Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo

Abstract

Delamanid, a new anti-tuberculosis drug, is metabolized to M1, a unique metabolite formed by cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety, in plasma albumin in vitro. The metabolic activities in dogs and humans are higher than those in rodents. In this study, we characterized the pharmacokinetics and metabolism of delamanid in animals and humans. Eight metabolites (M1-M8) produced by cleavage of the imidazooxazole moiety of delamanid were identified in the plasma after repeated oral administration by liquid chromatography-mass spectrometry analysis. Delamanid was initially catalyzed to M1 and subsequently metabolized by three separate pathways, which suggested that M1 is a crucial starting point. The major pathway in humans was hydroxylation of the oxazole moiety of M1 to form M2 and then successive oxidation to the ketone form (M3) mainly by CYP3A4. M1 had the highest exposure among the eight metabolites after repeated oral dosing in humans, which indicated that M1 was the major metabolite. The overall metabolism of delamanid was qualitatively similar across nonclinical species and humans but was quantitatively different among the species. After repeated administration, the metabolites had much higher concentrations in dogs and humans than in rodents. The in vitro metabolic activity of albumin on delamanid probably caused the species differences observed. We determined that albumin metabolism is a key component of the pharmacokinetics and metabolism of delamanid. Nonhepatic formation of M1 and multiple separate pathways for metabolism of M1 suggest that clinically significant drug-drug interactions with delamanid and M1 are limited.

Metabolic Mechanism of Delamanid, a New Anti-Tuberculosis Drug, in Human Plasma

“…However, quantitative differences were observed among species (Sasahara et al, 2015). For instance, M1 concentration after repeated administration was much higher in a human and dog than in rodents, consistent with the more rapid formation of M1 in human and dog plasma in vitro ( Fig.…”

“…When delamanid was incubated with liver microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate, metabolites were nearly undetectable in the incubation mixture, suggesting that delamanid was not metabolized by cytochrome P450 enzymes. However, eight metabolites, including the abundant metabolite (R)-2-amino-4,5-dihydrooxazole derivative ], in human and animal plasma were detected and identified in the investigation for the in vivo pharmacokinetics and metabolism of delamanid, as described in the companion article (Sasahara et al, 2015) in this issue of Drug Metabolism and Disposition. The maximum plasma concentration of M1 was nearly half that of delamanid (0.32 mM versus 0.78 mM) following twice daily administration of 100 mg delamanid for 56 days (Gler et al, 2012;Shimokawa et al, 2014;Sasahara et al, 2015), suggesting that M1 is the major metabolite.…”

“…However, eight metabolites, including the abundant metabolite (R)-2-amino-4,5-dihydrooxazole derivative ], in human and animal plasma were detected and identified in the investigation for the in vivo pharmacokinetics and metabolism of delamanid, as described in the companion article (Sasahara et al, 2015) in this issue of Drug Metabolism and Disposition. The maximum plasma concentration of M1 was nearly half that of delamanid (0.32 mM versus 0.78 mM) following twice daily administration of 100 mg delamanid for 56 days (Gler et al, 2012;Shimokawa et al, 2014;Sasahara et al, 2015), suggesting that M1 is the major metabolite. On the basis of the chemical structure of M1, it is proposed that delamanid is cleaved directly at its 6-nitro-2,3-dihydroimidazo(2,1-b)oxazole moiety by some extrahepatic mechanism (Matsumoto et al, 2006).…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…371 Spontaneous mutations conferring resistance to delamanid are relatively frequent, occurring in approximately one in 100 000 to 1 000 000 bacilli. 369,[372][373][374] In human beings, delamanid is highly protein bound (>99·5%), is metabolised by albumin, 375 has a half-life of 34 h, and its DM-6705 metabolite has a half-life of more than 150 h. 375 Delamanid has low oral bioavailability, so it has to be given with food, and dosing must be separated in time from dosing of other medications. Co-administration with ritonavirboosted protease inhibitors or efavirenz does not markedly affect delamanid exposure.…”

Antitubercular Agent Delamanid and Metabolites as Substrates and Inhibitors of ABC and Solute Carrier Transporters

“…When delamanid is orally administered to humans and animals, at least four metabolites are detected in plasma: the primary (R)-2-amino-4,5-dihydrooxazole derivative, metabolite 1 (M1; DM-6705); its subsequent oxidative metabolites, the (4RS,5S)-2-amino-4,5-dihydro-4-hydroxyoxazole derivative [metabolite 2 (M2); (4RS,5S)-DM-6720] and the (S)-2-imino-oxazolidin-4-one derivative [metabolite 3 (M3); (S)-DM-6718]; and its hydrolysis metabolite, the (R)-4,5-dihydro-2-oxooxazole derivative (metabolite 4 [M4]; DM-6704) ( Fig. 1) (22). Delamanid is not metabolized by NADPH-dependent reactions, including those catalyzed by CYP enzymes, in human or animal liver microsomes (4).…”