). RESULTS: Four of the herbals tested, echinacea, ginseng, lemon balm, and skullcap, were found to be strong inhibitors of the CYP450 enzymatic bioactivation pathways of TAM with IC50 values as percent of a single dose ranging from 0.019% to 0.34%. Two of the herbals, skullcap and lemon balm, were found to inhibit the carboxyesterase pathway of IR with values of 0.21 and 0.25, respectively. CONCLUSIONS: Our data suggests that based on the measured IC50 values that skullcap and lemon balm could have potential negative clinical impact on the bioactivation of TAM but not likely with IR.