Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites.

Icenticaftor (QBW251) is a potentiator of the CFTR protein and is currently in clinical development for the treatment of chronic obstructive pulmonary disease and chronic bronchitis. An absorption, distribution, metabolism, and excretion (ADME) study was performed at steady state to determine the pharmacokinetics, mass balance, and metabolite profiles of icenticaftor in humans. In this open-label study, six healthy men were treated with unlabeled oral icenticaftor (400 mg b.i.d.) for 4 days. A single oral dose of [14C]icenticaftor was administered on Day 5, and unlabeled icenticaftor was administered b.i.d. from the evening of Day 5 to Day 12. Unchanged icenticaftor accounted for 18.5% of plasma radioactivity. Moderate to rapid absorption of icenticaftor was observed (median Tmax: 4 hours), with 93.4% of the dose absorbed. It exhibited moderate distribution (Vz/F: 335 L) and was extensively metabolized, principally through N-glucuronidation, O-glucuronidation, and/or O-demethylation. The metabolites M8 and M9, formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively, represented the main entities detected in plasma (35.3% and 14.5%, respectively) in addition to unchanged icenticaftor (18.5%). The apparent mean T1/2 of icenticaftor was 15.4 hours in blood and 20.6 hours in plasma. Icenticaftor was eliminated from the body mainly through metabolism followed by renal excretion, and excretion of radioactivity was complete after 9 days. In vitro phenotyping of icenticaftor showed that cytochrome P450 and uridine diphosphate glucuronosyltransferase were responsible for 31% and 69% of the total icenticaftor metabolism in human liver microsomes, respectively. This study provided invaluable insights into the disposition of icenticaftor. Significance Statement The ADME of a single radioactive oral dose of icenticaftor was evaluated at steady state to investigate the nonlinear pharmacokinetics observed previously with icenticaftor. [14C]Icenticaftor demonstrated good systemic availability after oral administration and was extensively metabolized and moderately distributed to peripheral tissues. The most abundant metabolites, M8 and M9, were formed by N-glucuronidation and O-glucuronidation of icenticaftor, respectively. Phenotyping demonstrated that [14C]icenticaftor was metabolized predominantly by UGT1A9 with a remarkably low Km value.

Drug-Drug Interaction Studies to Evaluate the Effect of Inhibition of UGT1A1 and CYP3A4 and Induction of CYP3A4 on the Pharmacokinetics of Tropifexor in Healthy Subjects.

Tropifexor, a farnesoid X receptor agonist, is currently under clinical development for the treatment of nonalcoholic steatohepatitis. Tropifexor undergoes glucuronidation by uridine 5'-diphosphoglucuronosyltransferase (UGT) 1A1 and oxidation by cytochrome P450 (CYP) 3A4, as reported in in vitro studies. Here, we report the results from 2 drug-drug interaction studies. Study 1 enrolled 20 healthy subjects to investigate the effect of the UGT1A1 inhibitor atazanavir (ATZ) on tropifexor pharmacokinetics (PK). Study 2 had 2 cohorts with 16 healthy subjects each to investigate the effect of the strong CYP3A4 inhibitor itraconazole and strong CYP3A4 inducer rifampin on the PK of tropifexor. Coadministration of ATZ reduced the maximum plasma concentration (Cmax ) of tropifexor by 40%; however, it did not lead to increased exposure of tropifexor (both area under the plasma concentration-time curve [AUC] from time 0 to the last quantifiable concentration [AUClast ] and AUC from time 0 to infinity [AUCinf ] reduced by only 10%), suggesting minor relevance of the UGT1A1 pathway for clearance of tropifexor and no expected drug-drug interactions based on UGT1A1 inhibition. Inhibition of CYP3A4 by itraconazole increased the Cmax of tropifexor by only 9% and exposure (both AUClast and AUCinf ) by 47%, suggesting a weak effect of strong CYP3A4 inhibitors on tropifexor PK. Inducing CYP3A4 with rifampin decreased Cmax (55%) and AUC (AUClast by 79% and AUCinf by 77%). Coadministration of tropifexor with either ATZ, itraconazole, or rifampin was well tolerated.

Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment.

Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200-µg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf,u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf,u , 1.64 [90%CI, 1.25-2.16]; Cmax,u , 1.30 [90%CI, 0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf,u (1.61 [90%CI, 1.04-2.49]) and comparable Cmax,u (1.02 [90%CI, 0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment.