Caly et al. 1 reported that ivermectin inhibited severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) in vitro for up to 48 hours using ivermectin at 5 μM. The concentration resulting in 50% inhibition (IC 50 ; 2 µM) was > 35× higher than the maximum plasma concentration (C max ) after oral administration of the approved dose of ivermectin when given fasted. Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total C max was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung C max after administration of each single dose. Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC 50 , even for a dose level 10× higher than the approved dose. Even with the high lung:plasma ratio, ivermectin is unlikely to reach the IC 50 in the lungs after single oral administration of the approved dose (predicted lung: 0.0873 µM) or at doses 10× higher that the approved dose administered orally (predicted lung: 0.820 µM). In summary, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Repurposing drugs for use in coronavirus disease 2019 (COVID-19) treatment is an ideal strategy but is only feasible when product safety has been established and experiments of repurposed drugs are conducted at clinically relevant concentrations.

The clinical effects of remimazolam (an investigational, ultra-short acting benzodiazepine being studied in procedural sedation) were measured using the modified observer's alertness-sedation scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic (PopPK-PD) model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical Phase 1-3 trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA/S-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic Emax model. Simulations were performed to identify the optimal remimazolam-fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with BMI > 25 kg/m 2 had 30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 g.The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 g is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.

Belumosudil is a selective Rho‐associated coiled‐coil containing protein kinase 2 inhibitor. A capsule formulation was used during early clinical development of belumosudil; it was later replaced by a tablet formulation, which mimicked the capsule's release properties and facilitated manufacturing scalability. To assess belumosudil's pharmacokinetics, including potential food effects, and evaluate the relative bioavailability of the 2 formulations, 2 phase 1 clinical trials were conducted. Administration of both belumosudil tablets and capsules with food increased exposure ≈2× as compared to the fasted state and delayed time to maximum concentration by 0.5 hour, indicating a decrease in the rate but increase in the extent of absorption with fed administration. Relative bioavailability was slightly higher when belumosudil was administered as tablets vs capsules, although the difference was not clinically meaningful. Safety and tolerability were generally consistent with the known safety profile of belumosudil. The results of these studies support administration of belumosudil with food.

Background The delta opioid receptor (DOR) has been identified as a therapeutic target for migraine, with DOR agonists exhibiting low abuse potential compared with conventional µ-opioid agonists. TRV250 is a novel small molecule agonist of the DOR that is preferentially selective for G-protein signaling, with relatively little activation of the β-arrestin2 post-receptor signaling pathway. This selectivity provides reduced susceptibility to proconvulsant activity seen with non-selective DOR agonists. TRV250 significantly reduced nitroglycerin-evoked hyperalgesia in rodents, indicating a potential utility in acute migraine without the risk of seizure activity or abuse potential. Objective This trial evaluated the safety, tolerability, and pharmacokinetics of ascending dose levels of TRV250 administered subcutaneously (SC) and the relative bioavailability of TRV250 administered orally compared with SC administration. Methods This was a two-part, single ascending dose study. Part A included four cohorts of healthy adults (N = 38). Each cohort was dosed on three occasions (placebo and two different dose levels of TRV250, allocated in randomized order and administered by SC route). In Part B, a single cohort of nine subjects received an oral dose of either TRV250 (n = 7) or placebo (n = 2) in a fed or fasted state. Serial blood samples were obtained for pharmacokinetic determination across a 24-h post-dose period. Safety assessments included clinical laboratory measures, vital signs, 12-lead electrocardiogram (ECG), and electroencephalogram (EEG) pre-and post-dosing. Results TRV250 was well tolerated. There were no serious adverse events (SAEs), and all AEs were mild in severity. Injection-site reactions and headache were the most common AEs. One subject was withdrawn from the study due to a TRV250-related AE of postural orthostatic tachycardia. There were no clinically relevant changes in physical examination, hematology, clinical chemistry, urinalysis, suicidal ideation, or vital signs, with the exception of orthostatic changes in some subjects. No subject experienced abnormalities in EEGs or experienced a change from baseline in heart-rate-corrected QT interval (QTcF) > 60 ms, or an absolute QTcF interval > 480 ms at any post-dosing observation. Peak and total plasma exposure to TRV250 increased in a dose-proportional manner following 0.1-30 mg SC doses, with the mean half-life ranging from 2.39 to 3.76 h. Oral bioavailability of TRV250 ranged from 14% (fasting) to 19% (fed) relative to SC dosing, while administration with food increased the AUC but decreased the rate of absorption as reflected by a modest delay in median time to maximum concentration and a slight reduction in maximum concentration. Conclusion The findings from the first-inhuman study support further evaluation of TRV250, a G-protein selective DOR agonist, in the treatment of acute migraine.

Belumosudil is a selective Rho‐associated coiled‐coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 has been shown to drive proinflammatory response and fibrosis that occurs with chronic graft‐versus‐host disease; therefore, inhibition of ROCK2 has emerged as a therapeutic target for chronic graft‐versus‐host disease. In this phase 1 two‐part study, the pharmacokinetics, mass balance, and metabolic profile of belumosudil were evaluated after single doses of unlabeled belumosudil oral tablets (200 mg), radiolabeled belumosudil intravenous (IV) microtracer infusions (100 μg), and radiolabeled oral capsules (200 mg). Absolute bioavailability based on area under the plasma concentration–time curve from time 0 to infinity for the oral dose/area under the plasma concentration–time curve from time 0 to infinity for the IV dose was calculated as 63.7%. Radiolabeled IV microtracer dosing demonstrated a low extraction ratio and distribution of belumosudil into tissues. The majority of total radioactivity was recovered in feces, with minimal amounts recovered in urine, suggesting minimal renal elimination of belumosudil. In addition to parent and main metabolite KD025m2, metabolites identified in plasma included the phase 2 metabolites O‐dealkylated belumosudil sulfate and belumosudil glucuronide. These metabolites (with the exception of the glucuronide) in addition to monohydroxy‐belumosudil, and belumosudil diol were identified in feces. No metabolites in urine accounted for >10% of the radioactive dose.