Concentration-QTcF Modeling of Icenticaftor from a Randomized, Placebo- and Positive-Controlled Thorough QT Study in Healthy Participants.

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be -1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and -5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean Cmax was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from -7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with -3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

Effects of triclabendazole and its metabolite exposure on the heart-rate-corrected QT intervals: A randomized, placebo- and positive-controlled thorough QT study in healthy individuals.

Triclabendazole is an effective and well-tolerated treatment for human fascioliasis. A placebo- and positive-controlled, four-sequence by four-period crossover study was conducted in 45 healthy participants to assess the effect of therapeutic (10 mg/kg twice daily [b.i.d.] for 1 day) and supratherapeutic (10 mg/kg b.i.d. for 3 days) oral doses of triclabendazole on corrected QT (QTc) interval prolongation. Moxifloxacin (400 mg, oral) was used as a positive control. The highest mean placebo-corrected change from baseline in QTcF (ΔΔQTcF) on day 4 with triclabendazole was 9.2 at therapeutic dose ms and 21.7 ms at supratherapeutic dose, at 4 h postdose. The upper limit of the two-sided 90% confidence interval exceeded 10 ms across all timepoints, except at predose timepoint on day 4 in the therapeutic group indicating that an effect of triclabendazole on cardiac repolarization could not be excluded. However, triclabendazole had no clinically significant effects on heart rate and cardiac conduction at the studied doses. In the moxifloxacin group, the mean ΔΔQTcF peak value was 13.7 ms at 3 h on day 4. The assay sensitivity was confirmed. Maximum plasma concentration of triclabendazole, sulfoxide metabolite, and sulfone metabolite occurred at ~3-, 4-, and 6-h postdose, respectively. No deaths, serious adverse events, study discontinuations due to treatment-emergent adverse events, or clinically relevant abnormalities in laboratory evaluations and vital sign values were observed. This study showed that triclabendazole had no clinically relevant effects on heart rate and cardiac conduction; however, an effect on cardiac repolarization (ΔΔQTcF >10 ms) could not be excluded.

Evaluation of a Low-Fat Low-Calorie Meal on the Relative Bioavailability of Trametinib and Dabrafenib: Results From a Randomized, Open-Label, 2-Part Study in Healthy Participants.

In this randomized, open-label, 2-part, 2 × 2 crossover, phase 1 study, the effect of a low-fat low-calorie (LFLC) meal on the relative bioavailability of a trametinib 2-mg tablet or dabrafenib 150-mg capsule was evaluated in healthy participants. Trametinib adjusted geometric mean ratios (90%CI) of fed : fasted for area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity were 0.76 (0.71-0.82) and 0.82 (0.77-0.88), respectively. For dabrafenib, the adjusted geometric mean ratios of AUC from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity (90%CI) for fed:fasted were 0.85 (0.79-0.91) and 0.86 (0.80-0.92), respectively. Consumption of an LFLC meal delayed trametinib and dabrafenib absorption, with an increase in time to maximum concentration of ≈15 and ≈30 minutes, respectively, compared to the fasted state. These findings indicate that consumption of an LFLC meal reduced the bioavailability and delayed the absorption of trametinib and dabrafenib, supporting current recommendations to administer both drugs in the fasting state; however, an occasional LFLC meal is unlikely to affect the pharmacokinetics of the drugs once steady state is reached and, by consequence, not likely to alter the overall intended efficacy.

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route.

The eye is a complex organ with a series of anatomic barriers that provide protection from physical and chemical injury while maintaining homeostasis and function. The physiology of the eye is multifaceted, with dynamic flows and clearance mechanisms. This review highlights that in vitro ocular transport and metabolism models are confined by the availability of clinically relevant absorption, distribution, metabolism, and excretion (ADME) data. In vitro ocular transport models used for pharmacology and toxicity poorly predict ocular exposure. Although ocular cell lines cannot replicate in vivo conditions, these models can help rank-order new chemical entities in discovery. Historic ocular metabolism of small molecules was assumed to be inconsequential or assessed using authentic standards. While various in vitro models have been cited, no single system is perfect, and many must be used in combination. Several studies document the use of laboratory animals for the prediction of ocular pharmacokinetics in humans. This review focuses on the use of human-relevant and human-derived models which can be utilized in discovery and development to understand ocular disposition of new chemical entities. The benefits and caveats of each model are discussed. Furthermore, ADME case studies are summarized retrospectively and capture the ADME data collected for health authorities in the absence of definitive guidelines. Finally, we discuss the novel technologies and a hypothesis-driven ocular drug classification system to provide a holistic perspective on the ADME properties of drugs administered by the ocular route.

Pharmacokinetics and safety of olopatadine hydrochloride 0.77% in healthy subjects with asymptomatic eyes: data from 2 independent clinical studies.

PURPOSE: To assess the pharmacokinetics and safety of hydrochloride ophthalmic solution 0.77% olopatadine from 2 independent (Phase I and Phase III, respectively) clinical studies in healthy subjects. MATERIALS AND METHODS: The Phase I, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥18 years old (N=36) to assess the systemic pharmacokinetics of olopatadine 0.77% following single- and multiple-dose exposures. The Phase III, multicenter, randomized (2:1), vehicle-controlled study was conducted in subjects ≥2 years old (N=499) to evaluate long-term ocular safety of olopatadine 0.77%. Subjects received olopatadine 0.77% or vehicle once daily bilaterally for 7 days in the pharmacokinetic study and 6 weeks in the safety study. RESULTS: In the pharmacokinetic study, olopatadine 0.77% was absorbed slowly and reached a peak plasma concentration (Cmax) of 1.65 ng/mL following single-dose and 1.45 ng/mL following multiple-dose exposures in 2 hours (time to reach maximum plasma concentration [Tmax]). After reaching peak concentrations, olopatadine showed a similar mono-exponential decay following single and multiple doses with mean elimination half-life ranging from 2.90 to 3.40 hours. No accumulation in olopatadine exposure (Cmax and area under the plasma concentration-time curve from 0 to 12 hours) was evident after multiple doses when compared to single dose. In the safety study, treatment-emergent adverse events were reported in 26.7% and 31.4% of subjects with olopatadine 0.77% and vehicle, respectively. Blurred vision was the most frequent ocular treatment-emergent adverse event in both treatment groups (olopatadine 0.77% vs vehicle, 4.8% vs 4.1%). No deaths or serious adverse events were reported during the study. CONCLUSION: Olopatadine 0.77% had minimal systemic exposure or accumulation in healthy subjects and was well tolerated in both adult and pediatric subjects.

Ocular pharmacokinetics comparison between 0.2% olopatadine and 0.77% olopatadine hydrochloride ophthalmic solutions administered to male New Zealand white rabbits.

PURPOSE: The primary objective of this study was to compare uptake and distribution of the commercially available formulation of 0.2% olopatadine and the newly developed 0.77% olopatadine hydrochloride ophthalmic solution formulation with improved solubility following a single (30 µL), bilateral topical ocular dose in male New Zealand white rabbits. METHODS: Each animal received a single 30-µL topical ocular dose (0.2% olopatadine or 0.77% olopatadine hydrochloride ophthalmic solution) to the right (OD) eye followed by the left (OS) eye for a total dose of 60 µL. Olopatadine concentrations were measured in ocular tissues (cornea, bulbar, conjunctiva, choroid, iris-ciliary body, whole lens, retina), aqueous humor, and plasma at prespecified time points over 24 h using a qualified liquid chromatography coupled with mass spectrometry (LC-MS/MS) analytical method. RESULTS: Olopatadine was absorbed into the eye and reached maximal levels (Cmax) within 30 min (0.5 h) to 2 h (Tmax) in ocular tissues and plasma for both treatment groups, except for the lens in which the Tmax was 4 h in the 0.2% olopatadine group and 8 h in the 0.77% olopatadine hydrochloride group, respectively. Tissues associated with the site of dosing, that is, the conjunctiva and cornea, had the highest concentrations of olopatadine in both the 0.2% olopatadine (609 and 720 ng/g) and 0.77% olopatadine hydrochloride (3,000 and 2,230 ng/g) dose groups. The greatest differences between 0.2% olopatadine and 0.77% olopatadine hydrochloride were associated with the overall duration and level of ocular exposures. CONCLUSIONS: The newly developed 0.77% olopatadine hydrochloride ophthalmic solution formulation resulted in a higher and more prolonged olopatadine concentration in the target tissue, that is, conjunctiva compared to the commercial formulation of 0.2% olopatadine ophthalmic solution.

A Novel Study Using Accelerated Mass Spectrometry to Evaluate the Pharmacokinetics of Total (14)C AL-8309 (Tandospirone) Following Topical Ocular Administration in Healthy Male Subjects.

The primary objective of this study is to characterize the pharmacokinetics of total (14)C concentrations following bilateral, topical ocular drops of (14)C-AL-8309B labeled either at the pyrimidyl ring (cohort A) position or at the imido-carbonyl ring (cohort B) position twice daily from day 1 through day 6 and once in the morning of day 7 in 16 healthy male subjects (8 per cohort). Each drop (approximately 24 µL) of (14)C-AL-8309B 1.75% ophthalmic solution (equivalent to 420 µg-equiv AL-8309) contained approximately 500 nCi of (14)C-AL-8309. AL-8309 systemic absorption was relatively slow; the time of maximum observed plasma concentrations ranged from 0.25 to 3 hours. Moderate accumulation (1.48- to 1.86-fold) was observed in the mean systemic total (14)C plasma concentrations at steady state (day 7) compared with single dose (day 1). The mean total (14)C eliminated was 3.5-fold and 3.7-fold greater in the urine than the feces for cohort A and cohort B, indicating that (14)C-AL-8309 is primarily excreted through renal elimination. Single and multiple topical doses of AL-8309B were found to be safe and well-tolerated in healthy subjects. This is the first reported use of accelerator mass spectrometry technology with a topically applied ophthalmic product.

Effects of PRX-00023, a novel, selective serotonin 1A receptor agonist on measures of anxiety and depression in generalized anxiety disorder: results of a double-blind, placebo-controlled trial.

PRX-00023, a serotonin 1A receptor agonist, was designed to provide high potency and selectivity for its target. To assess the possible therapeutic utility in anxiety, a randomized, double-blind, placebo-controlled trial was conducted in 311 subjects who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for generalized anxiety disorder. All subjects underwent a 1-week placebo run-in and were randomized to receive once-daily capsules containing either PRX-00023 (80 mg/d) or placebo for an additional 8 weeks. The primary outcome measure was the Hamilton Anxiety Scale (HAM-A). The Montgomery-Asberg Depression Rating Scale was used as a secondary endpoint to measure depressive symptoms. Statistical testing was performed with analysis of covariance, between baseline and week 8, with baseline values as a covariate. The anxiolytic effect of PRX-00023, compared with placebo, showed trends across all anxiolytic measures but failed to reach significance on the primary endpoint (HAM-A total score). Among the components of the HAM-A total score, the anxious mood item was significantly different from placebo in the PRX-00023-treated group (-1.015 vs -0.748; P = 0.02). The scores of the Montgomery-Asberg Depression Rating Scale were significantly improved compared with placebo at week 8 (-4.5 vs -1.6; P = 0.0094 in the last observation carried forward analysis). PRX-00023 was well tolerated; of note, there were no drug-related serious adverse events, and more patients discontinued due to adverse events in the placebo group (2.9%) than in the PRX-00023 group (1.4%). The most common adverse event was headache, observed in 15.7% and 10.9% of PRX-00023- and placebo-treated patients, respectively. Furthermore, there was no evidence of impaired sexual function, as measured by the Massachusetts General Hospital Sexual Function Scale. Collectively, these results support further clinical investigation of higher doses of PRX-00023 in anxiety and depression.

Tolerability, pharmacokinetics, and neuroendocrine effects of PRX-00023, a novel 5-HT1A agonist, in healthy subjects.

PRX-00023 is a novel, nonazapirone 5-HT1A agonist in clinical development for treatment of affective disorders. The objectives of the initial clinical phase I studies (a single ascending dose study and multiple dose-ascending and high-dose titration studies) were to measure the pharmacokinetics, pharmacodynamic (neuroendocrine) effects, and tolerability of PRX-00023 in healthy subjects. The studies evaluated 10-mg to 150-mg doses of PRX-00023 in up to 112 healthy male and female subjects aged 18 to 54 years. Single and multiple oral doses of PRX-00023 were found to be safe and well tolerated in healthy subjects. PRX-00023 was absorbed relatively rapidly, with a tmax of 0.5 to 2 hours, and eliminated with a half-life of approximately 12 hours. PRX-00023 treatment transiently increased blood prolactin levels 2 to 3 hours after administration, consistent with its mechanism as a 5-HT1A agonist.

Pharmacokinetics and safety of galantamine in subjects with hepatic impairment and healthy volunteers.

The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open-label study in which a single oral 4-mg dose of galantamine was administered to volunteers with mild (Child-Pugh score of 5-6, n = 8), moderate (Child-Pugh score of 7-9, n = 8), or severe hepatic impairment (Child-Pugh score of 10-15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma-concentration curve from zero to infinity (AUC0-infinity) (+33%) and terminal half-life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similarto those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild ormoderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.

Population analysis of the pharmacokinetics and pharmacodynamics of RWJ-270201 (BCX-1812) in treating experimental influenza A and B virus in healthy volunteers.

OBJECTIVE: Our objective was to assess the pharmacokinetics and pharmacodynamics of RWJ-270201 (BCX-1812), an oral neuraminidase inhibitor for the treatment of influenza A and B virus in healthy volunteers. METHODS: This was a double-blind, randomized, placebo-controlled, parallel group study. A total of 80 adult male and female subjects were enrolled for the influenza A challenge study. This was a 5-arm study (100 mg/qd, 200 mg/qd, 200 mg/bid, 400 mg/qd, and placebo). In the challenge B virus model, 60 subjects were enrolled for a 3-arm study (800 mg on Day 1 followed by 400 mg on Days 2-5; 800 mg on Days 1-5; and placebo). The pharmacokinetics of RWJ-270201 (BCX-1812) were characterized with the use of a population approach and were described by a 2-compartmental model with first-order absorption and elimination. The pharmacodynamic data, mean log viral titers, were described with the use of an empirical equation relating the viral growth and the effect of drug on changes in viral titers. RESULTS: Pharmacokinetic analyses show that weight was the most significant covariate for all estimated pharmacokinetic parameters. The pharmacodynamic data, mean log viral titers showed a decrease in viral titers with increase in plasma exposure. The decrease in viral titer started to occur 12 hours following the drug dosing, and viral suppression lasted 72 hours to 96 hours. The exposures associated with a 50% decrease in viral titers were 1089 ng-h/mL and 1898 ng-h/mL, respectively. CONCLUSIONS: A PK/PD model was well utilized to characterize the effect of RWJ-270201 (BCX-1812) on the influenza A and B virus. The results from this model showed that both the loading dose and the standard dose regimens are efficacious against A and B virus. RWJ-270201 (BCX-1812) is under clinical development for the treatment of influenza A and B infections in adult and high-risk populations. It is a potent and selective inhibitor of both influenza A and B virus neuraminidases and inhibits the viral cleavage of sialic acid from cell surface glycoproteins and glycolipids. Consequently, RWJ-270201 (BCX-1812) prevents infection by stopping the release of newly formed virus from the surface of infected cells and preventing viral spread across the mucous lining of the respiratory tract. It therefore represents an attractive agent for antiviral therapy.