Multiple-ascending doses of ACT-1014-6470, an oral complement factor 5a receptor 1 (C5a1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement.

AIMS: Targeting the complement factor 5a receptor 1 (C5a1 receptor) offers potential to treat various autoimmune diseases. The C5a1 receptor antagonist ACT-1014-6470 was well tolerated in a single-ascending dose study in healthy subjects. This double-blind, randomized, placebo-controlled study aimed to investigate the safety, tolerability, pharmacokinetics (PK) and target engagement of multiple-ascending doses of ACT-1014-6470. METHODS: Per dose level, 10 healthy male and female subjects of nonchildbearing potential (1:1 sex ratio) were enrolled to assess 30, 60 and 120 mg ACT-1014-6470 administered twice daily for 4.5 days under fed conditions. Adverse events, clinical laboratory data, vital signs, electrocardiogram and PK blood samples were collected up to 120 h post last dose and ex vivo stimulated matrix metalloproteinase 9 was quantified as target engagement biomarker. At the 60-mg dose level, PK samples were collected until 8 weeks post last dose. RESULTS: The total adverse event number was 57 and no treatment-related safety pattern was apparent. At steady state, ACT-1014-6470 reached maximum plasma concentrations after 2-3 h and the half-life estimated up to Day 10 was 115-146 h across dose levels. Exposure parameters increased dose-proportionally, steady state was attained between Day 3-5, and ACT-1014-6470 accumulated 2-fold. At the 60-mg dose level, ACT-1014-6470 was quantifiable until 8 weeks after the last dose. Matrix metalloproteinase 9 release was suppressed to endogenous background concentrations up to the last sampling time point, confirming sustained target engagement of ACT-1014-6470. CONCLUSION: The compound was generally safe and well tolerated at all dose levels, warranting further clinical investigations.

First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist.

AIMS: The orexin system is involved in anxiety behaviour and corresponding physiological reactions and constitutes a target for treatment of anxiety disorders. ACT-539313 is a potent, selective orexin-1 receptor antagonist being developed for the treatment of anxiety disorders. This first-in-human study investigated its single-dose pharmacokinetics (PK) including food effect, pharmacodynamics (PD), safety and tolerability. METHODS: This double-blind, placebo-controlled, randomized study included 40 healthy male subjects. Ascending oral doses of 10-400 mg ACT-539313 were investigated in 5 dose groups of 8 subjects (of whom 2 received placebo per dose group). At 100 mg, subjects received ACT-539313 in fasted and fed conditions in a fixed sequential design. PK, PD (objective and subjective measures of sedation and effects on central nervous system), safety and tolerability were assessed. RESULTS: In fasted conditions, ACT-539313 was rapidly absorbed (median time to maximum plasma concentration [Cmax ] 0.7-3.5 h) and cleared from plasma with a mean terminal half-life of 3.3-5.7 h across dose levels. A 1.63-fold (90% confidence interval: 1.26-2.11) increase in Cmax and no change in area under the concentration-time curve extrapolated to infinity was observed under fed compared to fasted conditions. No relevant PD signals were detected except for a trend of reduced saccadic peak velocity around time to Cmax . The most commonly reported adverse events were somnolence and headache. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory or 12-lead electrocardiogram were observed. CONCLUSIONS: ACT-539313 exhibits good safety and tolerability at single doses of up to and including 400 mg that warrant further investigations.

First-in-man study of ACT-709478, a novel selective triple T-type calcium channel blocker.

OBJECTIVE: Increased activity of T-type Ca2+ channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. ACT-709478 is an orally available triple T-type Ca2+ channel blocker. The aim of this first-in-man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of ACT-709478 in healthy subjects. METHODS: This double-blind, placebo-controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1-400 mg ACT-709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60 mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests. RESULTS: The maximum plasma concentration (Cmax ) was reached within 3 to 4 hours (≤60 mg) and within 20 to 28 hours (>60 mg), and across all dose levels the terminal half-life (95% confidence interval) ranged from 36 (29-45) to 43 (22-86) hours. Multiple peaks were observed and Cmax and area under the plasma concentration-time curve (AUC)0-∞ increased in a less than dose-proportional manner. A 1.6-fold increase in Cmax and no change in AUC0-∞ was observed in fed compared to fasted conditions. A significant correlation (P < 0.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo. SIGNIFICANCE: ACT-709478 exhibits good tolerability and safety after single-dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.

Absolute oral bioavailability of selexipag, a novel oral prostacyclin IP receptor agonist.

PURPOSE: The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) versus intravenous (i.v.) formulation of selexipag in healthy subjects. METHODS: A pilot phase in three healthy male subjects, which preceded the main study, consisted of a single 20-minute i.v. infusion of 50 µg selexipag. Its objectives were to ensure the safety of the i.v. formulation and to select the i.v. dose for the main study. The main study had a randomized, two-way crossover design in 16 healthy male subjects. Subjects received a single oral dose of 400 µg selexipag and a single 80-minute i.v. infusion of 200 µg selexipag. RESULTS: Three subjects in the pilot and 15 in the main phase completed the study as planned, whereas one subject of the main study withdrew the consent. A geometric mean total body clearance (95% confidence interval (CI)) of 17.9 L/h (15.0-21.5) and a volume of distribution of 11.7 L (10.6-13.0) were determined. The absolute oral bioavailability of selexipag (90% CI) was 49.4% (42.6-57.2). Selexipag was well-tolerated; no adverse event (AE) occurred during the pilot phase, and the main observed AEs were headache, nausea, and vomiting. CONCLUSION: A single i.v. administration of selexipag in healthy subjects was safe and well-tolerated. The bioavailability of selexipag after oral administration is approximately 50%.

Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment.

AIM: The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS: Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with mild, moderate and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 µg or 400 µg was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS: Exposure increased with the severity of hepatic impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with mild hepatic impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate hepatic impairment when compared with healthy subjects. The two subjects with severe hepatic impairment showed similar dose-normalized exposure to that of subjects with moderate hepatic impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS: Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment.

Contractile function and energy metabolism of skeletal muscle in rats with secondary carnitine deficiency.

The consequences of carnitine depletion upon metabolic and contractile characteristics of skeletal muscle remain largely unexplored. Therefore, we investigated the effect of N-trimethyl-hydrazine-3-propionate (THP) administration, a carnitine analog inhibiting carnitine biosynthesis and renal reabsorption of carnitine, on skeletal muscle function and energy metabolism. Male Sprague-Dawley rats were fed a standard rat chow in the absence (CON; n = 8) or presence of THP (n = 8) for 3 wk. Following treatment, rats were fasted for 24 h prior to excision of their soleus and EDL muscles for biochemical characterization at rest and following 5 min of contraction in vitro. THP treatment reduced the carnitine pool by ∼80% in both soleus and EDL muscles compared with CON. Carnitine depletion was associated with a 30% decrease soleus muscle weight, whereas contractile function (expressed per gram of muscle), free coenzyme A, and water content remained unaltered from CON. Muscle fiber distribution and fiber area remained unaffected, whereas markers of apoptosis were increased in soleus muscle of THP-treated rats. In EDL muscle, carnitine depletion was associated with reduced free coenzyme A availability (-25%, P < 0.05), impaired peak tension development (-44%, P < 0.05), and increased glycogen hydrolysis (52%, P < 0.05) during muscle contraction, whereas PDC activation, muscle weight, and water content remained unaltered from CON. In conclusion, myopathy associated with carnitine deficiency can have different causes. Although muscle atrophy, most likely due to increased apoptosis, is predominant in muscle composed predominantly of type I fibers (soleus), disturbance of energy metabolism appears to be the major cause in muscle composed of type II fibers (EDL).

Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects.

AIMS: This study investigated the effect of a fixed dose combination of lopinavir/ritonavir on the pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679. METHODS: This was an open label, randomized, single centre, two way, crossover study. Twenty healthy male subjects were treated with a single dose of 400 µg selexipag alone and in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily. RESULTS: The results showed that lopinavir/ritonavir approximately doubled the exposure to selexipag. The area under the plasma concentration-time curve from time zero to infinity (AUC(0,∞) and the maximum plasma concentration (Cmax) of selexipag were 2.2- and 2.1-fold higher, respectively, than under selexipag alone, with a 90% confidence interval (CI) of the geometric mean ratio (GMR) of 1.9, 2.7 and 1.7, 2.6, respectively. For ACT-333679, the clinically more relevant component of selexipag, systemic exposure was increased by 8% (GMR of AUC(0,∞) 1.1, 90% CI 0.9, 1.3), when lopinavir/ritonavir was co-administered with selexipag. The most frequently reported adverse event (AE) was headache. A single dose of selexipag, administered either alone or together with multiple doses of lopinavir/ritonavir, was safe and well tolerated. CONCLUSIONS: Lopinavir/ritonavir does not affect the PK parameters of selexipag and ACT-333679 to a clinically relevant extent. Therefore, adaptation of the selexipag dose is not required when co-administered with inhibitors of the organic anion-transporting polypeptide (OATP) 1B1/ 1B3, P-glycoprotein (P-gp) and/or CYP3A4.

Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects.

OBJECTIVE: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. METHODS: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. RESULTS: Dose levels of selexipag up to 1,600 µg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. CONCLUSIONS: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials.

Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.

BACKGROUND AND OBJECTIVES: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin. METHODS: In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed. RESULTS: Midazolam maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated. CONCLUSIONS: Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity. CLINICAL TRIAL REGISTRATION: This trial (NCT05480488) was registered on 29 July, 2022.

Value of Assessing 1-Hydroxymidazolam in Drug-Drug Interaction Studies with Midazolam as a Substrate of Cytochrome P450 3A.

The purpose of this overview was to perform an exploratory analysis of in-house drug-drug interaction (DDI) studies conducted with investigational drugs and oral midazolam to assess the value of measuring 1-OH-midazolam (1-OHM) in such studies. The perpetrator effect of the investigational drugs on cytochrome P450 3A (CYP3A) was assessed by analyzing both midazolam and 1-OHM in plasma and evaluating their pharmacokinetic parameters. Given the almost exclusive metabolism of the parent drug by CYP3A to the main metabolite 1-OHM, an increase in midazolam and a decrease in 1-OHM exposure in the case of CYP3A inhibition caused by a perpetrator drug would be expected. The opposite would be anticipated in the case of CYP3A induction. For this analysis, the perpetrator potential of eight different investigational drugs was incorporated. Among the 10 studies included, the identified CYP3A inhibitors (n = 4) and inducers (n = 1) were classified based on the data generated with midazolam per se, with 1-OHM levels not contributing to the interpretation of the data as they did not corroborate the findings of the parent compound. Therefore, it was concluded that continued analysis of 1-OHM in plasma may be questionable as it does not add value to the interpretation of the results when performing CYP3A DDI studies with an investigational drug as a perpetrator.

Transfer of the Dual Orexin Receptor Antagonist Daridorexant into Breast Milk of Healthy Lactating Women.

The novel dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of adult patients with insomnia. The aim of this post-marketing study was to measure daridorexant and its major metabolites in breast milk and plasma of 10 healthy lactating subjects. This single-center, open-label study evaluated the transfer of the analytes into breast milk. A single dose of 50 mg was orally administered in the morning. Milk and blood samples were collected pre-dose and over a period of 72 h after dosing. The pharmacokinetics of daridorexant in milk and plasma were assessed including the cumulative amount and fraction of dose excreted, daily infant dose, and relative infant dose. Safety and tolerability were also investigated. All subjects completed the study. Daridorexant was rapidly absorbed into and distributed from plasma. Daridorexant and its major metabolites were measurable in breast milk. The cumulative total amount of daridorexant excreted over 72 h was 0.010 mg, which corresponds to 0.02% of the maternal dose. This corresponds to a mean daily infant dose of 0.009 mg/day and a relative infant dose of less than 0.22% over 24 h. The maternal safety profile was similar to that observed in previous studies. Low amounts of daridorexant and its metabolites were detected in the breast milk of healthy lactating women. Since the exposure and potential effects on the breastfed infant are unknown, a risk of somnolence or other depressant effects cannot be excluded.

Effect of Daridorexant on the Pharmacokinetics of P-Glycoprotein Substrate Dabigatran Etexilate and Breast Cancer Resistance Protein Substrate Rosuvastatin in Healthy Subjects.

BACKGROUND AND OBJECTIVE: The dual orexin receptor antagonist daridorexant was approved in 2022 for the treatment of insomnia at doses up to 50 mg once per night. This study aimed at investigating the effect of daridorexant 50 mg at steady state on the pharmacokinetics of dabigatran, the active moiety of dabigatran etexilate, and rosuvastatin, sensitive substrates of P-glycoprotein and breast cancer resistance protein, respectively. METHODS: This single-center, open-label, fixed-sequence study enrolled 24 healthy male subjects who were dosed orally with dabigatran etexilate 75 mg on days 1 (Treatment A1) and 9 (Treatment C1) as well as rosuvastatin 10 mg on days 3 (Treatment A2) and 11 (Treatment C2). On days 7-14, daridorexant (50 mg once daily) was administered. Blood samples for the pharmacokinetics of both substrates and the pharmacodynamics of dabigatran, i.e., two coagulation tests, were collected and safety assessments performed. Noncompartmental pharmacokinetic parameters and pharmacodynamic variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment C1/C2 versus A1/A2. RESULTS: Geometric mean ratios (90% confidence interval) of dabigatran maximum plasma concentration and area under the plasma concentration-time curve were 1.3 (1.0-1.7) and 1.4 (1.1-1.9), respectively, whereas the time to maximum plasma concentration and terminal half-life were comparable between treatments. Pharmacodynamic variables showed a similar pattern as dabigatran pharmacokinetics in both treatments. Rosuvastatin pharmacokinetics were unchanged upon concomitant daridorexant administration. All treatments were well tolerated. CONCLUSIONS: A mild inhibition of P-glycoprotein was observed after administration of daridorexant (50 mg once daily) at steady state, whereas breast cancer resistance protein was not affected. CLINICAL TRIAL REGISTRATION: NCT05480475; date of registration: 29 July, 2022.

Effect of Severe Renal Impairment on Pharmacokinetics, Safety, and Tolerability of ACT-1014-6470, a Novel Oral Complement Factor 5a Receptor 1 Antagonist.

The aim of this study was to examine the safety and the effect of severe renal impairment (RI) on the pharmacokinetics of ACT-1014-6470, a novel oral complement factor 5a receptor 1 antagonist. A phase 1 single-center, open-label, single-dose, parallel-group study was conducted in subjects with severe RI (n = 8) compared to demographically pairwise matched subjects with normal renal function (n = 8). Plasma levels of ACT-1014-6470 were measured up to 120 hours following an oral 40-mg dose. Safety evaluations included adverse events (AEs), vital signs, hematology, coagulation, clinical chemistry tests, and electrocardiograms. All 16 subjects completed the study. Relative to subjects with normal renal function, ACT-1014-6470 time to maximum plasma concentration was delayed with a median of differences of 3 hours. The maximum plasma concentration and the area under the plasma concentration-time profile from time zero to infinity were comparable indicated by geometric mean ratios (90%CI) of 0.85 (0.53-1.37) and 1.17 (0.73-1.85), respectively. Four transient and mild AEs in three subjects with severe RI were reported; three AEs were considered not related to ACT-1014-6470. These results support the use of ACT-1014-6470 in subjects with mild to severe RI without the need of dose adjustment.

Effect of nivasorexant (ACT-539313), a selective orexin-1-receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects.

Nivasorexant, a selective orexin-1-receptor antagonist, has recently been assessed in the treatment of humans with binge-eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single-center, open-label, fixed-sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19-44 µM, respectively, while showing a significant time-dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single- (i.e., area under the plasma concentration-time curve [AUC] ratio increased by 1.04-, 2.05-, and 1.56-fold, respectively) and repeated-dose (i.e., AUC ratio increased by 1.47-, 6.84-, and 3.71-fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

Modeling time-delayed concentration-QT effects with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5a1 receptor) antagonist.

The novel oral complement factor 5a receptor 1 antagonist ACT-1014-6470 was well tolerated in single- and multiple-ascending dose studies, including 24 h Holter electrocardiogram (ECG) recordings evaluating its cardiodynamics based on data from single doses of 30-200 mg and twice-daily (b.i.d.) dosing of 30-120 mg for 4.5 days. By-time point, categorical, and morphological analyses as well as concentration-QT modeling and simulations were performed. No relevant effect of ACT-1014-6470 on ECG parameters was observed in the categorical and morphological analyses. After single-dose administration, the by-time point analysis indicated a delayed dose-dependent increase in placebo-corrected change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF) at >6 h postdose. After b.i.d. dosing, ΔΔQTcF remained elevated during the 24-h recording period, suggesting that the effect was not directly related to ACT-1014-6470 plasma concentration. The concentration-QT model described change from baseline in QTcF (ΔQTcF)-time profiles best with a 1-oscillator model of 24 h for circadian rhythm, an effect compartment, and a sigmoidal maximum effect model. Model-predicted ΔΔQTcF was derived for lower doses and less-frequent dosing than assessed clinically. Median and 90% prediction intervals of ΔΔQTcF for once-daily doses of 30 mg and b.i.d. doses of 10 mg did not exceed the regulatory threshold of 10 ms but would achieve ACT-1014-6470 plasma concentrations enabling adequate target engagement. Results from cardiodynamic assessments identified dose levels and dosing regimens that could be considered for future clinical trials, attempting to reduce QT liability.

Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor 1 antagonist ACT-1014-6470 in vitro and in vivo.

ACT-1014-6470 is an orally available complement factor 5a receptor 1 antagonist and a novel treatment option in auto-inflammatory diseases. The in vitro inhibition potential of ACT-1014-6470 on cytochrome P450 isozymes (CYPs) and its effect on the pharmacokinetics (PK) of the CYP2C19 and CYP3A4 substrates omeprazole and midazolam, respectively, in humans were assessed. In vitro assays were conducted with isoform-specific substrates in human liver microsomes. In an open-label, two-period, fixed-sequence cocktail study, single doses of 20 mg omeprazole and 2 mg midazolam were administered concomitantly to 20 healthy male subjects alone (treatment A) and after a single dose of 100 mg ACT-1014-6470 (treatment B) under fed conditions. Safety and PK assessments were performed. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of noncompartmental PK parameters of treatment B versus treatment A were calculated. In vitro, no time-dependent inhibition was observed and the lowest inhibition constant of 4.3 µM ACT-1014-6470 was recorded for CYP2C19. In humans, GMRs (90% CI) of omeprazole PK were 1.9 (1.5-2.5) for maximum plasma concentration (Cmax ) and 1.9 (1.5-2.3) for area under the plasma concentration-time curve from 0 to 12 h (AUC0-12 h ). Midazolam PK showed GMRs (90% CI) of 1.1 (1.1-1.2) for Cmax and 1.5 (1.4-1.6) for AUC0-24 h . All treatments were well-tolerated. In line with in vitro results and regulatory risk factor calculation, the increased exposure to omeprazole and midazolam in humans after concomitant administration with a single dose of 100 mg ACT-1014-6470 reflected a weak inhibition of CYP2C19 and CYP3A4.

First-in-human study with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients.

Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of single-ascending doses of ACT-1014-6470, a novel orally available complement factor 5a receptor 1 antagonist, were assessed in a randomized, double-blind, placebo-controlled Phase 1 study. Six ACT-1014-6470 doses (0.5-200 mg) were selected after predictions from a Complex Dedrick plot. In each group, ACT-1014-6470 or matching placebo was administered to six and two healthy male individuals under fed conditions, respectively, including a cross-over part with 10 mg administered also under fasted conditions. Pharmacokinetic blood sampling and safety assessments (adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, and QT telemetry) were performed. ACT-1014-6470 was absorbed with a time to maximum plasma concentration (tmax ) of 3 h across dose levels and eliminated with a terminal half-life of 30-46 h at doses ≥ 2.5 mg. Exposure increased approximately dose proportionally. Under fed compared to fasted conditions, ACT-1014-6470 exposure was 2.2-fold higher and tmax delayed by 1.5 h. Pharmacokinetic modelling predicted that twice-daily oral administration is warranted in a subsequent multiple-dose study. No clinically relevant findings were observed in safety assessments. ACT-1014-6470 was well tolerated at all doses and could provide a novel therapy with more patient-friendly administration route compared to biologicals.

Multiple-dose clinical pharmacology of the selective orexin-1 receptor antagonist ACT-539313.

AIMS: Compounds that selectively target orexin-1 receptors may be beneficial for the treatment of various disorders. The role of selective orexin-1 receptor antagonists (1-SORAs) in addictive behavior and stress/anxiety-related disturbances has been demonstrated in animals. ACT-539313, an orally active, potent 1-SORA, has been assessed in a clinical single-ascending dose study and exhibited good safety and tolerability. In the two reported studies on ACT-539313, multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability were investigated and in a proof-of-mechanism study a CO2 challenge was applied as pharmacological model for induction of anxiety and panic symptoms (sequential inhalation of air, 7.5% CO2, and 35% CO2). METHODS: Two double-blind, placebo-controlled, randomized, multiple-dose studies included 58 healthy male and female subjects. In Study 1, multiple-ascending oral doses of 30, 100, and 200 mg twice daily (b.i.d.) ACT-539313 were investigated in 3 dose groups of 8 or 12 subjects (of whom 2 received placebo per dose group). Study 2 was conducted as a randomized two-way crossover design, enrolling 21 male and 9 female subjects who received 200 mg ACT-539313 or matching placebo b.i.d. for 2.5 days followed by a CO2 challenge, with a washout period in between. PK, PD (objective and subjective measures of sedation, alertness, effects on central nervous system (CNS), and anxiety/panic symptoms), safety, and tolerability were assessed. RESULTS: At steady state, ACT-539313 was rapidly absorbed with a median time to maximum plasma concentration of 1.8-2.3 h and eliminated with a mean half-life of 3.8-6.5 h. Overall exposure increased dose-proportionally. In Study 1, PD effects confirmed activity of ACT-539313 on the CNS, without consistent or marked effects of sedation, reduced alertness or visuo-motor impairment. In the CO2 challenge, cortisol concentrations were lower during initial air inhalation after treatment with ACT-539313 compared to placebo, while no difference was detected after CO2 inhalation. Trends for lower scores in subjective anxiety assessments were observed for ACT-539313. Besides reports of stress related to the challenge, the most frequently reported adverse events were somnolence and headache. No clinically relevant effects in other safety assessments were observed. CONCLUSIONS: Multiple-dose administration of ACT-539313 was safe and well tolerated up to multiple doses of 200 mg b.i.d. The drug's PK properties as well as the pattern of a decrease in stress-related symptoms after the CO2 challenge support further investigations of ACT-539313.

Impact of the Selective Orexin-1 Receptor Antagonist ACT-539313 on the Pharmacokinetics of the CYP3A Probe Drug Midazolam in Healthy Male Subjects.

ACT-539313 is a potent and selective orexin-1 receptor antagonist. CYP3A is the major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of ACT-539313 in man. The main objective of this study was to investigate the effect of ACT-539313 on the pharmacokinetics of orally administered midazolam. Thereby, this single-center, open-label, fixed-sequence study investigated the CYP3A interaction potential of ACT-539313 following single- (on day 2) and repeated-dose (on day 11) twice-daily administration of 200 mg ACT-539313. Exposure to midazolam was higher during concomitant administration of single as well as after repeated doses of ACT-539313 over 10 days compared to midazolam alone (day 1). In the presence of ACT-539313, the geometric mean ratio of the maximum plasma concentration and the area under the plasma concentration-time curve from time 0 to 24 hours increased by 1.18- and 1.79-fold on day 2, and by 2.13- and 4.54-fold on day 11, respectively. A similar outcome was also shown in the additionally evaluated urinary 6ß-hydroxycortisol/cortisol ratio (6ß-CR), as the geometric mean ratio of the 6ß-CR showed a decrease to 0.78 on day 2 and to 0.61 on day 11. The most commonly reported adverse events (AEs) included somnolence and headache. All AEs were transient and of mild intensity. No treatment-related effects on vital signs, clinical laboratory, and electrocardiogram were observed. In summary, the observed corresponding decrease of both the validated, exogenous (midazolam/1-hydroxymidazolam ratio) and a frequently used endogenous (6ß-CR) marker of CYP3A activity is indicative of CYP3A inhibition occurring after ACT-539313 treatment.

Multiple-Ascending Dose Study in Healthy Subjects to Assess the Pharmacokinetics, Tolerability, and CYP3A4 Interaction Potential of the T-Type Calcium Channel Blocker ACT-709478, A Potential New Antiepileptic Drug.

BACKGROUND: ACT-709478 is a selective, orally available T-type calcium channel blocker being studied as a potential new treatment in epilepsy. ACT-709478 had previously been investigated in a single-ascending dose study up to a dose of 400 mg. OBJECTIVES: The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of ACT-709478. In addition, the drug-drug interaction potential of multiple doses of ACT-709478 with the cytochrome P450 3A4 substrate midazolam was investigated. METHODS: This double-blind, placebo-controlled, randomized study included 46 healthy male and female subjects. Ascending multiple oral doses of ACT-709478 were administered to 10 (cohorts 1-2) or 12 (cohorts 3-4) subjects (two taking placebo per cohort). In cohorts 1-2, 30 or 10 mg ACT-709478 was administered once daily for 12 days. An up-titration regimen was used in cohorts 3-4 with administration of 10, 30, and 60 mg for 7 days each in both cohorts and an additional dose level of 100 mg ACT-709478 once daily for 8 days in cohort 4. Single doses of midazolam were administered at baseline and concomitantly to 60 mg and 100 mg ACT-709478 in cohort 4. Blood sampling for pharmacokinetic evaluations and safety assessments (clinical laboratory, vital signs, adverse events, and electrocardiogram) were performed regularly. Holter electrocardiograms were recorded at baseline and for 24 h at steady state and central nervous system effects were assessed with pharmacodynamic tests at baseline and steady state. RESULTS: ACT-709478 was absorbed with a time to reach the maximum plasma concentration of 3.5-4.0 h and eliminated with a half-life of 45-53 h. Steady state was reached after 5-7 days of dosing and exposure increased dose-proportionally. An accumulation index of approximately three fold was observed in cohorts 1 and 2. Exposure to midazolam was lower upon concomitant administration of 60 and 100 mg ACT-709478 compared to midazolam alone while the half-life and time to reach the maximum plasma concentration of midazolam remained unchanged, suggesting a weak induction at the gastrointestinal but not hepatic level. Pharmacokinetic parameters of 1-hydroxymidazolam were not affected by ACT-709478 administration. The most frequent adverse events were dizziness, somnolence, and headache. A tolerability signal was detected in cohort 1 (30 mg once daily); therefore, the dose was decreased to 10 mg once daily in cohort 2. The subsequently established up-titration regimen, starting with 10 mg once daily, considerably improved tolerability. Multiple doses up to 100 mg once daily were well tolerated. No treatment-related effects were detected on vital signs, clinical laboratory tests, Holter electrocardiogram variables, or in the pharmacodynamic tests. CONCLUSIONS: ACT-709478 exhibits good tolerability up to 100 mg once daily using an up-titration regimen and pharmacokinetic properties that support further clinical investigations. A weak induction of gastrointestinal cytochrome P450 3A4 activity was observed, unlikely to be of clinical relevance. CLINICALTRIALS. GOV IDENTIFIER: NCT03165097.