Elevated bradykinin levels are responsible for the development of clinical symptoms in patients with hereditary angioedema (HAE). Icatibant is a bradykinin type 2 receptor antagonist indicated for the acute treatment of HAE attacks. A population modeling and simulation approach was used to examine sources of variability impacting icatibant pharmacokinetics (PK) and provide guidance on icatibant dosing in pediatric patients with HAE. An exposure-response analysis was performed for the time to onset of symptom relief (TOSR). Data from 141 adults (133 healthy, 8 with HAE) who received subcutaneous icatibant 30 mg and 31 pediatric patients with HAE who received 0.4 mg/kg (capped at 30 mg) were included in the analysis. Icatibant PK was described by a 2-compartment model with linear elimination. Complete absorption of icatibant was expected within 1 hour of dosing. The apparent clearance and central volume of distribution were 15.4 L/h and 20.4 L, respectively. Icatibant PK was mainly dependent on body weight. The mean TOSR was very short (1.38 hours). A flat exposure-response was observed, confirming that the relationship plateaued at the level of exposure observed in pediatric patients. Simulations confirmed that weight band-based dosing regimens (10 mg [12-25 kg], 15 mg [26-40 kg], 20 mg [41-50 kg], 25 mg [51-65 kg], and 30 mg [>65 kg]) resulted in exposure similar to the 0.4-mg/kg dose. This analysis showed that icatibant undergoes rapid absorption, reaches levels required for therapeutic response, and promptly relieves HAE symptoms. A weight band-based dosing regimen is appropriate in pediatric patients with HAE.

Objectives: Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). Methods: This phase 2, multicenter, open-label, dose-optimization study (ClinicalTrials.gov registry: NCT02402166) was conducted at seven U.S. sites between April 15, 2015, and June 30, 2016. Children (4-5 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD and having ADHD Rating Scale-IV Preschool version (ADHD-RS-IV-PS) total scores >= 28 (boys) or >= 24 (girls) were eligible. Open-label LDX (8-week duration) was initiated at 5 mg and titrated to 30 mg until achieving an optimal dose. Assessments included treatment-emergent adverse events (TEAEs), vital sign changes, ADHD-RS-IV-PS total score changes, and pharmacokinetic evaluations. Results: Among 24 participants, the most frequently reported TEAE was decreased appetite (8/24; 33%). At week 8/early termination, mean (standard deviation) systolic and diastolic blood pressure and pulse changes from baseline were -1.1 (7.31) and 1.5 (6.93) mmHg and -0.8 (12.75) bpm, respectively. The mean (95% confidence interval) change from baseline ADHD-RS-IV-PS total score at the final on-treatment assessment was -26.1 (-32.2 to -20.0). Pharmacokinetic parameters of d-amphetamine, a major active metabolite of LDX, were characterized: d-amphetamine exposure increased with LDX dose; mean t(max) and t(1/2), respectively, ranged from 4.00 to 4.23 hours and 7.18 to 8.46 hours. Conclusions: In preschool-aged children with ADHD, LDX was generally well tolerated and reduced ADHD symptoms, consistent with observations in children 6-17 years of age. Based on these findings, a starting LDX dose as low as 5 mg in phase 3 studies in preschool-aged children is supported.

Ontamalimab (SHP647) is a fully human, immunoglobulin G2 , antihuman mucosal addressin cell adhesion molecule-1 (MAdCAM-1) monoclonal antibody being developed for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). A population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted using clinical phase 2 study data to evaluate the PK and PD of ontamalimab following subcutaneous administrations of 7.5, 22.5, 75, and 225 mg every 4 weeks in patients with moderate to severe UC or CD. A total of 440 patients with UC (n = 249; 56.6%) or CD (n = 191; 43.4%) were included in the analysis. A 2-compartment model with parallel linear and nonlinear elimination adequately characterized concentration-time profiles of ontamalimab. The apparent clearance and volume of distribution were 0.0127 L/h (0.305 L/day) and 6.53 L, respectively. Apparent clearance and volume of distribution were mainly dependent on baseline albumin and body weight, respectively. No differences in the PK properties of ontamalimab were observed between patients with UC or CD. The presence of antidrug antibodies did not impact the PK of ontamalimab. Nonlinear elimination occurred at very low concentrations and was unlikely to contribute to the elimination half-life under steady-state conditions. A linear PK/PD model described the relationship between ontamalimab and free MAdCAM-1. Minimum concentrations of ontamalimab at steady state following 75 mg every 4 weeks were associated with >95% suppression of circulating free MAdCAM-1. The PK/PD properties characterized support phase 3 testing in UC and CD.

Maribavir is an orally bioavailable benzimidazole riboside in clinical development for treatment of cytomegalovirus infection in patients who undergo transplantation. Maribavir was evaluated in a thorough QT (TQT) study to determine any effects on cardiac repolarization. The effect of maribavir 100 and 1,200 mg oral doses on the baseline‐adjusted and placebo‐adjusted corrected QT (QTc) interval (delta delta QTc (ddQTc)) and other electrocardiogram (ECG) parameters was assessed in a randomized, phase I, placebo‐controlled, four‐period crossover study in healthy participants (men and women ages 18–50 years). Additionally, maribavir pharmacokinetics, safety, and tolerability were investigated. Moxifloxacin (400 mg) was used as a positive control to demonstrate the study’s ability to detect QT prolongation. Digital 12‐lead Holter ECG monitoring was performed over 22 hours following study drug administration. Individual, Fridericia’s, and Bazett’s QTc intervals were calculated. Of 52 randomized participants (29 ± 8.1 years old; 31 men (60%)), 50 (96%) completed the study. For both 100‐mg and 1200‐mg doses of maribavir, analysis of ddQTc demonstrated that the upper bound of the two‐sided 90% confidence interval was below the 10‐ms threshold at all time points. The concentration–effect analysis demonstrated no relationship between ddQTc and plasma concentrations of maribavir (and its metabolite). There were no clinically meaningful changes in heart rate and systolic blood pressure. The most common adverse event was dysgeusia; no serious adverse events were reported. This TQT study demonstrated that maribavir did not have impact on cardiac repolarization.

PURPOSE:TAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of ocular hypertension (OHT) and primary open-angle glaucoma (POAG). TAK-639 is postulated to lower intraocular pressure (IOP) through a novel mechanism of action (MOA) that increases trabecular meshwork outflow. We investigated the safety and tolerability of TAK-639 in subjects with OHT or POAG.METHODS:This was a phase 1, multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose escalation study. Subjects (aged 18-90 years) with OHT or POAG were randomized 5:2 to TAK-639 or placebo. Three dose levels were planned (0.1%, 0.3%, 0.6% TAK-639), each with four dosing regimens (QD, BID, TID, QID). Safety measures included treatment-emergent adverse events (TEAEs) and ophthalmologic examinations. Pharmacokinetics and pharmacodynamics (reduction of IOP) were also evaluated.RESULTS:In total, 63 subjects were randomized and received 0.1%, 0.3% and 0.6% TAK-639, as single dose, QD, or BID, and 0.1% and 0.3% TID. The study was terminated before 0.6% TID or QID dosing cohorts were studied; instead, 0.6% BID was repeated in a new cohort. TEAEs were instillation related and of mild-to-moderate intensity. There were no TEAEs leading to premature discontinuation, and no serious TEAEs. The most common treatment-related TEAEs were instillation site pain and transient corneal staining with fluorescein. There were no clinically significant concerns across dose groups for all other safety measures, including drop comfort, best corrected visual acuity, slit-lamp biomicroscopy, and corneal epithelial integrity. Little or no systemic exposure was observed. There was a marginal reduction in IOP in one cohort at the highest dose (0.6%) and regimen (BID) tested, suggesting biological plausibility of targeting the trabecular meshwork through this mechanism.CONCLUSION:TAK-639 was generally well tolerated up to 0.6% BID. Further non-clinical studies will improve understanding of the MOA and the penetration of TAK-639 to the anterior chamber.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life‐threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one‐compartment model with first‐order rate of absorption and linear clearance, showing slow absorption and a long half‐life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect‐response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti‐inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady‐state minimum concentration (Cmin,ss; 25.4 μg/mL) that was ~ 4.5‐fold higher than the half‐maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure‐response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

The sustainability of pharmacokinetics (PK) and pharmacodynamics (PD) following long-term treatment of lanadelumab, a plasma kallikrein inhibitor, in the ongoing HELP open-label extension (OLE) study for prevention of HAE attacks was evaluated. N=109 rollovers (patients who continued from the HELP study) and N=103 non-rollovers received 300mg Q2W for ≤26 months in the OLE. PK/PD in patients who received ≥10 months' treatment in the OLE were compared with patients in HELP who received 300mg Q2W for 6 months. PD was assessed using cHMWK, a biomarker of plasma kallikrein activity. Analyses were performed using previously-established population PK and PK/PD models. Lanadelumab geometric mean PK parameters in the OLE for rollovers, including CL/F (0.0293 L/h), Vc/F (15.2 L), Cave (30100 ng/mL), Cmin (23900 ng/mL), and Cmax (34400 ng/mL), were comparable to those for rollovers/non-rollovers combined, and for patients administered 300mg Q2W during HELP. The mean rate of formation (12.4%/h), rate of degradation (0.385 h-1), maximum inhibitory effect (53.6%), and Cave (19.3%) of cHMWK for rollovers in the OLE were similar to rollovers/non-rollovers combined, and to patients in HELP. The sustainability of lanadelumab PK/PD following long-term treatment is supported by low HAE attack rates, which were comparable in rollovers/non-rollovers combined during the OLE (0.220 attacks/4 weeks) and during HELP in patients who received 300mg Q2W (0.257 attacks/4 weeks). PK, PD, and exposure-response of lanadelumab in patients who received 300mg Q2W for 6 months in HELP were similar to those observed after 10 months of treatment in the OLE, indicating sustained effect over long-term treatment.

Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 in development for the induction and maintenance of clinical remission in patients with ulcerative colitis (UC). This study aimed to assess the long-term pharmacokinetics (PK) of ontamalimab in patients with UC, and the effects of concomitant medications on PK parameters. A 12-week induction study (TURANDOT; NCT01620255) was performed to assess the PK, efficacy and safety of ontamalimab (7.5, 22.5, 75 and 225 mg subcutaneous [s.c.] every four weeks [Q4W]) in patients with UC. Individuals who completed the induction study were eligible for enrollment in an open-label extension (OLE) study (TURANDOT II; NCT01771809) to assess the long-term PK, efficacy and safety of ontamalimab (75 or 225 mg s.c. Q4W up to week 72). Population PK analyses were performed using nonlinear mixed-effects modelling. Exposure-response analyses were performed to assess the relationships between minimum concentration (Cmin,ss) of ontamalimab and clinical response, clinical remission and mucosal healing. The effect of concomitant treatments (used for ≥20% of treatment duration) on PK parameters was also evaluated. The PK population included 130 (39.8%) women and 197 (60.2%) men, of median age of 40 years. A 1-compartment model with linear elimination adequately described the PK of ontamalimab. Population estimates of apparent clearance (CL/F) and volume of distribution (V/F) were 0.00917 L/h (0.22 L/day) and 7.44 L, respectively. Albumin had a significant effect on the variability of CL/F. Individuals with albumin levels of 30 g/L and 47 g/L are expected to have CL/F values 44% higher and 23% lower, respectively, than a typical patient with an albumin level of 39 g/L. Anti-inflammatory agents affected CL/F, such that CL/F is expected to be 14% higher in patients receiving than not receiving these agents. Other medications including immunosuppressants, steroids and treatments for peptic ulcers and gastroesophageal reflux disease had no effect on CL/F. Weight was the only covariate that significantly affected V/F. The half-life of ontamalimab was 23.4 days. Concentrations of ontamalimab over 72 weeks in the OLE study were consistent with those observed in the 12-week induction study. Ontamalimab Cmin,ss was related to efficacy, such that at week 16 (week 28 in total including induction), patients with higher Cmin,ss values were more likely to have clinical response, clinical remission and mucosal healing than those with lower Cmin,ss. The exposure to ontamalimab was sustained following prolonged treatment in patients with UC for up to 72 weeks. Higher ontamalimab exposure was associated with a higher probability of clinical response.

AbstractAimTo assess safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adults.MethodsA phase 1, double‐blind, randomized, placebo‐controlled, single‐ and multiple‐dose study in Japanese and Caucasian subjects. Subjects received lisdexamfetamine 20 mg or placebo on Day 1, then lisdexamfetamine 20 mg/d (Days 4‐8), 50 mg/d (Days 9‐13), 70 mg/d (Days 14‐18), or matching placebo. Pharmacokinetic parameters for lisdexamfetamine and d‐amphetamine were estimated by noncompartmental analysis.ResultsFifteen Japanese and 19 Caucasian subjects were enrolled and randomized. The lisdexamfetamine and d‐amphetamine plasma concentration‐time curves were similar for both ethnic groups following single and multiple doses. Mean area under the concentration‐time curves for d‐amphetamine were higher (by 11%‐15%) in Japanese than Caucasian subjects following multiple dosing of lisdexamfetamine. Mean bodyweight was 17% lower in Japanese than Caucasian subjects. Weight‐corrected means for oral clearance were similar in both ethnic groups, with no unexpected accumulation of d‐amphetamine. Lisdexamfetamine was generally well tolerated by both ethnic groups, with no serious adverse events reported. The 10/12 Japanese and 11/16 Caucasian subjects who received lisdexamfetamine completed the study; two Japanese and three Caucasian subjects discontinued due to adverse events. Most adverse events were of mild severity.ConclusionPharmacokinetics were generally similar for Japanese and Caucasian subjects; the minor differences observed were likely due to bodyweight differences in the two ethnic groups. Lisdexamfetamine was generally well tolerated. Adverse events were consistent with the established safety profile of lisdexamfetamine and were similar in both ethnic groups.

Introduction: Maribavir, a potent and orally bioavailable antiviral, is being evaluated in Phase 3 trials for the treatment of CMV infections in transplant patients and received FDA Breakthrough Therapy designation.A thorough understanding of the clinical pharmacology of maribavir is necessary to guide the appropriate use of the drug in transplant patients who often have multiple comorbidities and require complex concurrent medication regimens.Objectives: To summarize the clinical pharmacology data of maribavir.Methods: Pharmacokinetic and pharmacodynamic assessments were performed in sixteen Phase 1 studies and three Phase 2 studies.Data were summarized to characterize maribavir's disposition (absorption, distribution, metabolism, and excretion) in healthy adult subjects and special populations (HIV-infected, hepatically impaired, renally impaired, and organ transplant recipients).A definitive QT study was conducted to evaluate the cardiac repolarization effect.The drug interaction risks were assessed using both nonclinical and clinical studies.Results: Maribavir is primarily eliminated through the CYP3A4 pathway and has a half-life of 5À7 hours.Co-administration with food or antacid, or crushing the tablet, had no impact on maribavir's exposure.Maribavir binds to plasma proteins with unbound fraction estimated at 1.5% and can penetrate the bloodÀretinal barrier.No pharmacokinetic difference is found among healthy subjects, transplant patients, subjects with severe renal impairment, or moderate hepatic impairment.Maribavir's exposure is increased by 46% by ketoconazole and decreased by 61% by rifampin.Maribavir increases tacrolimus exposure by 51%, does not affect voriconazole exposure, and is not expected to affect exposures of most other concurrent medications.Maribavir has no effects on QT intervals.Conclusions: Extensive clinical pharmacology data have been generated to support the clinical use and dose of maribavir for the treatment of CMV infections in transplant recipients.Maribavir can be taken with or without food.No maribavir dose adjustment is needed in patients with mild-to-moderate hepatic impairment or renal impairment or with concurrent medications, except for CYP3A4 inducers.

SHP465 mixed amphetamine salts extended release is a once-daily, single-entity, mixed amphetamine salts capsule product for attention-deficit/hyperactivity disorder. The objective of this study was to evaluate amphetamine pharmacokinetics following SHP465 mixed amphetamine salts under three administration conditions. Healthy adults (n = 16) enrolled in an open-label, randomized, three-period crossover study with three single-dose 50-mg SHP465 mixed amphetamine salts treatments (fasting ≥ 10 h before administration [reference]; high-fat meal consumption 30 min before administration; sprinkling capsule contents on applesauce) separated by ≥ 7-day washouts. Blood samples for evaluating d- and l-amphetamine pharmacokinetics were collected pre-dose and up to 60 h post-dose. Assessments included maximum plasma concentration, time to maximum plasma concentration, and area under the plasma concentration–time curve from 0 to infinity. Exponentiated least-squares mean ratios with 90% confidence intervals for test treatments relative to the reference treatment were calculated, with the absence of an effect indicated by the 90% confidence intervals falling within the 80–125% range. Least-squares mean (90% confidence interval) ratios for maximum plasma concentration and area under the plasma concentration–time curve from 0 to infinity indicated neither consuming a high-fat meal (d-amphetamine: 85.33 [80.44, 90.50] and 91.11 [86.69, 95.75], respectively; l-amphetamine: 85.22 [80.18, 90.59] and 88.74 [83.89, 93.87]) nor sprinkling the capsule contents on applesauce (d-amphetamine: 95.76 [90.28, 101.57] and 95.77 [91.13, 100.65]; l-amphetamine: 96.90 [91.16, 103.00] and 94.78 [89.60, 100.26]) altered amphetamine exposure. Consuming a high-fat meal prolonged median time to maximum plasma concentration for d- and l-amphetamine by 5.0 and 4.5 h, respectively, relative to reference treatment. These findings demonstrate SHP465 mixed amphetamine salts capsules can be swallowed whole with or without food or the capsule contents can be sprinkled on applesauce.

Lanadelumab is a plasma kallikrein (pKal) inhibitor (monoclonal antibody) indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients ≥12 years of age. 2-chain high-molecular weight kininogen (cHMWK), a product of active pKal, has been evaluated as a potential biomarker for the effect of lanadelumab. Exposure-response (ER) analyses were performed to support dosing of lanadelumab in patients with HAE. Data from 125 patients in the HELP Study treated with placebo, lanadelumab 150 mg Q4W, 300 mg Q4W, or 300 mg Q2W for 6 months were analyzed. The longitudinal ER model included a logarithm of the Poisson distribution to assess the impact of treatment duration and drug exposure on the number of HAE attacks/month. Time to first attack was assessed using Kaplan-Meier analyses and Cox proportional hazard modeling with steady state exposure and cHMWK suppression as continuous parameters. The relationship between lanadelumab and the number of attacks/month was described using a placebo model (linear time-response model) and an Emax-type model for drug effect (ER model). The ER was very steep, with plateauing of effect observed at Month 5-6. An Emax of -3.74 HAE attacks/month was estimated. Higher exposure to lanadelumab and suppression of cHMWK following administration of lanadelumab 300 mg Q2W were associated with a significant prolongation in the time to first attack. Exposure-response analyses suggest that longer chronic treatments with the 300 mg Q2W regimen were associated with further improvement in HAE control (number of HAE attacks/month) and a significant delay in time to first attack.

Introduction Maribavir, a potent and orally bioavailable antiviral, is being evaluated in Phase 3 trials for the treatment of cytomegalovirus (CMV) infections in transplant patients. Often numerous concomitant medications are administered to these patients to manage their comorbidities. A thorough evaluation of maribavir potential for drug–drug interactions (DDIs) is warranted and required for the regulatory approval. Objectives To thoroughly evaluate potential DDIs for maribavir. Methods Extensive in vitro studies were conducted to evaluate the potential involvement of cytochrome P450s (CYPs), uridine diphosphate glucuronosyltransferases (UGTs) and transporters on the disposition of maribavir, as well as the inhibitory and induction effect of maribavir on these enzymes and transporters. Clinical Phase 1 studies included a human mass-balance study, two probe-cocktail studies, and five DDI studies with ketoconazole, rifampin, antacid, voriconazole, and tacrolimus. Results Maribavir is metabolized primarily in the liver through CYP3A4 (70–85%) and CYP1A2 (15–30%). Renal clearance is a minor route ( Conclusions Maribavir has low risk for DDI. Inhibitors of CYP3A4 and/or P-gp may increase maribavir exposure, but dose adjustment of maribavir is not necessary. Potent inducers of CYP3A4 and P-gp decrease maribavir exposure, necessitating maribavir dose increase. Maribavir may increase exposure of immunosuppressants, such as tacrolimus. Therefore, monitoring of concomitant immunosuppressants' blood concentration should be considered at initiation, co-administration, and discontinuation of maribavir. Maribavir is not expected to interact with other concurrent medications.

Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug-drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) activity using probe substrates in healthy volunteers. During this phase 1 open-label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed-effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin Cmax , AUClast , and AUC0-∞ with and without maribavir was 1.257 (1.139-1.387), 1.187 (1.088-1.296), and 1.217 (1.110-1.335), respectively, outside the "no-effect" window (0.8-1.25). GMR (90%CI) of dextromethorphan AUClast and AUClast ratio of dextromethorphan/dextrorphan were 0.877 (0.692-1.112) and 0.901 (0.717-1.133), respectively, marginally outside the no-effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P-gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P-gp substrates should be evaluated individually, and caution should be exercised with P-gp substrates with narrow therapeutic windows.

Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat.

Volixibat is a potent inhibitor of the apical sodium-dependent bile acid transporter in development for the treatment of nonalcoholic steatohepatitis. This phase 1, open-label study investigated the absorption, distribution, metabolism, and excretion of [14C]-volixibat in heathy men.