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 .

Mass balance and metabolism of aclidinium bromide following intravenous administration of [¹4C]-aclidinium bromide in healthy subjects.

Aclidinium bromide is a novel, inhaled long-acting muscarinic antagonist with low systemic activity developed for the treatment of COPD. It is an ester compound rapidly hydrolysed in plasma into inactive alcohol and acid metabolites. In this Phase I, open-label study, the rates and routes of elimination of radioactivity following intravenous administration of [¹4C]-aclidinium bromide were determined. The metabolites of aclidinium were also characterized and identified in plasma and excreta. Twelve healthy males were randomized (1:1) to receive a single intravenous 400 µg dose of [phenyl-U-¹4C]- or [glycolyl-U-¹4C]-aclidinium bromide (via 5 min infusion) to label alcohol or acid metabolites of aclidinium, respectively. Safety and tolerability were assessed over a 9-day period. Following intravenous administration, the parent compound was rapidly hydrolysed into its acid and alcohol metabolites. Primary excretion routes for [phenyl-U-¹4C]- and [glycolyl-U-¹4C]-aclidinium were renal (urine: 65% and 54%, respectively; feces: 33% and 20%, respectively), with 1% excreted as unchanged aclidinium. A total of three treatment-emergent adverse events in two subjects were reported and were related to infusion site pain. Overall, aclidinium is rapidly hydrolysed into two main metabolites, which are predominantly excreted in urine. Aclidinium bromide 400 µg administered intravenously was safe and well tolerated in healthy subjects.

Safety and tolerability of aclidinium administered intravenously and absolute bioavailability of inhaled aclidinium in healthy male participants.

Aclidinium bromide is a long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease treatment. This 2-part, phase I study evaluated the safety and tolerability of single ascending intravenous (IV) doses of aclidinium to determine its maximum tolerated dose (MTD; part I) and its absolute bioavailability (part II). Healthy male participants (N = 24) were randomized (1:1) in each part: 3-period crossover, placebo-controlled, single-ascending, alternating IV doses of aclidinium (25-400 µg) in part I and 2-period crossover, single-alternating IV and inhaled doses of aclidinium (200 µg) in part II. A ≥7-day washout separated treatment periods. Pharmacokinetic data were collected in both parts. Following IV or inhaled aclidinium, time to reach maximum plasma concentration following drug administration (t(max) ) was 5 to 7 minutes for all doses. After maximum plasma drug concentration (C(max)), aclidinium was rapidly cleared from plasma. Aclidinium absolute bioavailability was <5% following a single inhaled 200-µg dose. Urinary excretion of unchanged aclidinium was very low, with a greater amount of inactive metabolites excreted compared with aclidinium, all of which were recovered within 12 hours postdose. The MTD following IV administration was not reached; all single IV (25-400 µg) and inhaled doses (200 µg) were well tolerated. In conclusion, the low and short-lived bioavailability of aclidinium and the low incidence of systemic side effects contribute to its positive safety and tolerability profile.

Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: A phase I, open-label, single-dose clinical trial.

BACKGROUND: Aclidinium bromide is an inhaled, long-acting muscarinic antagonist currently in development for the treatment of chronic obstructive pulmonary disease. Renal impairment may affect drug clearance. OBJECTIVE: This study was conducted to evaluate the pharmacokinetic (PK) parameters, safety, and tolerability of aclidinium bromide and its metabolites in patients with normal and impaired renal function to determine whether dosing adjustments are required when renal dysfunction is present. METHODS: This was a Phase I, open-label, single-center, single-dose clinical trial conducted in Munich, Germany. Adults with varying degrees of renal function were assigned to 4 groups (n = 6 for each) based on creatinine clearance, including normal renal function (>80 mL/ min), mild renal insufficiency (>50-≤80 mL/min), moderate renal insufficiency (>30-≤50 mL/min), and severe renal insufficiency (<30 mL/min). Single doses of aclidinium bromide 400 µg were administered using a multidose dry powder inhaler. Blood and urine samples were obtained before dosing and at various time points up to 48 hours after dosing to analyze the PK parameters of aclidinium bromide and its metabolites. Plasma PK Parameters were AUC0₋(t), MJC0₋(∞) C(max), T(max), t(½) CL/F and apparent volume of distribution during the terminal phase Xz; urinary parameters were the amount of aclidinium or acid or alcohol metabolite excreted in urine, the percentage of the dose excreted in urine (fe), and renal clearance (CL(R)). Tolerability was assessed using physical examination, vital signs, 12-lead ECG recordings, laboratory tests, and adverse-event (AE) reports. The Wilcoxon rank sum test was used to compare the median PK values between the normal and impaired renal function groups. Pearson correlation coefficients and linear regression models were used to analyze the relationship between creatinine clearance and AUC0₋(∞) and between creatinine clearance and CL(R) for aclidinium and its metabolites. RESULTS: A total of 16 men and 8 women were included in the study. All participants were white; mean (SD) age was 55 (10.7) years and weight was 70.8 (9.2) kg. Aclidinium Cmax was observed in plasma by 5 minutes after dosing (ie, median Tmax) and did not differ significantly among the renal function groups. Plasma concentrations of aclidinium declined after reaching Cmax, with median t(½) values ranging from 2.07 to 4.18 hours across all renal function groups. Most of the individual t(½) values were between 1.5 and 3.5 hours, regardless of the degree of renal insufficiency. No significant relationship between AUC0₋(∞)) and creatinine clearance was observed (Pearson correlation coefficient = -0.0446; P = NS). Urinary excretion of aclidinium was very low, with a mean 0.090% (median 0.078%) of the dose recovered from the urine in participants with normal renal function. Eight AEs were reported in 7 participants after drug administration; all were mild to moderate in severity and resolved spontaneously. There were no serious drug-related AEs and no deaths. CONCLUSIONS: The plasma PK parameters of aclidinium bromide were not significantly altered after a single inhaled dose of aclidinium bromide 400 µg in this small group of patients with various degrees of impaired renal function. The very low urinary excretion of aclidinium in all renal function groups indicates that renal function plays a minor role in aclidinium plasma clearance. Aclidinium appeared well tolerated in the population studied. These results suggest that aclidinium dose adjustment on the basis of renal function may not be necessary.

Safety and pharmacokinetics of multiple doses of aclidinium bromide, a novel long-acting muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, in healthy participants.

Systemic exposure to anticholinergics used for chronic obstructive pulmonary disease (COPD) may lead to side effects. This study assessed safety, tolerability, and pharmacokinetics of multiple doses of aclidinium bromide, a novel, long-acting antimuscarinic. Sixteen healthy participants received aclidinium bromide 200, 400, or 800 microg or placebo by dry-powder inhaler for 5 days, with > or =7 days washout. Aclidinium bromide and metabolite pharmacokinetics were assessed. Aclidinium bromide plasma levels were below the lower limit of quantification (LLOQ: 0.05 ng/mL) after 200 microg and in most participants after 400 microg. Plasma levels in all participants were below the LLOQ at all doses, including the highest dose, beyond 1 hour postdose. AUC(0-t) and C(max) at steady state were, respectively, 0.08 ng.h/mL and 0.12 ng/mL (aclidinium bromide), 0.40 ng.h/mL and 0.14 ng/mL (alcohol metabolite), and 13.47 ng.h/mL and 2.26 ng/mL (acid metabolite). The t(max) for aclidinium bromide 800 microg was 15 minutes (first kinetic time point). Adverse event frequency was comparable between treatment groups and placebo. The most commonly reported adverse events, probably treatment related, were coughing (n = 2) and dysphagia (n = 1); 94% of adverse events were mild. These data suggest a low systemic bioavailability and favorable safety profile for aclidinium bromide with repeated dosing for COPD.

Incurred sample reproducibility: views and recommendations by the European Bioanalysis Forum.

Following intensive discussions, review, alignment of procedures and multiple surveys among their member companies, the European Bioanalysis Forum (EBF) is providing a recommendation on how to integrate incurred sample reproducibility (ISR) in the bioanalytical process. The recommendation aims to provide guidance throughout the lifecycle of a validated method, including the application of the method in study support. In its recommendation, the EBF considers both the internal discussions with EBF member companies, as well as the input provided in international meetings where ISR was discussed. The ultimate goal of the EBF recommendation is to ensure that bioanalytical methods can provide accurate and reproducible concentration data for pharmacokinetic and/or toxicokinetic evaluation, without any compromise, while safeguarding the optimal use of laboratory resources.

Identification of the human liver enzymes involved in the metabolism of the antimigraine agent almotriptan.

Almotriptan is a novel highly selective 5-hydroxytryptamine(1B/1D) agonist developed for the acute oral treatment of migraine. The in vitro metabolism of almotriptan has been investigated using human liver subcellular fractions and cDNA-expressed human enzymes, to study the metabolic pathways and identify the enzymes responsible for the formation of the major metabolites. Specific enzymes were identified by correlation analysis, chemical inhibition studies, and incubation with various cDNA expressed human enzymes. Human liver microsomes and S9 fraction metabolize almotriptan by 2-hydroxylation of the pyrrolidine group to form a carbinolamine metabolite intermediate, a reaction catalyzed by CYP3A4 and CYP2D6. This metabolite is further oxidized by aldehyde dehydrogenase to the open ring gamma-aminobutyric acid metabolite. Almotriptan is also metabolized at the dimethylaminoethyl group by N-demethylation, a reaction that is carried out by five different cytochrome P450s, flavin monooxygenase-3 mediated N-oxidation, and MAO-A catalyzed oxidative deamination to form the indole acetic acid and the indole ethyl alcohol derivatives of almotriptan. The use of human liver mitochondria confirmed the contribution of MAO-A to the metabolism of almotriptan. Both, the gamma-aminobutyric acid and the indole acetic acid metabolites have been found to be the major in vivo metabolites of almotriptan in humans. In addition, different clinical trials conducted to study the effects of CYP3A4, CYP2D6, and MAO-A on the pharmacokinetics of almotriptan confirmed the involvement of these enzymes in the metabolic clearance of this drug and that no dose changes are required in the presence of inhibitors of these enzymes.

Absolute bioavailability, pharmacokinetics, and urinary excretion of the novel antimigraine agent almotriptan in healthy male volunteers.

Absolute bioavailability, pharmacokinetics, and urinary excretion of almotriptan, a novel 5-HT(1B/1D) receptor agonist, were studied in 18 healthy males following single intravenous (i.v.) (3 mg), subcutaneous (s.c.) (6 mg), and oral (25 mg) doses. Volunteers received each dose in a randomized sequence separated by a 7-day washout. Blood and urine samples for pharmacokinetic evaluations were taken for up to 24 hours after dosing. The disposition kinetics of almotriptan after i.v. and s.c. administration showed biphasic decline described by a two-compartment model. The fastest disposition phase was well observed, although estimates of the rate constant showed high variability. After s.c. administration of almotriptan, the bioavailability was 100% with a time to maximum plasma concentration (tmax) of 5 to 15 minutes, whereas after oral administration, the bioavailability was about 70% with a tmax of 1.5 to 3.0 hours. No significant differences were observed between administration routes in the elimination half-life (t(1/2), obtaining mean values ranging from 3.4 to 3.6 hours. The volume of distribution, total clearance, and t(1/2) indicated that almotriptan was extensively distributed and rapidly cleared from the body irrespective of dose or route of administration. The primary route of elimination was renal clearance (approximately 50%-60% of total body clearance). About 65% of the i.v. and s.c. dose and 45% of the oral dose were excreted unchanged in urine in 24 hours, with nearly 90% of this in the first 12 hours. Renal clearance was approximately 2- to 3-fold that of the glomerular filtration rate in man, suggesting that almotriptan is eliminated in part by renal tubular secretion.

Almotriptan, a new anti-migraine agent: a review.

Almotriptan is a new anti-migraine agent with nanomolar affinity for human 5-HT(1B), 5-HT(1D), and 5-HT(1F) receptors, weak affinity for 5-HT(1A) and 5-HT(7) receptors and no significant affinity for more than 20 other pharmacological receptors. Almotriptan was effective in animal models predictive of anti-migraine activity in humans and had a good safety profile in animal studies. From the toxicological point of view, almotriptan has a profile similar to that of other marketed triptans. In animal studies, at levels substantially higher than required for therapeutic activity in humans, almotriptan was devoid of any oncogenic, genotoxic or teratogenic effects. Almotriptan is well absorbed orally; its absolute bioavailability in humans is 70%. Its peak plasma levels are reached at 1 to 3 h after its administration; its elimination half-life is 3 to 4 h. Almotriptan is metabolized by monoamine oxidase-mediated oxidative deamination and cytochrome P450-mediated oxidation as the major metabolic route and by flavin monooxygenase as the minor route. No dose adjustment is required for gender or age, and only in the case of severe renal impairment the dose should not exceed 12.5 mg over a 24-h period. There was no significant interaction between a single dose of almotriptan and propranolol, fluoxetine or verapamil, at multiple doses. The efficacy of almotriptan in the treatment of acute migraine was demonstrated in clinical trials on more than 3000 patients with migraine. At two h after oral administration of almotriptan, 12.5 mg, the percentages of patients showing pain relief and a pain-free score were 64 and 36%, respectively. The effects of almotriptan were significantly better than those of placebo. When almotriptan was administered in the early phase of migraine, the percentage of pain-free patients at 2 h rose to 84%. In a phase III, double-blind and placebo-controlled study, the incidence of adverse events with almotriptan was not statistically different from that of placebo. Based on the available data, it appears that almotriptan is the triptan of choice when good efficacy and high tolerability are desired.