Pharmacokinetics, Safety, and Tolerability of a Single 5-Day Treatment of Tirbanibulin Ointment 1% in 100 cm2 : A Phase 1 Maximal-Use Trial in Patients with Actinic Keratosis.

Tirbanibulin ointment 1% is approved in the United States and Europe for the treatment of actinic keratosis with demonstrated efficacy, safety, and tolerability when applied over a field up to 25 cm2 . This Phase 1 maximal-use trial determines the plasma pharmacokinetics, safety, and tolerability of tirbanibulin ointment 1% applied to 100 cm2 of the face or balding scalp in adults with actinic keratosis. Twenty-eight patients self-applied tirbanibulin once daily for a single 5-day treatment course. On Day 5, the mean maximum plasma concentration was 1.06 ng/mL and area under the plasma concentration-time curve during a dosing interval was 16.2 ng â€¢ h/mL. Systemic exposure was approximately 4-fold higher than in a previous pharmacokinetic study with a 25 cm2 field, consistent with the increase in the treated area. Tirbanibulin applied to a 100-cm2 treatment field showed favorable safety and tolerability. The most common treatment-emergent adverse events were application site reactions (in 35.7% of patients). All treatment-emergent adverse events and most of the tolerability signs were mild/moderate and resolved or returned to baseline by Day 29. In summary, under maximal-use conditions, tirbanibulin ointment 1% was safe and well tolerated supporting its potential use over a field up to 100 cm2 .

No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P-glycoprotein (P-gp) drug transporter.

Dimethylfumarate (DMF) has long been used as part of a fixed combination of fumaric acid esters (FAE) in some European countries and is now available as an oral monotherapy for psoriasis. The present investigation determined whether DMF and its main metabolite monomethylfumarate (MMF) interact with hepatic cytochrome P450 (CYP) enzymes and the P-glycoprotein (P-gp) transporter, and was performed as part of DMF's regulatory commitments. Although referred to in the available product labels/summary of product characteristics, the actual data have not yet been made publicly available. In vitro inhibition experiments using CYP-selective substrates with human liver microsomes showed 50% inhibitory concentrations (IC50) of >666 µmol/L for DMF and >750 µmol/L for MMF. MMF (≤250 µmol/L; 72 hours) was not cytotoxic in cultured human hepatocyte experiments and mRNA expression data indicated no CYP induction by MMF (1-250 µmol/L). DMF (≤6.66 mmol/L) showed moderate-to-high absorption (apparent permeability [Papp] ≥2.3-29.7 x 10-6 cm/s) across a Caucasian colon adenocarcinoma (Caco-2) cell monolayer, while MMF (≤7.38 mmol/L) demonstrated low-to-moderate permeability (Papp 1.2-8.9 × 10-6 cm/s). DMF was not a substrate for P-gp (net efflux ratios ≤1.22) but was a weak inhibitor of P-gp at supratherapeutic concentrations (estimated IC50 relative to solvent control of 1.5 mmol/L; [3H]digoxin efflux in Caco-2 cells). This inhibition is unlikely to be clinically relevant. MMF was not a substrate or inhibitor of P-gp. Thus, DMF and MMF should not affect the absorption, distribution, metabolism or excretion of coadministered drugs that are CYP and P-gp substrates.

Pharmacokinetics of aclidinium bromide/formoterol fumarate fixed-dose combination compared with individual components: A phase 1, open-label, single-dose study.

Inhaled, long-acting bronchodilators represent a cornerstone of maintenance treatment for chronic obstructive pulmonary disease (COPD). Aclidinium bromide/formoterol fumarate 400/12 µg fixed-dose combination (FDC) has recently been licensed for use in adults with COPD in the European Union. This phase 1, randomized, open-label, 3-way, complete crossover, single-dose study assessed the pharmacokinetics, safety, and tolerability of an FDC, aclidinium bromide 400 µg, and formoterol fumarate 12 µg, all administered via Genuair™ to 30 healthy subjects. The rate and extent of absorption were comparable for aclidinium/formoterol FDC and individual monotherapies; aclidinium/formoterol FDC and aclidinium alone: Cmax , 270 and 215 pg/mL, respectively; AUC0-t , 229 and 222 pg · h/mL, respectively; aclidinium/formoterol FDC and formoterol alone: Cmax , 11 and 9.3 pg/mL, respectively; AUC, 36 and 32.4 pg · h/mL, respectively. There were no major differences in relative bioavailability between the combination and monotherapies: the aclidinium Cmax and AUC0-t were 26% and 3% higher, respectively, with aclidinium/formoterol FDC compared with aclidinium alone, and 18% and 11% higher, respectively, compared with formoterol alone. Aclidinium/formoterol FDC was well tolerated; the incidence of adverse events was low and similar to the monotherapies. Aclidinium/formoterol FDC was not associated with any major differences in rate and extent of absorption or relative bioavailability compared with monotherapies.

Aclidinium bromide, a novel long-acting muscarinic antagonist for COPD with improved preclinical renal and urinary safety profile.

AIMS: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently in registration phase for the treatment of chronic obstructive pulmonary disease. Since urinary difficulty and retention have been reported for anticholinergic agents such as tiotropium and ipratropium, it is important to examine the preclinical urinary and renal safety profile of aclidinium. MAIN METHODS: The effect of aclidinium on urine and electrolyte excretion, renal function and voiding cystometry was analysed in conscious water-loaded Wistar rats (10-1000 µg/kg, s.c.), anaesthetised Beagle dogs (1000 µg/kg, i.v.) and anaesthetised guinea pigs (3-100µg/kg, intratracheally), respectively. Aclidinium plasma levels were determined in an independent study. Active comparators were tiotropium (all studies) and ipratropium (cystometry only). KEY FINDINGS: Aclidinium 1000 µg/kg had no effect on urine excretion in rats, in contrast to tiotropium 100 µg/kg which significantly decreased this parameter (p<0.05). Aclidinium 1000 µg/kg also had no effect on renal function in Beagle dogs. In guinea pigs, aclidinium 3-100 µg/kg had no effect on urinary bladder function, whereas tiotropium and ipratropium 100 µg/kg decreased the peak micturition pressure (p<0.05), increased the volume of urine retained in the bladder (p<0.01) and showed a trend to decrease the volume of urine excreted. SIGNIFICANCE: Aclidinium had no significant effect on urinary and renal function in the animal models studied. These results, together with the rapid plasma clearance of aclidinium reported previously, suggest a lower propensity to induce urinary retention in humans than tiotropium and ipratropium.

Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects.

In this phase I trial, the effect of aclidinium, a novel, inhaled long-acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 µg, aclidinium 800 µg, matching placebo, or open-label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate-corrected QT interval (QTcI). Secondary measures included Bazett-corrected QT interval (QTcB), Fridericia-corrected (QTcF) intervals, 12-lead electrocardiogram (ECG) readings, and 24-hour 12-lead Holter ECG parameters. Adverse events, vital signs, and laboratory and pharmacokinetic parameters were also assessed. Maximum mean QTcI change from time-matched baseline on day 3 was -1.0 milliseconds at 2 hours for aclidinium 200 µg, -1.8 milliseconds at 5 minutes for 800 µg, +11.0 milliseconds at 4 hours for moxifloxacin, and -1.2 milliseconds at 23.5 hours for placebo. Aclidinium had no significant effects on secondary ECG measures. Aclidinium plasma concentrations were generally below the lower limit of quantitation (0.05 ng/mL) after 200 µg and were detected only up to 1 hour after the 800-µg dose in the majority of cases. It is concluded that aclidinium bromide, at doses up to 800 µg, has a favorable cardiovascular safety profile with no effect on QT interval.