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. 2020 Sep;127(3):221-233.
doi: 10.1111/bcpt.13409. Epub 2020 Apr 20.

Absorption, distribution, metabolism and excretion of molidustat in healthy participants

Silvia Lentini  1 , Dorina van der Mey  1 , Armin Kern  2 , Uwe Thuss  2 , Andreas Kaiser  3 , Kumi Matsuno  4 , Michael Gerisch  2
Affiliations

Absorption, distribution, metabolism and excretion of molidustat in healthy participants

Silvia Lentini et al. Basic Clin Pharmacol Toxicol. 2020 Sep.

Abstract

The absorption, distribution, metabolism and excretion of molidustat were investigated in healthy male participants. In study 1, a mass balance study, radiolabelled molidustat 25 mg (3.57 MBq) was administered as an oral solution (n = 4). Following rapid absorption, molidustat-related radioactivity was predominantly distributed in plasma rather than in red blood cells. The total recovery of the administered radioactivity was 97.0%, which was mainly excreted renally (90.7%). Metabolite M-1, produced by N-glucuronidation, was the dominant component in plasma (80.2% of the area under the concentration-time curve for total radioactivity) and was primarily excreted via urine (~85% of dose). Only minor amounts of unchanged molidustat were excreted in urine (~4%) and faeces (~6%). Study 2 investigated the absolute bioavailability and pharmacodynamics of molidustat (part 1, n = 12; part 2, n = 16). Orally administered molidustat immediate release tablets had an absolute bioavailability of 59%. Following intravenous administration (1, 5 and 25 mg), total body clearance of molidustat was 28.7-34.5 L/h and volume of distribution at steady state was 39.3-50.0 L. All doses of molidustat transiently elevated endogenous erythropoietin levels, irrespective of the route of administration. Molidustat was considered safe and well tolerated at the administered doses.

Keywords: ADME (absorption; biotransformation; disposition; erythropoietin; excretion); metabolism.

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Conflict of interest statement

Silvia Lentini, Dorina van der Mey, Armin Kern, Uwe Thuss, Andreas Kaiser and Michael Gerisch are employed by Bayer AG. Kumi Matsuno is employed by Bayer Yakuhin Ltd. Dorina van der Mey and Michael Gerisch have stock options for Bayer AG, which are unrelated to primary employment. Medical writing support was provided by Cerys Evans, PhD, of Oxford PharmaGenesis, Oxford, UK, and was funded by Bayer Yakuhin Ltd.

Figures

Figure 1
Figure 1
Concentrations of molidustat in plasma (µg/L) and of radioactivity in plasma and blood (µgEq/L) following a single oral dose of [14C]molidustat 25 mg (geometric mean/SD, semi‐logarithmic scale, n = 4). LLOQ, lower limit of quantification; SD, standard deviation
Figure 2
Figure 2
Arithmetic mean cumulative amounts of [14C]molidustat‐associated radioactivity (%) excreted in urine and faeces following a single oral dose of [14C]molidustat 25 mg (n = 4)
Figure 3
Figure 3
Proposed biotransformation pathway of molidustat. aPosition of 14C label
Figure 4
Figure 4
Plasma concentration‐time profiles of molidustat (A) and M‐1 (B) following a single molidustat 25 mg iv infusion over 30 min and a single oral dose of molidustat 50 mg, up to 48 h after each dose (geometric mean/SD, [part 2 of study 2], n = 16, semi‐logarithmic scale). iv, intravenous; LLOQ, lower limit of quantification; SD, standard deviation; tab, tablet
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