Pirmenol Hydrochloride Hydrate

Drug-induced long QT syndrome (diLQTS) is a rare but serious adverse drug reaction. Drug-drug interaction (DDI) is one of the risk factors for the development of diLQTS. However, the combinations of drugs that increase the risk of diLQTS have not been extensively investigated. This study was performed to analyse the potential DDIs that elevate the incidence of diLQTS using a spontaneous reporting system.

The Japanese Adverse Drug Event Report database from April 2004 to January 2020 was used to assess adverse event reports. We calculated the reporting odds ratio and 95% confidence interval for signal detection.

Signals for concomitant use risk were detected in 31 drug combinations. Combinations of antipsychotics and antidepressants were the most common (olanzapine & fluvoxamine, olanzapine & trazodone, quetiapine & paroxetine, sulpiride & fluvoxamine, sulpiride & trazodone). Sixteen, 17 and 21 combinations were designated as requiring precaution for concomitant use in at least one of the package inserts in Japan, the United States and the United Kingdom, respectively, although no such precautions were described for the remaining combinations. On the contrary, a combination of bepridil & clarithromycin was categorized as "X (avoid combination)" and two combinations (chlorpromazine & haloperidol, amiodarone & metildigoxin) were classified as "D (modify regimen)" in the Lexicomp^® risk rating.

This study identified 31 combinations of drugs that may elevate the risk of diLQTS. The use of these drug combinations should be monitored more carefully in future.

The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (R_u) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature. The fraction excreted unchanged into urine (f_e) was calculated for healthy subjects by dividing the R_u value by the total recovery rate. The contribution of renal excretion to total clearance from the systemic circulation (R_ren) was estimated by subjecting oral clearance and creatinine clearance to regression in subjects with normal and impaired renal function. BA was estimated as f_e/R_ren and compared with the observed BA (BA_obs). The predicted BA values for 9 drugs fell within ±20% of their BA_obs. The examined approach makes it possible to estimate BA values for drugs with mean renal excretion values in healthy subjects and oral clearance in subjects with various renal function, without intravenous pharmacokinetic data.