Characterisation of the absorption, distribution, metabolism, excretion and mass balance of doravirine, a non-nucleoside reverse transcriptase inhibitor in humans

Abstract

Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [C]doravirine (350 mg, ∼200 µCi) trial (n = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (n = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials. Following oral [C]doravirine administration, all of the administered dose was recovered. The absorbed dose was eliminated primarily via metabolism. An oxidative metabolite (M9) was the predominant metabolite in excreta and was the primary circulating metabolite (12.9% of circulating radioactivity). Following IV administration, doravirine clearance and volume of distribution were 3.73 L/h (95% confidence intervals (CI) 3.09, 4.49) and 60.5 L (95% CI 53.7, 68.4), respectively. In vitro, doravirine is not highly bound to plasma proteins (unbound fraction 0.24) and has good passive permeability. The metabolite M9 was generated by cytochrome P450 3A (CYP3A)4/5-mediated oxidation. Doravirine was a P-gp substrate but P-gp efflux is not expected to play a significant role in limiting doravirine absorption or to be involved in the elimination of doravirine. In conclusion, doravirine is a low clearance drug, primarily eliminated by CYP3A-mediated metabolism.

A Study to Evaluate Doravirine Pharmacokinetics When Coadministered With Acid‐Reducing Agents

“…8 In the current trial, a lack of clinically meaningful effects on doravirine PK was anticipated based on doravirine's pH-independent aqueous solubility and high permeability. 19 In addition, the chemical structure of doravirine 20 does not contain the chelating motifs that render HIV integrase strand transferase inhibitors susceptible to divalent cation binding by cations present in antacid salts, with a subsequent loss of bioavailability. 21,22 Along with the data from the current trial, these properties support that doravirine is unlikely to interact with acid-reducing agents or cationcontaining antacids.…”

Evaluation of the Pharmacokinetic Interaction Between Doravirine and Methadone

“…[14][15][16][17] In the United States, doravirine is indicated for administration once daily at a dose of 100 mg, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. 25 In vitro studies and clinical drug interaction studies indicated that CYP3A-mediated metabolism is a major contributor to the elimination of doravirine. 22,23 The rapid absorption of doravirine has been shown to result in a median time to maximum concentration (t max ) of 1 to 4 hours and a half-life of 12 to 19 hours for single oral doses of 6 to 1200 mg, 23 and a geometric mean maximum plasma concentration (C max ) of 2.26 μM was achieved at steady state following once-daily dosing.…”

“…25 In vitro studies and clinical drug interaction studies indicated that CYP3A-mediated metabolism is a major contributor to the elimination of doravirine. 25 Based on metabolism and elimination pathways, methadone and doravirine are not expected to demonstrate any meaningful DDIs upon coadministration. The oxidative metabolite M9 was the major metabolite of doravirine observed both in vitro in preparations from human liver and in vivo in human excreta and plasma.…”

“…24 Low clearance (3.73 L/hr) and a moderate volume of distribution (60.5 L) were observed following intravenous administration of doravirine. 25 In vitro studies and clinical drug interaction studies indicated that CYP3A-mediated metabolism is a major contributor to the elimination of doravirine. 20,22,[26][27][28] Consistent with this finding, the majority of an absorbed oral dose of [ 14 C]-labeled doravirine in healthy subjects was recovered as oxidative metabolites.…”

“…The oxidative metabolite M9 was the major metabolite of doravirine observed both in vitro in preparations from human liver and in vivo in human excreta and plasma. 25 Renal excretion is a minor route of elimination of doravirine in humans and excretion in urine accounts for ß6% of an oral dose. 23 Doravirine was also found to be a substrate of P-glycoprotein, but it was deemed unlikely that P-glycoprotein plays a significant role in doravirine absorption.…”