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Item Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers(Wiley, 2016-10) Abdelhady, Ahmed M.; Shugg, Tyler; Thong, Nancy; Li Lu, Jessica Bo; Kreutz, Yvonne; Jaynes, Heather A.; Robarge, Jason D.; Tisdale, James E.; Desta, Zeruesenay; Overholser, Brian R.; Pharmacology and Toxicology, School of MedicineBackground Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n=57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ΔΔQTcF were observed at 6 hrs (14 ms; 95% CI [1; 27]), 12 hrs (18 ms; 95% CI [−4; 40] and 18 hrs (6 ms; 95% CI [−1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P<0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG.Item The Effects of Progestin-Only Hormone Treatment on QT Interval in the Adolescent Female(Elsevier, 2021-01) Kean, Adam C.; Ayers, Mark D.; Farrell, Anne G.; Kean, Kelly A.; Brooks, Patricia W.; Shew, Marcia L.; Pediatrics, School of MedicineWe describe the effect of exogenous progestin on the corrected QT interval (QTc) in adolescent females. In post-menarcheal females, <18 years old, we compared QTc in milliseconds (ms) on ECG evaluations in those taking exogenous progestin vs those who are not. There were 40 controls and 21 treated participants. The age range was 10–17 years. There were no differences between the groups with regard to race, height, weight, BMI, or blood pressure. In the controls, the mean QTc was 403 ±19 milliseconds (ms) vs. 397 ±15 ms in those treated (p = 0.22). Those on progestin therapy had a shorter QTc by the same magnitude difference (six ms) as the hormonal naïve group in the adult literature. We report no adverse effects of progestin associated with QTc prolongation and a trend suggesting a decreased QTc in a population of post-menarcheal adolescent females.