Microdosing studies using accelerated mass spectrometry as exploratory investigational new drug trials

Abstract

Innovative attempts have been made to overcome nonproductivity and high expenditure in the clinical stages of new drug development. Microdosing studies using subpharmacological doses provide early insight into the body's disposition toward candidate compounds, and are innovative exploratory trials that can promote productivity in drug development. Highly sensitive analytical technology is crucial in microdosing studies that employ qualitative and quantitative assays of target materials in humans. Accelerator mass spectrometry (AMS) has facilitated the adoption of a human microdosing study in the early phase of clinical drug development. Results derived from AMS microdosing studies using labeled compounds can provide various types of information for candidate selection, including pharmacokinetic characteristics and metabolic profiles of candidate compounds. The applicability of microdosing studies is currently expanding into absolute bioavailability and mass balance studies. Although it remains uncertain whether microdosing adequately predicts the pharmacokinetics of therapeutic doses, further development of microdosing studies using AMS may benefit the field of new drug development and could pose a new challenge to researchers. The use of advanced technology in candidate selection will contribute to improved productivity and competitiveness in pharmaceutical research and development. The introduction of microdosing studies using AMS in Korea will present a newly applicable method for innovative clinical trials and contribute to development potential in global competition.

High‐sensitive LC‐MS/MS method for the simultaneous determination of mirodenafil and its major metabolite, SK‐3541, in human plasma: Application to microdose clinical trials of mirodenafil

“…For the mirodenafil and SK-3541 microdosing analysis (clinical dosing analysis), stock solutions were serially diluted with methanol and added to drug-free plasma to obtain final concentrations of 2, 5, 10, 20, 50, 200, and 500 pg/mL of both mirodenafil and SK-3541 (2,5,10,20,50,200, and 500 ng/mL of both mirodenafil and SK-3541 for clinical dosing). The udenafil stock solution was diluted further to 1 ng/mL (10 ng/mL for clinical dosing) in methanol for routine use as an internal standard (IS).…”

“…The intraday precision and accuracy were determined by analyzing six replicates of the LLOQ sample and three different QC samples (2,8,100, and 400 pg/mL for microdosing and 2, 8, 100, and 400 ng/mL for clinical dosing) on the same day. The interday precision and accuracy were also evaluated by analyzing ten replicates of the LLOQ sample and three different QC samples (2,8,100, and 400 pg/mL for microdosing and 2, 8, 100, and 400 ng/mL for clinical dosing) on five different days (two replicates per day).…”

“…The interday precision and accuracy were also evaluated by analyzing ten replicates of the LLOQ sample and three different QC samples (2,8,100, and 400 pg/mL for microdosing and 2, 8, 100, and 400 ng/mL for clinical dosing) on five different days (two replicates per day). The precision was expressed as the relative standard deviation (RSD,%) and the accuracy was expressed as:…”

“…The intra and interday precision and accuracy of the method were measured by assaying the LLOQ and three different QC samples (2,8,100, and 400 pg/mL for microdosing and 2, 8, 100, and 400 ng/mL for clinical dosing) on five different days and are summarized in Table 1. Both the precision and accuracy were well within the 15% acceptance range and at the LLOQ level within precisions of 20% and accuracies of 80-120%.…”

“…Drug concentration measurements using AMS and positron emission tomography require the synthesis of radiolabeled drugs, such as 14 C or 11 C, which can be costly and time consuming. Furthermore, AMS involves time-consuming sample processing and high operating costs [2][3][4].…”