Olodaterol has a high affinity and high selectivity to the human beta2-adrenoceptor.
In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta2-adrenoceptors compared to beta1-adrenoceptors and 2299-fold greater agonist activity compared to beta3-adrenoceptors.
The compound exerts its pharmacological effects by binding and activation of beta2-adrenoceptors after topical administration by inhalation.
Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3',5' adenosine monophosphate (cAMP). Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells.
Olodaterol has the pre-clinical profile of a long-acting selective beta2-adrenoceptor agonist (LABA) with a fast onset of action and a duration of action of at least 24 hours.
Beta-adrenoceptors are divided into three subtypes, beta1-adrenoceptors predominantly expressed on cardiac smooth muscle, beta2-adrenoceptors predominantly expressed on airway smooth muscle and beta3-adrenoceptors predominantly expressed on adipose tissue. beta2-agonists cause bronchodilation. Although the beta2-adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart. The precise function of beta2-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
The effect of olodaterol on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomised, placebo- and active (moxifloxacin) controlled study. Olodaterol at single doses of 10, 20, 30 and 50 microgram, demonstrated that compared with placebo, the mean changes from baseline in QT interval over 20 minutes to 2 hours after dosing increased dose-dependently from 1.6 (10 microgram olodaterol) to 6.5 ms (50 microgram olodaterol), with the upper limit of the two-sided 90% confidence intervals being less than 10 ms at all dose levels for individually corrected QT (QTcI).
The effect of 5 microgram and 10 microgram olodaterol on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled Phase 3 trials. There were no dose- or time-related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between olodaterol 5 microgram, 10 microgram and placebo.
Information on the pharmacokinetics of olodaterol has been obtained from healthy subjects, COPD and asthma patients following oral inhalation of doses at and above the therapeutic dose.
Olodaterol showed linear pharmacokinetics with a dose-proportional increase of systemic exposure after single inhaled doses of 5 to 70 microgram and multiple once daily inhaled doses of 2 to 20 microgram.
On repeated once daily inhalation steady-state of olodaterol plasma concentrations was achieved after 8 days, and the extent of exposure was increased up to 1.8-fold as compared to a single dose.
Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30% whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption.
Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. In vitro binding of [14C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%.
Olodaterol is a substrate for the P-gp, OAT1, OAT3 and OCT1 transporter. Olodaterol is not a substrate for the following transporters: BCRP, MRP, OATP2, OATP8, OATP-B, OCT2 and OCT3.
Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta2-receptors. This metabolite however is not detectable in plasma after chronic inhalation of the recommended therapeutic dose or doses of up to 4-fold higher. Olodaterol thus is considered the only compound relevant for pharmacological action.
Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7 and 1A9 were shown to be involved in the formation of olodaterol glucuronides.
Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min.
Following intravenous administration of [14C]-labelled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in faeces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of the radioactivity (0.7% unchanged olodaterol) was recovered in urine, while the major portion was recovered in faeces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5-7% of the dose.
Olodaterol plasma concentrations after inhalation decline in a multiphasic manner with a terminal half-life of approximately 45 hours.
A pharmacokinetic meta-analysis was performed utilizing data from 2 controlled clinical trials that included 405 patients with COPD and 296 patients with asthma who received treatment with olodaterol.
The analysis showed that no dose adjustment is necessary based on the effect of age, gender and weight on systemic exposure in COPD patients after inhalation of olodaterol.
There were no clinically relevant increases of systemic exposure in patients with renal impairment.
There was no evidence for differences in elimination of olodaterol, nor did protein binding differ, between subjects with mild or moderate hepatic impairment and their healthy controls. A study in subjects with severe hepatic impairment was not performed.
Comparison of pharmacokinetic data within and across studies revealed a trend for higher systemic exposure in Japanese and other Asians than in Caucasians.
No safety concerns were identified in clinical studies with Caucasians and Asians of up to one year with olodaterol at doses up to twice the recommended therapeutic dose.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Studies on genotoxicity and carcinogenic potential revealed no special hazard for humans.
Increased incidences were observed of mesovarian leiomyoma in rats and of uterus leiomyoma and leiomyosarcoma in mice. This is considered a class effect which is observed in rodents after long-term exposure to high doses of β2-agonists. Up to now, β2-agonists have not been associated with cancer in humans.
In the rat, no teratogenic effects occurred after inhalation of doses up to 1054 microgram/kg/day (approximately 1600 times the maximum recommended human daily inhalation dose (MRHDID) in adults (5 microgram) on a mg/m² basis). In pregnant NZW rabbits the administered inhalation dose of 2489 microgram/kg/day (exposure multiple versus the MRHDID of >3500 on AUC0-24) of olodaterol exhibited fetal toxicity characteristically resulting from beta-adrenoceptor stimulation; these included patchy ossifications, short/bent bones, partially open eye, cleft palate, cardiovascular abnormalities.
No significant effects occurred at an inhalation dose of 974 microgram/kg/day (approximately 1580 times the MRHDID in adults on a mg/m² basis).