Lack of ethnic differences of moxifloxacin and metabolite pharmacokinetics in East Asian men

Abstract

This study was designed to investigate ethnic differences in the pharmacokinetics (PKs) of moxifloxacin and its metabolites, M1 (sulfo conjugate) and M2 (acyl-glucuronate), among Japanese, Chinese, and Korean populations, following oral administration. We used a population PK modeling approach using data from a clinical study involving 79 healthy male volunteers. A comprehensive population PK model considering the PK mechanism of moxifloxacin and its metabolites was newly built. The structures of the final model were two-compartment for moxifloxacin and one-compartment for M1 and M2, with first-order absorption with lag time for all three compounds. The formation of M1 and M2 from moxifloxacin via a first-pass effect and subsequent metabolic clearance in the system were also modeled. Lean body mass on the central volume of distribution (V ) and estimated glomerular filtration rate on renal clearance (CL ) were identified as covariates of PKs of moxifloxacin. Additionally, bioavailability was slightly higher in Koreans, whereas CL , non-renal clearance (CL ), and V were slightly lower. Regarding M1 and M2, body surface area on CL of M2 and UGT1A1*6 on F of M2 were modeled. Korean ethnicity was observed to influence CL of M2, F of M2, and the metabolic clearance of moxifloxacin to M2. However, the exposure levels of moxifloxacin, M1, and M2 in Koreans were comparable to those in Japanese and Chinese because the effects of Korean ethnicity on some PK parameters were counterbalanced. These results suggest that PKs for moxifloxacin and its metabolites among East Asian populations are essentially similar.

Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling

“…10,47 However, we did find that MRP2 transports the moxifloxacin-glucuronide (M2). Based on this, we hypothesized, in agreement with Kaneko et al, 45 that not moxifloxacin itself, but moxifloxacin-glucuronide is transported from the liver to the intestines. This is followed by rapid hydrolysis by gut bacteria, resulting in the excretion of moxifloxacin in the feces, 45,46 similar to bilirubin deconjugation.…”

“…Based on this, we hypothesized, in agreement with Kaneko et al, 45 that not moxifloxacin itself, but moxifloxacin-glucuronide is transported from the liver to the intestines. This is followed by rapid hydrolysis by gut bacteria, resulting in the excretion of moxifloxacin in the feces, 45,46 similar to bilirubin deconjugation. 48 This theory is supported by the observation that moxifloxacin-glucuronide is excreted in the bile of rat liver perfusions.…”

“…Furthermore, sensitivity analyses of P-gp activity in our PBPK model showed hardly any influence on the elimination of moxifloxacin (AUC ratio with and without P-gp, 0.91). In accordance with Kaneko et al, 45 we suggest that biliary excretion of moxifloxacin through P-gp-mediated transport is only minor. In addition, we hypothesize that M2 is actively transported into the bile via MRP2, but will be hydrolyzed in the intestinal lumen back to moxifloxacin via gut bacterial proteases.…”

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

“…22 Moxifloxacin is mainly metabolized to glucuronide and sulfate conjugates. Exposure to the metabolites was shown to be lower, 52 while apparent half-lives were similar to that of moxifloxacin, 53 which makes the metabolites an unlikely cause of such delay in returning to baseline.…”

Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia

“…We searched the reports on race difference of PK parameters of quinolones. Results showed that the PK of levofloxacin, moxifloxacin and ciprofloxacin do not show race difference (Fish & Chow, 1997;North et al, 1998;Hasunuma et al, 2016;Kaneko et al, 2018;Tolentino-Hernandez et al, 2020). For each drug, the PK parameters in various races get close to each other after correction by weight (Fish & Chow, 1997;Kaneko et al, 2018;Tolentino-Hernandez et al, 2020).…”