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HepQuant tests quantify liver function from clearance of deuterium- and 13C-labeled cholates administered either intravenously and orally (SHUNT) or orally (DuO). Hepatic impairment studies have relied on clinical or laboratory criteria like Child-Pugh classification to categorize the degree of hepatic dysfunction. We compared HepQuant tests with Child-Pugh classification in predicting the pharmacokinetics of ampreloxetine. Twenty-one subjects with hepatic impairment (8 Child-Pugh A, 7 Child-Pugh B, and 6 Child-Pugh C), and 10 age- and sex-matched controls were studied. The pharmacokinetics of ampreloxetine were measured after oral administration of a single dose of 10 mg. Disease severity index (DSI), portal-systemic shunting (SHUNT%), hepatic reserve, and hepatic filtration rates (HFRs) were measured from serum samples obtained after intravenous administration of [24- 13 C]-cholate and oral administration of [2,2,4,4- 2 H]cholate. Ampreloxetine plasma exposure (AUC 0-inf ) was similar to controls in Child-Pugh A, increased 1.7-fold in subjects with Child-Pugh B, and 2.5-fold in subjects with Child-Pugh C and correlated with both Child-Pugh score and HepQuant parameters. The variability observed in ampreloxetine exposure (AUC 0-inf ) in subjects with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) was explained by HepQuant parameters. Multivariable regression models demonstrated that DSI, SHUNT%, and Hepatic Reserve from SHUNT and DuO were superior predictors of ampreloxetine exposure (AUC 0-inf ) compared to Child-Pugh score. HepQuant DSI, SHUNT%, and hepatic reserve were more useful predictors of drug exposure than Child-Pugh class for ampreloxetine and thus may better optimize dose recommendations in patients with liver disease. The simple-to-administer, oral-only DuO version of the HepQuant test could enhance clinical utility., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Baloxavir marboxil, the prodrug of baloxavir acid, is an anti-influenza antiviral. Here, a pharmacokinetics-time to alleviation of symptoms (PK-TTAS) model was developed and used to (I) characterize the PK-TTAS relationship, (II) quantify the impact of covariates, and (III) predict TTAS in different ethnic groups. Data from 1781 otherwise-healthy (OwH) or high-risk (HR) patients included in phase II (JapicCTI-153090) and III studies (NCT02954354 and NCT02949011) were used; patients received either placebo or oral baloxavir marboxil. The natural distribution of TTAS in placebo-treated patients was modeled, then TTAS data from the baloxavir marboxil arms were added to model the impact of baloxavir acid concentration on TTAS. PK parameters estimated by a population PK model and informed by phase I data (NCT03959332 and KCT0003535) were included to simulate TTAS in Chinese and South Korean patients. Composite symptom score at baseline (TSS0), ethnicity, sex, and patient type (OwH or HR) significantly impacted the natural TTAS distribution. TTAS reduced with increasing baloxavir acid concentrations. Compared with placebo, high and low baloxavir acid exposures (AUC 0-inf 5.13-16.65 and 0.72-5.13 μg.hr/mL, respectively) significantly reduced TTAS; no covariates affected the drug effect on TTAS. Simulated TTAS was similar between OwH or HR Chinese, South Korean, and other Asian patients, with median reductions from placebo between 18.3-18.8 hours and 21.2-22.0 hours in OwH and HR patients, respectively, assuming TSS0 > 10. Ethnicity (Asian vs. non-Asian) did not significantly impact the drug effect on TTAS; predicted TTAS was similar across different Asian populations. This suggests Chinese and South Korean patients may benefit from similar efficacy as other Asian patients., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

For patients requiring long-term anticoagulation, oral vitamin K antagonists (VKAs) such as warfarin have overwhelming efficacy data and present significant challenges. In addition to the potential exposure to numerous drug-drug and drug-food interactions, patients receiving warfarin require frequent monitoring. It had been hoped that the integration of pharmacogenomic with clinical information would improve anticoagulation control with warfarin, but trials have not supported this aim. Novel oral anticoagulants (NOACs) offer both advantages and disadvantages and deserve consideration in appropriate patients.

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

Background and Objective: There is a clinical need for new oral anticoagulants to prevent and treat thromboembolic diseases. Given its integral role in the coagulation cascade, factor Xa is a particularly promising target for new anticoagulation therapies. The aim of this study was to investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 59--7939, an oral, direct factor Xa inhibitor., Methods: This single-center, randomized, single-blinded, placebo-controlled, dose-escalation study included 108 healthy white male subjects aged 19 to 45 years. Subjects received single oral doses of either BAY 59--7939 (1.25--80 mg) or placebo; in addition, 1 group received 2 doses of BAY 59--7939 (5--mg tablet and oral solution) or placebo in a crossover design., Results: Oral BAY 59--7939 in single doses up to 80 mg was safe and well tolerated and was not associated with an increased risk of bleeding compared with placebo. Pharmacodynamic effects (inhibition of factor Xa activity, prothrombin time, activated partial thromboplastin time, and Hep Test) and plasma concentration profiles were dose-dependent. Maximum inhibition of factor Xa activity was achieved 1 to 4 hours after administration of BAY 59--7939 and ranged from 20% to 61% for the 5- to 80-mg doses. BAY 59--7939 selectively inhibited factor Xa activity; thrombin (factor IIa) and antithrombin were unaffected. Inhibition of factor Xa activity and prolongation of prothrombin time correlated well with BAY 59--7939 plasma concentrations (r=0.949 and 0.935, respectively)., Conclusions: BAY 59--7939 was well tolerated with predictable pharmacodynamics and pharmacokinetics across a wide range of doses in healthy male subjects. BAY 59--7939 was shown to be an effective and specific factor Xa inhibitor.

Background: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated., Methods: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen., Results: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P <.010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P <.010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P <.010)., Conclusions: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.

Objective: The effect of reboxetine on electrocardiographic parameters, particularly the QTc interval, was assessed in 20 healthy subjects (15 male, 5 female)., Methods: In a 5-way crossover study, subjects received placebo, 2 mg, 4 mg, or 6 mg reboxetine, or 6 mg reboxetine and 200 mg ketoconazole twice daily for 7 days. Plasma samples, vital signs, and 12-lead electrocardiograms (ECGs) were obtained during one dosing interval of days 1, 4, and 7. Additional ECGs were recorded immediately after an exercise paradigm, so that the RR versus QT relationship might be used in calculating QTc. Plasma concentrations of R,R (-)reboxetine and the more active S,S (+)reboxetine were measured by HPLC-dual mass spectrometry., Results: No statistically significant differences among treatments in mean dose-corrected pharmacokinetic parameters were observed, except that the dose-corrected area under the concentration-time curve from time zero to 12 hours and the peak plasma concentration were significantly increased on days 4 and 7 in the presence of ketoconazole. As expected, heart rate increased from baseline (approximately 8-11 beats/min) at > or =8 mg reboxetine daily. No statistically significant prolongation of QTc (Fridericia correction) occurred after any of the treatments. No relationships between DeltaQTc and plasma concentrations of reboxetine enantiomers were apparent. Similar results were obtained with Bazett's correction and two linear corrections that relied on exercise data generated before drug administration., Conclusions: Reboxetine, at systemic exposures approximately twice the recommended dose, did not significantly affect cardiac repolarization in healthy subjects. Use of QT versus RR relationship in the drug-free state to correct QT for heart rate in the drug-treated state may provide an acceptable alternative to classic correction equations.

Background: Moclobemide, an antidepressant with selective monoamine oxidase-A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study., Methods: The effect of omeprazole on the pharmacokinetics of moclobemide was studied in 16 healthy volunteers. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study II, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration., Results: The inhibition of moclobemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor metabolizers, no remarkable changes in the pharmacokinetic parameters were observed., Conclusion: Our results show that CYP2C19 is an important enzyme in the elimination of moclobemide and that it is extensively inhibited by omeprazole in extensive metabolizers, but not in poor metabolizers.

Objectives: To elucidate pharmacokinetics and pharmacodynamics of landiolol hydrochloride, newer developed ultra-short-acting beta-blocker, in patients with various cardiac tachyarrhythmias., Background: The short duration of action and titratability of landiolol hydrochloride make it ideal for use in patients with a clinical need for beta-blockers., Methods: In a total of 31 examinations we infused the drug in 19 patients (mean age, 55 +/- 14 years). After the persistence of the tachyarrhythmias was confirmed, continuous infusion was started at rates of 0.005, 0.01, 0.02, 0.04, and 0.08 mg/kg/min for 5 minutes (for paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, and ventricular tachycardia) or 15 minutes (for ventricular premature complex). We analyzed the pharmacokinetics of 16 examinations. A one-compartment model provided a close fit for each blood concentration-time curve., Results: The maximum blood concentrations obtained clearly showed the dose dependency and revealed very short half-lives (range, 2.3 to 4.0 minutes). Area under the blood concentration-time curves also increased, showing dose dependency. In paroxysmal atrial fibrillation, landiolol hydrochloride reduced the heart rate from 111 +/- 20 to 90 +/- 10/min. Sinus rhythm was restored, without any adverse effects, in three of five patients with paroxysmal supraventricular tachycardia and one patient with ventricular tachycardia. There was no significant change in peripheral blood pressure., Conclusions: Landiolol hydrochloride has a shorter elimination half-life than any other beta-blocker, and it can be administered safely to patients with various tachyarrhythmias.

Background: Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme. Reboxetine, a selective norepinephrine reuptake inhibitor, is metabolized by cytochrome P450 3A4. The potential interaction of reboxetine with this representative from the azole derivative class was examined., Methods: Eleven healthy volunteers received (1) 4 mg reboxetine orally on the second day of a 5-day regimen of 200 mg ketoconazole once daily and (2) 4 mg reboxetine orally in a crossover design. Plasma concentrations of reboxetine enantiomers [R,R(-)-reboxetine and the more active S,S(+)-reboxetine] were measured by high-performance liquid chromatography-tandem mass spectrometry. Effects of ketoconazole on enantiomer pharmacokinetics were assessed by ANOVA., Results: Ketoconazole increased R,R(-)-reboxetine and S,S(+)-reboxetine mean area under the plasma concentration-time curves (AUC) by 58% and 43%, respectively (P < .02). Oral clearance of both enantiomers was consequently decreased 34% and 24%, respectively, by ketoconazole (P < .005). Ketoconazole did not significantly affect maximal plasma concentrations (P > .1). Mean terminal half-life after administration of ketoconazole (21.5 hours and 18.9 hours) was significantly longer than after reboxetine alone (14.8 hours and 14.4 hours; P < or = .005). The AUC ratio for R,R(-)-reboxetine to S,S(+)-reboxetine was reduced by ketoconazole administration (2.76 after ketoconazole versus 2.39; P < .003)., Conclusion: Ketoconazole decreases clearance of both reboxetine enantiomers. Although the adverse effect profile for reboxetine was not altered by ketoconazole, the results of this study suggest that caution should be used and that a reduction in reboxetine dose should be considered when the two are coadministered.

Background: Reboxetine [(R,S)-2[(R,S)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulfonate] is a racemic compound that consists of equal proportions of R,R- and S,S-enantiomers. This study investigated the hemodynamic effects of reboxetine and the R,R-enantiomer compared with placebo in volunteers. The pharmacokinetics of reboxetine and its enantiomers were also investigated in the study., Methods: Nine healthy, male volunteers received single doses of 4 mg reboxetine, 2 mg R,R-enantiomer, and placebo at weekly intervals. Reboxetine and the R,R-enantiomer were well tolerated in all volunteers., Results: The heart rates of patients in the supine and standing positions were increased after reboxetine administration compared with the R,R-enantiomer (P < .05, except supine heart rate at 6 hours) and placebo (P < .05). Supine systolic and diastolic blood pressure was also increased by 3 +/- 4 and 1 +/- 4 mm Hg, respectively, after reboxetine compared with R,R-enantiomer (-2 +/- 4 and -4 +/- 3 mm Hg) and placebo (-4 +/- 4 and -4 +/- 4 mm Hg) administration. The systolic and diastolic blood pressure measurements for subjects while standing did not differ significantly among treatments. There was no significant difference between the maximum plasma concentration, mean time to maximum plasma concentration, plasma half-life, or area under the plasma concentration-time curve (AUC) of the R,R-enantiomer after reboxetine or R,R-enantiomer administration. The ratio of the mean AUC values for the R,R- and S,S-enantiomers was 2.1., Conclusion: These findings suggest that the S,S-enantiomer is responsible for the hemodynamic effects of reboxetine in humans. Increases in supine blood pressure after reboxetine administration may be interpreted as regression to the mean value and not caused by any treatment effect.