A Phase I, Open-label, Randomized, 2-Way Crossover Study to Evaluate the Relative Bioavailability of Intranasal and Oral Varenicline.

PURPOSE: To estimate the systemic bioavailability of OC-01 (varenicline) nasal spray, an investigational treatment for dry eye disease, relative to oral varenicline approved for smoking cessation. METHODS: The Study to Evaluate the Relative Bioavailability of Varenicline Administered as OC-01 (Varenicline) Nasal Spray as Compared to Varenicline Administered Orally as Chantix (ZEN study) was a Phase I, open-label, randomized, single-center, 2-way crossover study. On day 1, 22 healthy participants were randomized 1:1 to a single intranasal dose of varenicline 0.12 mg in OC-01 nasal spray or a single oral dose of varenicline 1 mg. On day 15, all participants crossed over to receive a single dose of the alternate treatment. Plasma samples were collected for 6 days after each dose, and pharmacokinetic parameters were estimated using noncompartmental analysis. Tolerability was monitored throughout. FINDINGS: After a single dose of intranasal varenicline 0.12 mg in OC-01 nasal spray, peak systemic exposure (mean plasma Cmax) was 0.34 ng/mL, which occurred at a median Tmax of 2.0 hours. In comparison, mean plasma Cmax after oral varenicline 1 mg was 4.63 ng/mL at a median Tmax of 3.0 hours. On the basis of geometric mean ratio point estimates, peak exposure (Cmax) and total exposure (AUC0-∞) after intranasal varenicline 0.12 mg were 7.0% and 7.5%, respectively, of the systemic exposure associated with oral varenicline 1 mg. Dose-normalized Cmax and AUC0-∞ for intranasal varenicline remained 39% and 33% lower versus oral varenicline, respectively. No new or unexpected tolerability signals were detected. IMPLICATIONS: At its highest intended single dose in OC-01 nasal spray, intranasal varenicline delivered less drug to the systemic circulation than oral varenicline at its highest approved single dose. ClinicalTrials.gov identifier: NCT04072146.

Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles.

Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.

Single-dose pharmacokinetics of bupropion hydrobromide and metabolites in healthy adolescent and adult subjects.

Data from 2 pediatric single-dose studies, conducted at the same center, were combined to evaluate exposure levels of bupropion and metabolites in adolescents 12-17 years old, compared with adults > 18 years. Pharmacokinetic analyses of bupropion and its metabolites were performed using normalization and pharmacological/convulsive weighting methods on exposure. When compared with adults (>18 years), subjects 12-14 years had an increase in weight-normalized exposure to bupropion (ie, Cmax , 78%; AUC0-t , 83%; and AUCinf , 85%). Variability in this younger age group was also higher, with observations of a 3- to 4-fold increase in exposure. When the changes in metabolites were accounted within pharmacological and convulsive-weighted exposures, the relative ratio of 12-14 years to adults in body weight-normalized Cmax was 127% and 110%, respectively. Subjects 15-17 years did not exhibit a difference in exposure compared with adults. The influence of age on bupropion pharmacokinetics demonstrates that, in general, healthy adolescent subjects cannot be considered smaller healthy adult subjects; the increase in exposure is inversely related to age and appears to be solely associated with bupropion, not with its metabolites. Because there are no clinical safety and efficacy data of bupropion in adolescents, this data may shift its risk-benefit profile.

Effect of hemodialysis on pharmacokinetics of ezogabine/retigabine and its N-acetyl metabolite in patients with end stage renal disease.

Ezogabine (EZG)/retigabine (RTG) and its metabolites are mainly eliminated renally. This Phase I study assessed the effect of hemodialysis on the pharmacokinetics of EZG/RTG and its N-acetyl metabolite (NAMR) in patients with end-stage renal disease; tolerability of EZG/RTG was a secondary endpoint. Patients (N=8) received EZG/RTG 100 mg orally 4 hours before (Period 1) or following (Period 2) dialysis. Blood (both periods) and dialysate (Period 1) samples were taken up to 68 hours post dose. Tolerability was assessed throughout both periods. The area under the concentration- time curve (0-68 hours) for EZG/RTG was 33% lower (geometric mean ratio [90% confidence interval]: 0.67 [0.61, 0.73]) on dialysis versus off dialysis and 43% lower for NAMR (0.57 [0.53, 0.62]). Median (range) reductions in plasma concentrations from dialysis start to end were 52% (17-59%) for EZG/RTG and 51% (27-72%) for NAMR. EZG/RTG 100 mg was generally tolerated.

Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug-drug interaction study.

INTRODUCTION: The potential for ezogabine/retigabine (EZG/RTG) and its N-acetyl metabolite (NAMR) to inhibit the transporter protein P-glycoprotein-(P-gp)-mediated digoxin transport was tested in vitro. EZG/RTG did not inhibit P-gp. However, NAMR inhibited P-gp in a concentration-dependent manner. Based on these in vitro results, NAMR had the potential to inhibit P-gp at therapeutic doses of EZG/RTG (600-1,200 mg/day). As digoxin has a narrow therapeutic index, inhibition of digoxin clearance may have an impact on its safety. METHODS: An open-label, single-center, two session, fixed-sequence study was conducted to assess the effect of co-administration of therapeutic doses of EZG/RTG on digoxin pharmacokinetics in healthy adults. In session 1, subjects received a single dose of digoxin 0.25 mg. In session 2, EZG/RTG was up-titrated over 6 weeks. Digoxin 0.25 mg was co-administered at EZG/RTG steady-state doses of 600, 900, and, based on tolerability, 1,050/1,200 mg/day. Blood samples were collected over 144 hours for determination of digoxin, EZG/RTG, and NAMR concentrations. Urine samples were collected over 48 hours for determination of digoxin concentrations. RESULTS: Of 30 subjects enrolled, 29 were included in the pharmacokinetic analysis. Compared with digoxin alone, co-administration with EZG/RTG led to small increases in the digoxin plasma area under the concentration-time curve (AUC)0-120 at doses of 600, 900, and 1,050/1,200 mg (geometric mean ratio 1.08, 90% confidence interval [CI] 1.01-1.15; 1.18, 90% CI 1.10-1.27; 1.13, 90% CI 1.05-1.21, respectively). Safety was consistent with previous repeat-dose studies of EZG/RTG in healthy subjects. CONCLUSION: Co-administration of EZG/RTG across the therapeutic range resulted in small, non-dose-dependent and non-clinically relevant increases in digoxin systemic exposure, suggesting that digoxin dose adjustment is not necessary.

The interaction potential of retigabine (ezogabine) with other antiepileptic drugs.

BACKGROUND: Retigabine is an antiepileptic drug (AED) that reduces neuronal excitability by enhancing neuronal KCNQ (Kv7) potassium channel activity. METHODS: This manuscript provides an overview of the drug-drug interaction potential of retigabine with other AEDs, using data collated from both in vitro work and clinical studies, either previously published or from relevant information collated during the development of retigabine. RESULTS: Retigabine is not a substrate for the major CYP enzymes and at clinically relevant concentrations there is little or no potential for retigabine to inhibit or induce the CYP enzymes or to inhibit the major renal drug transporters. The addition of retigabine to a range of existing AEDs showed little or no effect on the AED trough concentrations apart from a 20% decrease in lamotrigine concentrations. Results from a small phase II study showed that co-administration of valproic acid and topiramate had no impact on the PK of retigabine whereas carbamazepine and phenytoin increased the clearance of retigabine by approximately 27% and 36%, respectively. Conversely, a population PK analysis of combined data from phase I, II and III studies showed that none of the coadministered AEDs affected retigabine clearance apart from lamotrigine which lowered retigabine clearance by 6.7%. CONCLUSION: Retigabine is not metabolized by CYP isozymes and does not induce or inhibit these isozymes at clinically relevant concentrations. Therefore, retigabine is associated with a low potential for PK interactions with other drugs via CYP450. Overall, there was little or no potential for retigabine to interact with other available AEDs. Although some PK interactions were observed with lamotrigine, these are unlikely to be clinically relevant.

The effect of ezogabine on the pharmacokinetics of an oral contraceptive agent.

OBJECTIVES: Ezogabine (EZG) is a potassium-channel opener that has been approved as adjunctive treatment for partial-onset seizures in adults with epilepsy. This Phase I clinical study evaluated the pharmacokinetics (PK), safety, and tolerability of coadministration of EZG and a combined oral contraceptive (OC). METHODS: An open-label drug-interaction study was conducted in healthy, female volunteers aged 18 - 55 years with regular menstrual cycles. The effects of steady-state 750 mg EZG on the PK of a combined OC agent containing 1 mg norethindrone and 0.035 mg ethinyl estradiol were evaluated, along with the effect of the contraceptive hormones on EZG PK. Safety was evaluated by clinical laboratory, vital sign, electrocardiogram, physical examination, and adverse event (AE) assessments. RESULTS: Of 30 enrolled volunteers, 25 completed all treatments. OC did not affect the PK of EZG. EZG increased norethindrone area under the concentration-time curve (AUC) by 28%, with no change in the maximum plasma concentration (Cmax). Ethinyl estradiol Cmax was 21% lower with no change in AUC. The majority of AEs were mild in severity, with the most commonly reported being gastrointestinal disorders and nervous system disorders. No deaths or serious AEs were reported in this study. Five volunteers discontinued treatment due to AEs. CONCLUSIONS: EZG did not have any clinically relevant impact on exposure of OC hormones in this study, and the OC hormones did not alter EZG PK parameters. This study provides PK evidence that doses of EZG and OCs do not need to be altered when co-administered.

Efficacy and tolerability exposure-response relationship of retigabine (ezogabine) immediate-release tablets in patients with partial-onset seizures.

BACKGROUND: Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (Kv7) potassium channel activity. OBJECTIVES: The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials. METHODS: Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC0-τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated. RESULTS: AUC0-τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC0-τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure-response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC0-τ. CONCLUSIONS: Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600-1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%-50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.

Clinical pharmacokinetics of retigabine/ezogabine.

BACKGROUND: Retigabine is an antiepileptic drug that reduces neuronal excitability by enhancing potassium channel activity. METHODS: This manuscript summarizes the pharmacokinetic and biopharmaceutical properties of retigabine collated from published and unpublished in vitro and clinical phase I-III studies in healthy volunteers or patients with partial-onset seizures. RESULTS: Retigabine is rapidly absorbed with a median time to C(max) of 0.5-2.0 hours. Thereafter, plasma concentrations decline in a mono-exponential manner, with a median half-life of 6-8 hours. The absolute oral bioavailability of retigabine is ~60%. Retigabine is metabolized extensively by N-acetylation and subsequent N-glucuronidation. In vitro and in vivo studies have shown that the drug-interaction potential of retigabine is low. The pharmacokinetics of retigabine are linear over the dose range 200-400mg three times daily (tid), with ~ 35-50% between-subject variability. Systemic exposure was not affected by a high fat meal, but C(max) was, ~14% and ~38% higher in the fed versus fasted state for the 200 and 400mg tablets, respectively. Retigabine drug-related material is primarily eliminated renally with unchanged retigabine accounting for ~36%. Retigabine plasma clearance decreased as severity of renal or hepatic impairment increased. Systemic exposure to retigabine is unaffected by gender when normalized for body weight. In elderly patients, retigabine systemic exposure was higher, and half-life was longer than in younger patients. CONCLUSIONS: Retigabine should be administered tid without regard to food. No adjustments required for gender, race, or genetic/polymorphisms. Dosage adjustments are recommended in elderly patients and those with moderate and severe renal or moderate hepatic impairment.

The effects of ethanol on the pharmacokinetics, pharmacodynamics, safety, and tolerability of ezogabine (retigabine).

BACKGROUND: The antiepileptic drug ezogabine (EZG; US adopted name for retigabine [the international nonproprietary name]) reduces neuronal excitability by enhancing potassium channel activity. EZG has been approved as adjunctive treatment for adults with partial-onset seizures. OBJECTIVE: The goal of this study was to examine the impact of coadministration of ethanol 1 g/kg on the safety and tolerability of EZG and the consequences of coadministration on pharmacokinetic (PK) and pharmacodynamic (PD) parameters in healthy volunteers. METHODS: In a randomized, 4-way crossover, partially double-blind study, volunteers received 4 oral treatments (EZG 200 mg + ethanol placebo [light apple juice]; placebo + ethanol 1 g/kg; EZG 200 mg + ethanol 1 g/kg; or placebo + ethanol placebo) separated by 5 to 21 days. RESULTS: PK and PD parameters were evaluated in 17 healthy volunteers (19 to 55 years) who were currently moderate alcohol drinkers. Ethanol coadministration increased EZG AUC(0-∞) and C(max) by 36% and 23%, respectively. EZG had no impact on ethanol PK. Ethanol alone impaired balance, blurred vision, and increased intoxication and dizziness. Objective tests (reaction times, response accuracy, attention, and manual tracking) were also impaired by ethanol. EZG treatment alone had no impact on PD measures other than a variable, transient increase in blurred vision (vision clear-crisp visual analog scale scores). Treatments were generally tolerated, with no serious adverse events or discontinuations owing to adverse events. CONCLUSIONS: Ethanol increased EZG exposure, which did not seem to be clinically relevant. Except for an increase in blurred vision, impairment effects observed were related primarily to ethanol and were not exacerbated by the addition of EZG, which was generally tolerated with or without ethanol.

The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: implications for clinical use.

Retigabine [RTG (international nonproprietary name); ezogabine (EZG; U.S. adopted name)] is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (K(v)7) potassium (K(+)) channels. RTG/EZG has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. In this review we discuss the activity that RTG/EZG has demonstrated across a broad spectrum of in vitro/in vivo animal models of seizures, including generalized tonic-clonic, primary generalized (absence), and partial seizures, in addition to the compound's ability to resist and block the occurrence of seizures induced by a range of stimuli across different regions of the brain. The potency of RTG/EZG in models refractory to several conventional AEDs and the work done to assess antiepileptogenesis and neuroprotection are discussed. Studies that have evaluated the central nervous system side effects of RTG/EZG in animals are reviewed in order to compare these effects with adverse events observed in patients with epilepsy. Based on its demonstrated effect in a number of animal epilepsy models, the synergistic and additive activity of RTG/EZG with other AEDs supports its potential use in therapeutic combinations for different seizure types. The distinct mechanism of action of RTG/EZG from those of currently available AEDs, along with its broad preclinical activity, underscores the key role of KCNQ (K(v)7) K(+) channels in neuronal excitability, and further supports the potential efficacy of this unique molecule in the treatment of epilepsy.

Pharmacokinetics of azithromycin and moxifloxacin in human conjunctiva and aqueous humor during and after the approved dosing regimens.

PURPOSE: To evaluate the ocular pharmacokinetics of azithromycin and moxifloxacin in human conjunctiva and aqueous humor in subjects undergoing cataract surgery. DESIGN: Multicenter, open-label, randomized study. METHODS: Subjects scheduled for routine cataract surgery and with normal-appearing conjunctiva were eligible. One conjunctival biopsy sample and 1 aqueous humor sample were obtained from subjects randomly assigned to 1 of 10 prespecified time points (1 to 312 hours) after treatment initiation of azithromycin ophthalmic solution 1% or moxifloxacin ophthalmic solution 0.5%. Samples were assayed using liquid chromatography tandem mass spectrometry. RESULTS: Azithromycin 1% provided high concentrations (peak level, 559.7 µg/g) in human conjunctiva that were sustained at levels 1 to 2 orders of magnitude higher than those of moxifloxacin 0.5% throughout the 7-day dosing period and for at least 7 days thereafter. Azithromycin also showed an extended half-life (65.7 hours) in conjunctiva relative to that of moxifloxacin (28.6 hours). Accordingly, the concentration of azithromycin was maintained well above the minimum inhibitory concentration required for inhibition of growth of 90% of tested bacterial isolates for at least 7 days, whereas moxifloxacin conjunctival levels fell to levels at or less than the minimum inhibitory concentration required for inhibition of growth of 90% of tested bacterial isolates approximately 24 hours after the last dose. Peak aqueous humor concentration of moxifloxacin was higher (0.77 µg/mL) than that of azithromycin (0.053 µg/mL). No clinically relevant safety findings were observed. CONCLUSIONS: Azithromycin 1% demonstrated high, therapeutic levels in the conjunctiva that were maintained up to 7 days after completion of a 1-week dosing regimen. Aqueous humor levels, however, were subtherapeutic with this dosing regimen. In comparison, moxifloxacin achieved lower conjunctival tissue levels, but higher aqueous humor levels.

Systemic peripheral artery relaxation by KCNQ channel openers and hydrogen sulfide.

BACKGROUND: Perivascular adipose tissue secretes an adipocyte-derived relaxing factor (ADRF) that opens voltage-dependent K (Kv) channels in peripheral arteries. We studied the role of KCNQ-type Kv channels and tested the hypothesis that hydrogen sulfide (H2S) could be an ADRF. METHODS: We performed isometric contraction studies on systemic arteries of rats and mice. RESULTS: In mesenteric arteries and aortas without perivascular adipose tissue, the KCNQ channel openers retigabine, VRX0530727, VRX0621238, and VRX0621688 produced concentration-dependent vasorelaxation; VRX0621688 was the most potent vasodilator. The KCNQ inhibitor XE991 (30 micromol/l) blocked the effects of both the drugs and ADRF. Inhibitors of cystathionine gamma lyase (CSE) beta-cyano-L-alanine (BCA, 5 mmol/l) and 4-propargyl glycine (PPG, 10 mmol/l) also blocked the relaxations. CSE is expressed in perivascular adipose tissue and endogenously generates H2S. The H2S donor NaHS produced concentration-dependent vasorelaxation, which was also blocked by XE991. The vasodilatory capacities of retigabine, VRX0530727, VRX0621238, and VRX0621688 were preserved following inhibition of H2S generation in perivascular fat. CONCLUSION: We suggest that KCNQ channel opening is a powerful mechanism to produce vasorelaxation of systemic arteries in rats and mice. Furthermore, KCNQ channels play a major role in the paracrine control of vascular tone by perivascular adipose tissue, which is at least in part mediated or modulated by H2S. In conditions of reduced H2S release from perivascular adipose tissue, these paracrine effects can be mimicked by synthetic KCNQ channel openers.