Safety, Tolerability, Pharmacokinetics, and Concentration-QTc Analysis of Tetrodotoxin: A Randomized, Dose Escalation Study in Healthy Adults.

Tetrodotoxin (TTX) is a highly specific voltage-gated sodium channel (VGSC) blocker in clinical evaluation as a peripheral-acting analgesic for chronic pain. This study presents the first published results of the safety including cardiac liability of TTX at therapeutic-relevant concentrations in twenty-five healthy adults. Randomized, double-blind, placebo-, and positive- (moxifloxacin) controlled study evaluated single ascending doses of 15 µg, 30 µg, and 45 µg TTX over 3 periods with a 7-day washout between each period. Subcutaneous injections of TTX were readily absorbed, reaching maximum plasma concentration (Cmax) within 1.5 h. Both extent of exposure (AUC) and Cmax increased in proportion to dose. No QT prolongation was identified by concentration-QTc analysis and the upper bounds of the two-sided 90% confidence interval of predicted maximum baseline and placebo corrected QTcF (ΔΔQTcF) value did not exceed 10 ms for all tetrodotoxin doses, thereby meeting the criteria of a negative QT study. Safety assessments showed no clinically relevant changes with values similar between all groups and no subject withdrawing due to adverse events. Paresthesia, oral-paresthesia, headache, dizziness, nausea, and myalgia were the most common TEAEs (overall occurrence ≥5%) in the TTX treatment groups. TTX doses investigated in this study are safe, well-tolerated, and lack proarrhythmic proclivity.

Thorough QTc Study of a Single Supratherapeutic Dose of Relebactam in Healthy Participants.

The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single-dose, double-blind (relebactam only), randomized, placebo- and positive-controlled, 3-period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open-label positive control), and IV placebo. Least squares mean and 2-sided 90% confidence interval for change from baseline in population-derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population-derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150-mg supratherapeutic dose (4.6-fold above the 250-mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a ß-lactamase inhibitor in antimicrobial therapy.

Effect of letermovir on levonorgestrel and ethinyl estradiol pharmacokinetics
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OBJECTIVE: Letermovir is an inhibitor of the terminase complex of cytomegalovirus (CMV) used as prophylactic therapy in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. As the combination oral contraceptive (COC) levonorgestrel/ethinyl estradiol (LNG/EE) may be coadministered in this target transplant population, the effects of letermovir on the pharmacokinetics (PK) of LNG and EE were investigated. MATERIALS AND METHODS: This was a phase I, open-label, fixed-sequence, two-period study conducted in healthy women (18 - 65 years old) of non-childbearing potential (protocol number: MK-8228 035). On day 1 of period 1, participants received a single dose of COC (LNG 0.15 mg/EE 0.03 mg). Following a 7-day washout, oral letermovir 480 mg was administered once-daily on days 1 - 12 of period 2, with a single dose of COC coadministered on day 8. Blood samples were collected to determine LNG and EE PK, and safety was assessed. RESULTS: The AUC0-∞ geometric mean ratios (90% confidence intervals) for COC + letermovir/COC alone were 1.36 (1.30, 1.43) for LNG and 1.42 (1.32, 1.52) for EE, indicating that letermovir coadministration increased COC exposure. Coadministration had no clinically-meaningful effect on Cmax, tmax, or apparent terminal T1/2 for either LNG or EE. All treatments were generally well tolerated. CONCLUSION: Letermovir coadministration with COC resulted in an increase in LNG and EE exposure in healthy adult women; however, levels were within the established safety margins. There was no decrease in LNG or EE exposure with no apparent risk of contraceptive failure on coadministration of letermovir and COC.
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No clinically meaningful pharmacokinetic interaction between the hepatitis C virus inhibitors elbasvir and grazoprevir and the oral contraceptives ethinyl estradiol and levonorgestrel.

PURPOSE: Oral contraceptive pills (OCPs) are an important element of hepatitis C virus (HCV) treatment in women of childbearing potential. These studies evaluated the safety and pharmacokinetic interactions between elbasvir (EBR) and grazoprevir (GZR) and ethinyl estradiol/levonorgestrel (EE/LNG). METHODS: Both studies were open-label, single-site, two-period, fixed-sequence, one-way interaction studies. In period 1, subjects received one tablet of EE/LNG (0.03 mg/0.15 mg). In period 2, subjects received EBR (50 mg once daily) for 13 days or GZR (200 mg once daily) for 10 days, with one tablet of EE/LNG on day 7 (GZR group) or 10 (EBR group). Each study enrolled 20 healthy, nonsmoking adult females. RESULTS: There was no clinically meaningful effect of multiple doses of EBR or GZR on the pharmacokinetics of EE or LNG. Geometric mean ratios (GMRs) for AUC0-∞ and Cmax in the presence and absence of EBR were 1.01 and 1.10 for EE and 1.14 and 1.02 for LNG, with 90% confidence intervals (CIs) that were contained in the interval [0.80, 1.25]. Similarly, the AUC0-∞ and Cmax GMRs in the presence and absence of GZR were 1.10 and 1.05 for EE and 1.23 and 0.93 for LNG, respectively. The 90% CIs for EE AUC0-∞ and for EE and LNG Cmax were contained in the interval [0.80, 1.25]; however, the 90% CI for the LNG AUC0-∞ [1.15, 1.32] slightly exceeded the upper bound. CONCLUSIONS: These results suggest that EBR/GZR can be co-administered to female patients with HCV of childbearing potential who are on OCPs to prevent pregnancy.

A thorough QTc study demonstrates that olmesartan medoxomil does not prolong the QTc interval.

Two studies (ROADMAP and ORIENT) evaluating the renoprotective effects of olmesartan medoxomil (OM) in patients with type 2 diabetes suggested OM is associated with increased cardiovascular mortality. We conducted a thorough QTc study to evaluate the effects of OM on cardiac repolarization. A randomized, double-blind, phase 1 study was conducted per E14 Guidance to assess the effects of single doses of OM therapeutic dose (40 mg), OM supratherapeutic dose (160 mg), placebo, or moxifloxacin (MOXI; 400 mg) on QTc in 56 healthy subjects. The primary endpoint was the baseline-adjusted, placebo-corrected QTc interval using Fridericia's formula (ΔΔQTcF) for OM and MOXI. Assay sensitivity was concluded if lower limit of 1-sided 95%CI > 5 milliseconds of ΔΔQTcF for MOXI. No threshold pharmacologic effect for OM was concluded if upper limit of 1-sided 95%CI <10 milliseconds for ΔΔQTcF at any timepoint. Pharmacokinetics, ECGs, and safety were assessed. Assay sensitivity was demonstrated. The largest upper limit of the 1-sided 95%CI for ΔΔQTcF was <5 milliseconds for OM. No clinically significant changes were observed in ECGs. Pharmacokinetics and safety profile were consistent with previous data. Therapeutic and supratherapeutic OM doses had no clinically significant effect on cardiac repolarization and were well tolerated.