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Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported.Two Phase 1 studies (overallAbsolute balovaptan bioavailability was high (103-116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45-47 hours, but single-dose CBalovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions.ClinicalTrials.gov NCT03764449; NCT01418963.

GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.

Balovaptan, an investigational vasopressin 1a receptor antagonist that has been evaluated for improvement of social communication and interaction, is primarily metabolized by cytochrome P450 3A4 (CYP3A4). Two single-center, non-randomized, two-period, phase 1 studies assessed the effect of the strong CYP3A4 inhibitor itraconazole (study NCT03579719) or the strong CYP3A4 inducer rifampicin (study NCT03586726) at steady state on the pharmacokinetics (PK) of steady-state balovaptan in healthy volunteers. Participants received balovaptan (5 or 10 mg/day) alone for 10 days, or in combination with itraconazole (200 mg/day) for 15 days, or rifampicin (600 mg/day) for 10 days, following balovaptan washout and itraconazole/rifampicin pre-dosing. Geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the area under the concentration-time curve over the dosing interval (AUC) and maximum plasma concentration (Cmax) of balovaptan dosed with vs. without itraconazole/rifampicin were estimated from a mixed effects model. Both studies comprised 15–16 healthy male and female volunteers. Itraconazole 200 mg/day elevated steady-state exposure to 5 mg/day balovaptan approximately 4.5–5.5-fold (Day 15 GMR [90% CI], 4.46 [4.06–4.90] for Cmax and 5.57 [5.00–6.21] for AUC) and extended the time to steady state from ~ 5 days to ~ 13–14 days. Rifampicin 600 mg/day resulted in ~ 90% reductions in both the Cmax (Day 10 GMR [90% CI], 0.14 [0.12–0.15]) and AUC (0.07 [0.06–0.07]) of balovaptan 10 mg/day. Time to balovaptan steady state could not be determined with rifampicin. There were no clinically significant safety findings in either study. Strong modulators of CYP3A4 activity will significantly alter the PK of balovaptan, with the effect of CYP3A4 induction greater than that of inhibition. Caution should be taken when concomitantly dosing balovaptan with moderate or strong CYP3A4 inducers or strong CYP3A4 inhibitors. NCT03579719; NCT03586726.

There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABABasmisanil, a selective GABABasmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life.Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome.The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

Plasma drug concentration and electrocardiogram (ECG) data from a drug–drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. ECG data were collected on multiple days during repeat dosing treatment regimens, thereby allowing the capture of QT data across a wide range of drug concentrations in each study participant and encompassing both “therapeutic” and “supra-therapeutic” exposures. The data were used to develop a non-linear mixed effect concentration-QT (C-QT) model that differentiated drug-induced QT prolongation from other factors altering QT interval duration. Food effects were accounted by quantitating their influences on the parameters describing the diurnal variation of QT. The final model demonstrated that itraconazole does not cause QT prolongation, while for basmisanil, the 1-sided upper 95% CI of the QT interval at 240 mg (the highest dose tested in ongoing phase 2 studies) with DDI, was below the 10 ms threshold considered to be of clinical significance by regulatory authorities. The empirical modelling was complemented with a human mechanistic cardiac single cell model that was used to simulate the change in action potential duration as a function of drug concentration. The results of the two approaches were in agreement, suggesting that the effect of basmisanil on QT interval duration can be attributed to the effect on hERG alone. The C-QT model for basmisanil can be used to derive the QT interval corrected changes in heart rate (QTc) and thus inform cardiac safety strategy in later development without the need for a separate, dedicated study.

Dalcetrapib targets cholesteryl ester transfer protein and increases high-density lipoprotein cholesterol (HDL-C) levels. It is in clinical development for the prevention of cardiovascular events and will likely be used in combination with standard of care, including statins. Three crossover studies in healthy males investigated the pharmacokinetic drug-drug interaction potential of 900 mg dalcetrapib and statins: two 3-period studies (dalcetrapib plus pravastatin or rosuvastatin) and a 2-period study (dalcetrapib plus simvastatin). Effect on lipids and safety were secondary end points. The 900 mg dose investigated is higher than the 600 mg dose currently being investigated in Phase III. Coadministration of dalcetrapib with pravastatin, rosuvastatin, or simvastatin was not associated with significant increases in statin exposure except for a 26% increase in rosuvastatin C(max) (90% CI 1.088 to 1.468) but not AUC(0-24) (90% CI 0.931 to 1.085). Dalcetrapib AUC(0-24) and C(max) were not significantly altered by coadministration with pravastatin, and were significantly lower when dalcetrapib was coadministered with rosuvastatin or simvastatin compared with dalcetrapib alone. The HDL-C increase with dalcetrapib was not compromised by coadministration with statins, and reduction in low-density lipoprotein cholesterol with dalcetrapib coadministered with statins was greater than with statins alone. Dalcetrapib alone and coadministered with statins was generally well tolerated.

Dalcetrapib, which targets cholesteryl ester transfer protein, is in clinical development for prevention of cardiovascular events and is likely to be used concomitantly with statins. Two studies investigated co-administration of dalcetrapib with atorvastatin and any effects of the timing of atorvastatin on the pharmacokinetics of dalcetrapib.Two crossover studies were performed in healthy subjects: a two-period study of dalcetrapib 900 mg concurrently with atorvastatin (concurrent dosing study) and a three-period study of dalcetrapib 600 mg (dose chosen for Phase III) with atorvastatin concurrently or serially 4 h after dalcetrapib (interval dosing study).The primary pharmacokinetic end points were AUC(0 - 24) and C(max); lipid effects and tolerability were secondary end points.In the concurrent study (n = 26), co-administration reduced dalcetrapib AUC(0 - 24) and C(max) and caused small changes in AUC(0 - 24) and C(max) of atorvastatin and its active metabolites. In the interval study (n = 52), serial and concurrent co-administration of atorvastatin resulted in similar reductions in dalcetrapib exposure that were comparable to those observed in the concurrent dosing study. Co-administration did not decrease the efficacy of dalcetrapib or atorvastatin and was generally well tolerated.These results indicate no clinically relevant interactions for co-administration of dalcetrapib with atorvastatin.

Background: Dalcetrapib (RO4607381/JTT-705) is currently under clinical investigation for the prevention of cardiovascular events. It inhibits the activity of cholesteryl ester transfer protein and has been reported to increase levels of high-density lipoprotein cholesterol. Objective: Because dalcetrapib is likely to be coadministered with agents that inhibit the cytochrome P450 (CYP) 3A4 isozyme, this study aimed to determine the effect of ketoconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of dalcetrapib. Methods: An open-label, 1-sequence study was conducted in 2 cohorts of healthy, nonsmoking male volunteers aged 18 through 65 years, with a body mass index of 18 to 32 kg/m 2 . The first cohort received dalcetrapib 600 mg on days 1 and 7 and ketoconazole 400 mg on days 2 through 7, and, based on the results of a planned interim analysis, the second cohort received dalcetrapib 900 mg alone on days 1 and 7 and ketoconazole on days 2 through 7. Pharmacokinetic and safety parameters were assessed at specific times throughout the study. To confirm CYP involvement in the metabolism of the inactive metabolite dalcetrapib- S -methyl, in vitro studies were performed using human liver microsomes and recombinantly expressed CYP isoforms. Results: Of the 26 participants, 96% were white, with a mean age of 38.1 years and a mean weight of 78.6 kg. In the in vivo portion of the study, coadministration of ketoconazole with dalcetrapib 600 mg had no significant effect on any pharmacokinetic parameter of dalcetrapib. Coadministration of ketoconazole with dalcetrapib 900 mg was associated with significant decreases in the dalcetrapib C max (-23%; P = 0.002) and AUC 0-∞ (-18%; P = 0.001) and a significant increase in oral clearance (22%; P = 0.001). Significant increases in the C max ( P = 0.001) and AUC 0-∞ ( P S -methyl were observed with coadministration of ketoconazole. The combination was generally well tolerated, with 32 of 35 adverse events (91.4%) being mild in intensity. The most frequent adverse events were headache (6/26 [23.1%] in the ketoconazole group; 4/18 [22.2%] in the group receiving dalcetrapib 900 mg plus ketoconazole) and diarrhea (4/26 [15.4%] in the ketoconazole group; 2/18 [11.1%] in the group receiving dalcetrapib 900 mg plus ketoconazole). The in vitro studies confirmed the involvement of CYP3A in the metabolism of dalcetrapib- S -methyl. Conclusions: In this clinical study in healthy male volunteers, coadministration of dalcetrapib 600 mg with the CYP3A4 inhibitor ketoconazole was not associated with any significant changes in the pharmacokinetic parameters of the parent compound. Coadministration of dalcetrapib 900 mg with ketoconazole was associated with significant decreases in the dalcetrapib C max and AUC, contrary to the increases that would be expected if dalcetrapib were a substrate for CYP3A4. The combination of dalcetrapib and ketoconazole was generally well tolerated.

The primary objective of this study was to investigate the drug-drug interaction potential of dalcetrapib on drugs metabolized via major cytochrome P450 (CYP) isoforms using both in vitro and clinical approaches. A secondary objective was to investigate the safety and tolerability of dalcetrapib alone or co-administered either with a combination of five probe drugs or with rosiglitazone.Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC(50) for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In addition, two drug-drug interaction studies were conducted in healthy males: dalcetrapib 900 mg plus the Cooperstown 5 + 1 drug cocktail, which includes substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and dalcetrapib 900 mg plus rosiglitazone, a substrate for CYP2C8. Pharmacokinetic and safety parameters were assessed.In vitro, dalcetrapib was inhibitory to all CYP enzymes tested. IC(50) values ranged from 1.5 +/- 0.1 microM for CYP2C8 to 82 +/- 4 microM for CYP2D6. Co-administration of dalcetrapib plus drug cocktail showed no clinically relevant effect of 900 mg dalcetrapib on activity of CYP1A2, CYP2C19, CYP2D6, CYP2C9, or CYP3A4 following repeated administration. Co-administration of dalcetrapib plus rosiglitazone showed no clinically relevant effect of dalcetrapib 900 mg on activity of CYP2C8. Dalcetrapib was generally well tolerated.Although in vitro studies indicated that dalcetrapib inhibits CYP activity, two clinical studies showed no clinically relevant effect on any of the major CYP isoforms at a 900 mg dose, which is higher than the 600 mg dose being explored in phase III studies. Dalcetrapib was generally well tolerated in these studies. However, these studies were limited to a small number of healthy males; additional, larger studies are necessary to study its safety.

Background Preclinical studies have reported that the relative bioavailability of dalcetrapib, a modulator of cholesteryl ester transfer protein (CETP) inhibitor activity, was ∼60% higher when administered in the fed state compared with the fasting state. Objective This article reports on 3 studies conducted to assess the effects of food intake, timing of administration with respect to meals, and meal size and content on the relative bioavailability of dalcetrapib in healthy male subjects. Methods Three Phase I studies were performed in healthy subjects: (1) a 2-period crossover study of a single dose of dalcetrapib 900 mg administered in the fed and fasting states (fed versus fasting study [1999]); (2) a 3-period crossover study of a single dose of dalcetrapib 600 mg administered after a light morning meal, a standard evening meal, and a light evening meal (meal timing/size study [2005]); and (3) a 4-period crossover study of a single dose of dalcetrapib 600 mg administered 30 minutes after a high-fat meal or a standard evening meal, and 30 minutes before or 3 hours after the latter (high-fat meal study [2007]). Blood samples for pharmacokinetic analyses (AUC 0–36 or AUC 0–∞ , C max ) were collected up to 36, 144, and 96 hours after study drug administration in the fed versus fasting, meal timing/size, and high-fat meal studies, respectively. CETP activity was measured using a radioisotopic method in the fed versus fasting study and a fluorometric method in the meal timing/size and high-fat meal studies. Tolerability was assessed using monitoring of adverse events, laboratory parameters, vital signs, and ECG. Results Six men were enrolled in the fed versus fasting study (mean age, 37 years; mean body mass index [BMI], 23.6 kg/m 2 ). Dalcetrapib exposure was increased by 64% (AUC 0–36 ) and 126% (C max ) after administration in the fed state. Eighteen men were enrolled in the analysis of the effects of meal timing and size on the properties of dalcetrapib (mean age, 30.5 years; mean BMI, 25.1 kg/m 2 ). When dalcetrapib was administered after a light morning or a light evening meal, comparable values were found for mean dalcetrapib AUC 0–∞ (7400 and 7860 ng·h/mL, respectively) and C max (589 and 552 ng/mL), whereas administration after a standard evening meal was associated with increased AUC 0–∞ (14.3%–14.7%) and C max (25.5%–35.3%). Forty-nine men were included in the analysis in the high-fat meal study (mean age, 32.3 years; mean BMI, 23.9 kg/m 2 ). Compared with administration after a standard evening meal, administration after a high-fat evening meal was associated with increased AUC 0–∞ (34.9%) and C max (43.7%). Between-treatment differences in exposure within each study also were reflected in apparent differences in CETP activity. All treatments were generally well tolerated. Conclusions Dalcetrapib exposure was increased in the fed state and, to a lesser extent, was dependent on the size and fat content of the meal. Exposure was independent of dosing time. Dalcetrapib was generally well tolerated.

Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects.Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900 mg, ezetimibe 10mg, dalcetrapib 900 mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption.Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p = 0.001), 32% (p0.001), and 12% (p = 0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% (p = 0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56-148%, p0.001) and with dalcetrapib + ezetimibe (32-38%, p0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p = 0.04) and 72% (p = 0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma (3)H-cholesterol level but increased (3)H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol.Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.

Background: Dalcetrapib is a modulator of cholesteryl ester transfer protein (CETP) activity developed to raise levels of high-density lipoprotein cholesterol (HDL-C) with the goal of further reduction of cardiovascular events additive to standard of care alone. In clinical studies, dalcetrapib has been shown to effectively increase levels of HDL-C with no significant safety concerns. Objective: The primary objective was to investigate the safety of single ascending and multiple ascending doses of dalcetrapib at doses markedly greater than that intended therapeutically (600 mg/day). Secondary objectives were to investigate the pharmacokinetics/pharmacodynamics and dose proportionality of dalcetrapib. Study Design: Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose phase I study. Healthy males (age 18–65 years, body mass index 18–?2) were randomized to four of five dalcetrapib doses (2100,2700, 3300, 3900 or 4500 mg) or placebo, with ≥10 days washout between doses (n= 15, single ascending doses) or to dalcetrapib (1800, 2100, 3000 or 3900 mg once daily) or placebo for 7 days (four cohorts, each n= 10, randomization 8:2, multiple ascending doses). Main Outcome Measure: Tolerability and safety were assessed by monitoring adverse events (AEs), laboratory parameters, vital signs and 12-lead ECG recordings. Primary pharmacokinetic assessments were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) and maximum observed plasma concentration (Cmax) [single doses] and AUC from time zero to 24 hours (AUC24) and Cmax (multiple doses). Pharmacodynamic assessments included CETP activity and lipids (multiple dosing only). Results: Exposure increased with dose but was less than proportional to increasing dose after single dosing, although deviation from dose proportionality could not be demonstrated for Cmax. Dose proportionality was consistent following multiple doses. Steady state was modelled to have been reached by approximately 4 days, with little to no accumulation. CETP activity reduction was dose dependent (maximum −55% after 3900 mg; placebo −2.6%) at 6 hours post-dose on day 1, while HDL-C increased by 12–19% (placebo −13%) on day 8 following treatment with 1800−3900 mg/day for 7 days. All AEs were mild or moderate in intensity and there were no serious AEs, deaths or withdrawals due to AEs. No clinically relevant effects on laboratory parameters, cardiac parameters or vital signs were noted. Conclusion: Single-dose dalcetrapib up to 4500 mg and multiple doses up to 3900 mg were generally safe and well tolerated.

Evaluate dalcetrapib's potential to prolong QT intervals in healthy subjects.This was a single-center, randomized, active and placebo-controlled, six-sequence, three-period cross-over study. Participants [18-65 years; body mass index (BMI) 18-30 kg/m(2)] were randomized to daily doses of dalcetrapib 600 mg (therapeutic) or 3,900 mg (supratherapeutic) or to dalcetrapib-matched placebo for 7 days. On Day 8, subjects received single-dose moxifloxacin 400 mg (active control) or placebo, following the placebo or dalcetrapib, respectively. Electrocardiographic parameters were recorded on Days -1, 1, 7, and 8. The primary endpoint was the difference to placebo of time-matched change from baseline in the study-specific corrected QT interval (QTcS) at seven time-points within 24 h after dalcetrapib 3,900 mg on Day 7. An upper 95% confidence interval (CI)10 ms confirmed the absence of a significant effect. Pharmacokinetic and lipid-related parameters were measured.Subjects (n = 49) were predominantly male (71%), and all were white, with a mean age of 45 years and mean BMI of 25 kg/m(2). For the primary analysis, the upper 95% CI for dalcetrapib 3,900 mg was10 ms at all time-points. Similar findings were obtained for dalcetrapib 600 mg. Following the administration of moxifloxacin, the QTcS increased by5 ms. At Day 7, exposure for dalcetrapib 3,900 mg was approximately eightfold higher than that for dalcetrapib 600 mg [mean area under the plasma concentration-time curve between time 0 and 24 h 68,500 vs. 8,280 ng*h/mL; mean peak concentration 6,810 vs. 861 ng/mL]. Cholesteryl ester transfer protein activity was inhibited by 30%, and high-density lipoprotein cholesterol increased by 26% for dalcetrapib 600 mg. Dalcetrapib was well tolerated.Dalcetrapib is not associated with QT interval prolongation, even at doses markedly greater than intended therapeutically.