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.

Phase 1 Renal Impairment Trial Results Supports Targeted Individualized Dosing of ELX-02 in Patients With Nephropathic Cystinosis.

The aim of this study was to assess the pharmacokinetics (PK) and safety of ELX-02 in a renally impaired population and apply these findings to the individualized dosing of patients with nephropathic cystinosis. This phase 1 renal impairment (RI; mild, moderate, or severe), single-dose, PK, and safety evaluation included 6 participants assigned to each RI group. Six healthy controls with normal renal function were matched to participants with renal impairment. All received a single subcutaneous dose of 1-mg/kg ELX-02 on day 1 and were monitored for 72 hours after dosing with serial blood and urine samples. An estimated glomerular filtration rate (eGFR)-PK model of ELX-02 was developed from the RI study data and used to implement individualized dosing in a phase 2a study in patients with nephropathic cystinosis to achieve a weekly targeted exposure (area under the plasma concentration-time curve [AUC]). In participants with RI, ELX-02 clearance decreased, and exposure increased with severity of RI. ELX-02 plasma exposure was similar to healthy controls in participants with mild RI, but increasing severity of RI resulted in significantly decreased clearance, increased maximum plasma concentration, AUC from time zero to infinity, and half-life compared to controls. ELX-02 urinary clearance showed a similar pattern. Relationships between eGFR and exposure were defined supporting individualized dose determination for prediction of dose and AUC in patients with nephropathic cystinosis, achieving overall mean 110.7% of AUC targets. ELX-02 was well tolerated by RI and nephropathic cystinosis populations. ELX-02 exhibits a consistent PK profile across increasing degrees of RI with reduced clearance, increased exposure, and prolonged renal elimination proportional to reductions in eGFR. The defined relationship between eGFR and plasma exposure enabled individualized dose adjustment in patients with nephropathic cystinosis.

Pharmacokinetics of clobazam oral soluble film.

OBJECTIVE: Clobazam oral soluble film (COSF) is a novel dosage form under development for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. The present study was undertaken to assess the pharmacokinetics of clobazam administered as single doses of COSF 20 and 10 mg compared with clobazam tablets (CTAB) 20 and 10 mg in healthy adults. A secondary objective was to assess the safety and tolerability of single doses of COSF 20 and 10 mg. METHODS: A total of 51 adult volunteers were enrolled in a single-dose, open-label, randomized four-sequence, four-period, crossover study with treatments (A) COSF 20 mg, (B) CTAB 20 mg, (C) COSF 10 mg, and (D) CTAB 10 mg. Pharmacokinetic sampling for clobazam and N-desmethylclobazam was carried out until 21 days postdose with a 28-day washout. Subjects were monitored for adverse events (AEs) throughout the study. Visual inspections of the administration site were performed before and after COSF administration to monitor for mucosal irritation. RESULTS: COSF at single doses of 10 and 20 mg was bioequivalent to CTAB at equivalent doses for both clobazam and its active metabolite N-desmethylclobazam. The pharmacokinetics of both formulations was dose-proportional at doses of 10 and 20 mg. The number of AEs and the number of subjects experiencing AEs were dose-related across the treatment groups, with somnolence the most common event. None of these events was severe or serious, and most were mild. There was no evidence for local irritation at the administration site following COSF. SIGNIFICANCE: COSF is a novel clobazam dosage form that is bioequivalent to CTAB. Because of its ease of administration, COSF may be expected to improve adherence, reduce likelihood of dosing error, and provide more accurate dosing than formulations of clobazam that are currently available.