Abstract Tiotropium/olodaterol (Stiolto™ Respimat®, Spiolto™ Respimat®) is a fixed-dose combination of the long-acting antimuscarinic agent tiotropium bromide (hereafter referred to as tiotropium) and the long-acting β2-adrenoreceptor agonist olodaterol delivered via the Respimat® inhaler. It is indicated for the maintenance treatment of airflow obstruction in adults with COPD. Several well-designed, phase III studies of 6–52 weeks’ duration evaluated the efficacy of once-daily tiotropium/olodaterol in patients with GOLD stage 2–3 or 2–4 COPD. Tiotropium/olodaterol maintenance therapy improved lung function to a greater extent than the individual components or placebo and provided clinically meaningful improvements in health-related quality of life and dyspnoea in 12- and 52-week studies. Tiotropium/olodaterol consistently improved 24-h lung function in 6-week studies, providing greater benefits than the monotherapies, placebo or twice-daily fixed-dose fluticasone propionate/salmeterol. Inspiratory capacity and exercise endurance were also improved with tiotropium/olodaterol following 6 or 12 weeks’ treatment. The tolerability profile of tiotropium/olodaterol in the phase III studies was
generally similar to that of the component monotherapies. The most common adverse events and serious adverse events during 52 weeks’ therapy were respiratory in nature, with COPD, unsurprisingly, reported most frequently with tiotropium/olodaterol and component monotherapies. Although further studies assessing the effect of tiotropium/olodaterol on exacerbations and comparative studies with other recommended therapies are needed to definitively position tiotropium/olodaterol, current evidence indicates that tiotropium/olodaterol is a useful treatment option for patients with COPD.
1 Springer, Private Bag 65901, Mairangi Bay 0754, Auckland,
New Zealand
Tiotropium/olodaterol: clinical considerations in COPD Provides greater bronchodilation by combining bronchodilators with different mechanisms of action Offers the convenience of once-daily administration via a single inhaler Improves lung function to a greater extent than component monotherapies Provides greater lung function benefits over 24 h than monotherapies or fluticasone propionate/salmeterol Improves health-related quality of life and dyspnoea to a clinically meaningful extent Improves inspiratory capacity and exercise endurance Generally well tolerated, with most adverse events of mild or moderate severity. Does not increase the risk of cardiovascular events
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1 Introduction
Chronic obstructive pulmonary disease (COPD) describes a group of progressively debilitating lung diseases that limit airflow and interfere with normal breathing [1, 2]. Chronic irritants (e.g. cigarette smoke and smoke from biomass fuels) are thought to modify the inflammatory response of the respiratory tract, inducing parenchymal tissue destruction (leading to emphysema) and the disruption of normal repair and defence mechanisms (leading to small airway fibrosis), resulting in progressive airflow limitation [2]. Management strategies for COPD include reducing exposure to risk factors and treatment with pharmacological agents [2]. Pharmacotherapy is aimed at reducing symptoms and the frequency and severity of exacerbations, as well as improving health-related quality of life (HR-QOL) and exercise tolerance [2]. Several pharmacological options are available, including bronchodilators (e.g. β2-adrenoreceptor agonists, anticholinergics and theophylline), inhaled corticosteroids (ICS) and phosphodiesterase-4(PDE4) inhibitors [2].
Bronchodilators are the cornerstone of symptom management in stable COPD, with inhaled therapy preferred over oral therapy and long-acting formulations, because of their ease of use and more effective bronchodilation, preferred over short-acting formulations [2, 3]. Combination therapy with bronchodilators of different drug classes and complementary mechanisms of action may improve bronchodilator response, while maintaining or reducing the risk of adverse events (AEs), providing a rationale for the development of fixed-dose dose combinations [2, 3]. Other potential advantages of fixed-dose dose combinations include the ease of use, which may lead to improved compliance and consequently improved patient outcomes, and optimization of the administered dose of the individual agents [3]. Tiotropium/olodaterol (Stiolto™ Respimat®, Spiolto™ Respimat®) is a fixed-dose combination of the long-acting antimuscarinic agent (LAMA) tiotropium bromide (hereafter referred to as tiotropium) and the long-acting β2-adrenoreceptor agonist (LABA) olodaterol delivered via the Respimat® inhaler. Tiotropium/olodaterol has recently been approved in the USA [4] and EU [5] for use in patients with COPD. This article reviews the therapeutic efficacy and tolerability of tiotropium/olodaterol in this indication and summarizes relevant pharmacological data.
2 Pharmacodynamic Properties of Tiotropium/Olodaterol
The pharmacodynamic properties of tiotropium and olodaterol have been reviewed previously [6, 7]. No new pharmacodynamic studies have been conducted with the tiotropium/olodaterol fixed-dose combination [8].
Tiotropium 2.1
Tiotropium is a LAMA with similar affinity for the muscarinic receptors M1 to M5 [4, 5, 9], of which the M1, M2 and M3 receptors are expressed in human lungs [10]. Tiotropium displays kinetic subtype selectivity as it dissociates more slowly from human M1 and M3 than from M2 receptors [9, 11, 12] (half-lives of 14.6 and 34.7 vs. 3.6 h) [9]. Tiotropium binds competitively and reversibly to the M3 receptors on airway smooth muscles and inhibits the action of acetylcholine at the muscarinic receptors, thereby indirectly leading to smooth muscle relaxation [4, 5, 13-15]. As tiotropium is an N-quaternary cholinergic compound, it’s effects are largely site-specific when administered by inhalation [4, 5]. Clinical studies in patients with COPD showed that the bronchodilatory effects of inhaled tiotropium were dose-dependent and lasted for at least 24 h [4, 5, 16, 17]. During up to 4 years’ therapy, tiotropium was associated with improved lung function and reduced exacerbations in patients with COPD [18-20]. In healthy volunteers (n = 53), tiotropium doses of 18 and 54 μg (i.e. three times the therapeutic dose) for 12 days did not significantly prolong QT interval [4, 5].
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Olodaterol 2.2
Olodaterol is a potent (half-maximal effective concentration of 0.1 nmol/L) and highly selective LABA (241- and 2299-fold greater selectivity for human β2 than β1 and β3 receptors in vitro) [21]. Olodaterol binds to and activates β2 receptors expressed on airway smooth muscle cells, resulting in the stimulation of intracellular adenyl cyclase and increased synthesis of cyclic-3', 5' adenosine monophosphate, which results in smooth-muscle relaxation and bronchodilation [4, 5, 15]. Inhaled olodaterol has a fast onset of action and a duration of action of at least 24 h [21, 22]. Clinical studies showed that olodaterol improved lung function in patients with COPD during 48 weeks treatment [23, 24].
In addition to being the predominant adrenergic receptor on airway smooth muscle cells, β2 receptors are expressed on several other cell-types, including lung epithelial and endothelial cells and in the heart, raising the possibility of cardiac effects even with highly selective β2-adrenoreceptor agonists like olodaterol [4, 5]. In some patients, olodaterol (like other β2-adrenoreceptor agonists) may be associated with clinically significant CV effects (e.g. increased pulse rate, increased systolic or diastolic BP and/or symptoms), which may require treatment discontinuation. However, in a subset of 772 patients in 48-week, phase III trials in patients with COPD, olodaterol monotherapy was not associated with dose- or time-related increases in heart rate or premature beats and there was no clinically meaningful difference between olodaterol and placebo for the change from baseline in premature beats. β2-adrenoreceptor agonists may also produce ECG changes (e.g. flattening of the T wave, prolongation of corrected QT interval), the clinical significance of which is unknown. In 24 healthy volunteers, a dose-related prolongation of 1.6–6.5 ms in corrected QT interval (QTc) was seen with single olodaterol doses of 10–50 μg. Because of the potential for adverse CV effects with LABAs, caution is advised when using these agents in patients with CV disorders [4, 5].
Tiotropium plus Olodaterol Combination 2.3
The combination of inhaled tiotropium and olodaterol had additive effects in animal models of COPD, providing greater protection against lipopolysaccharide-induced airway hyperresponsiveness in guinea pigs [25] and acetylcholine-induced bronchoconstriction in beagle dogs [26] than the individual agents. In addition, greater attenuation of tumour growth factor β-mediated neutrophilic inflammation was seen with the combination of tiotropium and olodaterol relative to the individual agents in vitro, suggesting additive anti-inflammatory effects [27]. Clinical studies in patients with COPD also showed additional benefits with tiotropium plus olodaterol combination therapy over the individual agents in 4-week, double-blind, phase II dose-ranging studies [28, 29]. Based on the results of these studies, tiotropium/olodaterol 2.5/5 and 5/5 µg/day fixed-dose combinations were selected for further development in phase III studies [8]. Efficacy data for the approved dosage of tiotropium/olodaterol 5/5 µg/day in patients with COPD are discussed in Sect. 4.
Changes in QT intervals with tiotropium/olodaterol fixed-dose combination were no different from those seen with tiotropium or olodaterol alone [4, 5]. In a pooled analysis of two pivotal 52-week studies (Sect. 4), 3.1–4.7 % of tiotropium/olodaterol 5/5 μg/day recipients compared with 2.3–4.6 % of tiotropium 5 μg/day and 3.6–4.4 % of olodaterol 5 μg/day recipients had changes of >30 ms in the baseline-corrected QTcF (Fridericia correction) interval at 40 minutes post-dose on days 85, 169 and 365 [4, 5].
Concomitant use of tiotropium with other anticholinergic agents has not been studied; therefore, coadministration of the tiotropium/olodaterol fixed-dose combination with other anticholinergic agents is not recommended [5] or should be avoided [4]. Coadministration of tiotropium/olodaterol with other adrenergic agents may potentiate the AEs associated with combination therapy [4, 5]. Xanthine derivatives, steroids or non-potassium sparing diuretics coadministered with tiotropium/olodaterol may potentiate hypokalaemic effects and ECG changes associated with olodaterol; monoamine oxidase inhibitors, tricyclic antidepressants and other QTc prolonging drugs may potentiate the effects of and beta-
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adrenergic receptor antagonists may weaken or antagonize the effects of olodaterol in the fixed-dose combination [4, 5]. Therefore, caution is advised when these agents are used concomitantly with the fixed-dose combination [4]. Local prescribing information should be consulted for further details regarding coadministration of tiotropium/olodaterol with other agents.
3 Pharmacokinetic Properties of Tiotropium/Olodaterol
The pharmacokinetic properties of the tiotropium/olodaterol fixed-dose combination were assessed in several phase I–III studies in healthy volunteers and in patients with COPD [8]. When administered via the inhaled route, the pharmacokinetics of tiotropium and olodaterol in the fixed-dose combination were similar to those of each active substance administered separately [4, 5, 8]. Tiotropium and olodaterol display linear pharmacokinetics when administered in the therapeutic range [4, 5].
Tiotropium 3.1
In healthy volunteers, ≈33 % of an inhaled dose of tiotropium reaches the systemic circulation, based on urinary excretion data [4, 5]. Peak plasma concentrations of tiotropium are reached 5–7 minutes after inhalation via the Respimat® inhaler [4, 5, 30]. Although the local concentration of tiotropium in the lung has not been assessed, it is expected that it would be substantially higher than that in the plasma [4]. The absolute bioavailability of tiotropium from an oral solution was 2–3 % [4, 5]; therefore, food is not expected to influence the absorption of tiotropium [4]. Steady-state was reached by day 7 and no accumulation of tiotropium was seen after multiple-dose administration [4, 5]. Tiotropium has a plasma protein binding of 72 % and a volume of distribution of 32 L/kg [4, 5]. Rodent studies suggest that tiotropium does not penetrate the blood-brain barrier to a relevant extent [4, 5].
Unchanged drug in the urine accounted for 74 % of an intravenous dose of tiotropium, indicating that tiotropium is metabolized to a small extent [4, 5]. Tiotropium is an ester that is cleaved nonezymatically into the alcohol N-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors [4, 5]. Less than 20 % of an intravenous dose was metabolized by cytochrome P450 (CYP) 2D6- and 3A4-mediated oxidation and subsequent glutathione conjugation to form a variety of phase II metabolites in in vitro studies with human liver microsomes and hepatocytes [4, 5]. After inhalation by COPD patients, 18.6 % of a dose at steady state was recovered in the urine; the remainder of the inhaled dose was mainly non-absorbed drug in the gut that is excreted in the faeces [4, 5]. Following an intravenous dose, the total clearance of tiotropium in healthy volunteers was 880 ml/min; the glomerular filtration rate of tiotropium was higher than its renal clearance, indicating that tiotropium is actively secreted into the urine [4, 5]. The terminal half-life of tiotropium was ≈25 h after inhalation of tiotropium 5μg once daily in patients with COPD [4].
Olodaterol 3.2
After inhalation via the Respimat® inhaler, the maximum concentration of olodaterol is reached within 10–20 minutes [4, 5]. The absolute bioavailability of inhaled olodaterol was estimated to be ≈30 % compared with an absolute bioavailability of <1 % when administered as an oral solution in healthy volunteers [4, 5]. Therefore, systemic availability of olodaterol is largely because of lung absorption, with only negligible contribution from any orally swallowed portion of the dose [4]. The plasma protein binding of olodaterol is ≈60 % and independent of its concentration; olodaterol has a high volume of distribution (1110 L), indicating that it is extensively distributed [4, 5]. Steady-state was reached by day 7 and exposure to olodaterol was increased by ≤1.8-fold compared with a single dose [4, 5]. Olodaterol is metabolized by direct glucuronidation [via uridine glycosyl transferase (UGT) 2B7, 1A1, 1A7 and 1A9] and by O-demethylation (largely via CYP2C9 and CYP2C8, and negligible contribution from CYP3A4) with
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subsequent conjugation. Six metabolites of olodaterol have been identified, of which only the unconjugated demethylation product binds to β2 receptors; however, this metabolite is not detected in the plasma after long-term inhalation of olodaterol at therapeutic or supratherapeutic (≤4-fold higher) doses [4, 5]. Olodaterol is a substrate of P-gp, OAT1, OAT3 and OCT1 transporters, but not of BCRP, MRP, OATP2, OATP8, OATP-B, OCT2 and OCT3 transporters [5].
In healthy volunteers, the total clearance of olodaterol was 872 mL/min and its renal clearance was 173 mL/min [4, 5]. After an intravenous radiolabelled dose of olodaterol, 38 % of the dose (19 % as unchanged drug) was recovered in urine and 53 % in the faeces [4, 5]. After oral administration, the majority (84 %) of a radiolabelled dose was recovered in the faeces and <9 % was recovered in the urine (0.7 % unchanged olodaterol) [4, 5]. More than 90 % of a dose was excreted within 6 days of intravenous and within 5 days of oral administration [4, 5]. After an inhaled dose of olodaterol in healthy volunteers, 5–7 % of the dose is excreted unchanged in the urine within the dosing interval at steady state [4, 5]. The plasma concentrations of olodaterol decline in a multiphasic manner, with a terminal elimination half-life of ≈45 h [4, 5]; however, after once-daily administration of a 5 μg dosage in patients with COPD, the effective half-life of olodaterol calculated from the peak plasma concentration was 7.5 h [4].
Special Populations and Potential Drug Interactions 3.3
No dosage adjustments of tiotropium/olodaterol fixed-dose combination are needed in the elderly or in renally or hepatically impaired patients [4, 5]. However, as tiotropium is excreted largely by the kidneys, caution is advised in patients with moderate to severe renal impairment receiving tiotropium/olodaterol; local prescribing information should be consulted for further details [4, 5]. Although a trend for higher systemic exposure to olodaterol was seen in Japanese and other Asians than in Caucasians, there were no safety concerns in Asian or Caucasian patients during up to 1 years’ treatment with up to twice the recommended dose [5].
The pharmacokinetics of tiotropium and olodaterol were not altered to a clinically relevant extent when administered as a fixed-dose combination [4]. No pharmacokinetic drug interaction studies have been conducted with the tiotropium/olodaterol fixed-dose combination; however, drug interaction data are available for the individual components [4]. Exposure to tiotropium was not altered to a clinically relevant extent when tiotropium was coadministered with medications used commonly in COPD patients (e.g. LABA and ICS) [4]. No relevant pharmacokinetic interactions were seen between olodaterol and fluconazole (CYP2C9 inhibitor) or ketoconazole (P-gp and CYP3A4, 2C8, 2C9 inhibitor) when coadministered [4, 5]. In in vitro studies, olodaterol did not inhibit CYP enzymes or drug transporters at the plasma concentrations achieved at therapeutic doses [4, 5].
4 Therapeutic Efficacy of Tiotropium/Olodaterol
Several large phase III studies have assessed the efficacy of orally inhaled tiotropium/olodaterol fixed-dose combination in patients with moderate to very severe COPD [Global initiative for chronic Obstructive Lung Disease (GOLD) stage 2–4 across studies]. Based on the findings from earlier dose-ranging studies [28, 29], two once-daily dosages of tiotropium/olodaterol, 2.5/5 or 5/5 μg, were evaluated in these studies. This section focuses on data for the approved dosage of tiotropium/olodaterol, 5/5 μg once daily, which generally provided greater benefits than the 2.5/5 μg once daily dosage in terms of improving lung function, HR-QOL and other COPD outcomes.
The effects of tiotropium/olodaterol 5/5 μg/day on lung function and HR-QOL were assessed in the TOnado (1 and 2) [31], VIVACITO [32], OTEMTO (1 and 2) [33] and ENERGITO [34] studies, and its effects on exercise endurance and inspiratory capacity were evaluated in the MORACTO (1 and 2) [35] and TORRACTO [36] studies. Limited data for the ENERGITO, MORACTO and TORRACTO studies are available from abstract presentations [34-36] and the
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European summary of product characteristics [5].. The key inclusion criteria (where available) were diagnosis of moderate to very severe COPD (GOLD 2–4) [31, 32] or moderate to severe COPD (GOLD 2–3) [33, 34], a post-bronchodilator forced expiratory volume in 1 s (FEV1) of <80 % of predicted normal [31, 32] or ≥30 to <80 % of predicted normal [33, 34], age ≥40 years, current or ex-smokers with a smoking history of ≥10 pack-years and post-bronchodilator FEV1/forced vital capacity (FVC) of <70 % [31-34].
Baseline data are available largely from the TOnado, VIVACITO and OTEMTO studies [31-33]. The majority of patients in these studies were GOLD stage 2 (50–64 %) or stage 3 (35–39 %), with only 11 % of patients in TOnado and 2 % of patients in VIVACITO of GOLD stage 4 severity [31-33]. Baseline characteristics were generally similar across treatment groups in individual studies. The mean post-bronchodilator FEV1 at baseline was 1.37 in TOnado, 1.55 L in VIVACITO, 1.54 L in OTEMTO, 1.72 L in MORACTO and 1.66 L in TORRACTO [31-36].
In all studies, the fixed-dose combination, individual components and placebo were administered once daily via the Respimat® Soft Mist™ inhaler. Patients were permitted to continue treatment with inhaled corticosteroids (≈40–47 % of patients) [31-33] and xanthines (≤10 %) [31, 32], as required, and salbutamol [32, 33] or salbutamol/albuterol [31] were provided as rescue medication for use throughout the study.
Lung Function 4.1
Tiotropium/olodaterol 5/5 μg/day fixed-dose combination improved lung function to a greater extent than the individual components (tiotropium 5 μg/day or olodaterol 5 μg/day) or placebo in patients with moderate to very severe COPD [31, 33].
In the pivotal 52-week, randomized TOnado 1 and 2 trials, FEV1 area under the curve (AUC) from 0–3 h (AUC0–3) and trough FEV1 responses (i.e. mean changes from baseline) at week 24 were significantly greater with tiotropium/olodaterol than with tiotropium or olodaterol monotherapy in patents with moderate to very severe COPD (Table 1; coprimary endpoints) [31]. Significant improvement in lung function with tiotropium/olodaterol relative to tiotropium was seen within 5 minutes after the first dose (mean increase in FEV1 0.137 vs. 0.058; p < 0.0001); there was no significant difference between the tiotropium/olodaterol and olodaterol groups at this timepoint (mean increase in FEV1 0.137 vs. 0.125 L) [4, 5]. The bronchodilation effect of tiotropium/olodaterol was sustained over the 52-week study periods, with significant (p < 0.05) improvements in these parameters seen with the fixed-dose combination relative to the individual components on all test days [31].
A combined analysis of the TOnado 1 and 2 studies supported the findings of the individual studies; in addition, subgroup analyses showed that the improvements in FEV1 AUC0–3 and trough FEV1 responses with tiotropium/olodaterol relative to tiotropium and olodaterol at week 24 were observed regardless of gender, baseline use of ICS [31] or prior LABA or LAMA maintenance therapy (post hoc analysis) [37]. When stratified according to disease severity, the FEV1 AUC0–3 and trough FEV1 responses were significantly (p < 0.005) greater with tiotropium/olodaterol than with the monotherapies both in patients with GOLD 2 and in those with GOLD 3–4 COPD; however, in general, numerically greater responses were seen with tiotropium/olodaterol in patients with less severe COPD (i.e. GOLD 2) than in those with more severe disease (i.e. GOLD 3–4) [37]. Secondary lung function parameters [forced vital capacity (FVC) AUC0–3 and trough FVC] at week 24 were also significantly (p < 0.0001) improved with tiotropium/olodaterol relative to the individual components [31].
Significant improvements in lung function (assessed by FEV1 AUC0–3 and trough FEV1; coprimary endpoints) with tiotropium/olodaterol relative to tiotropium or placebo were also seen in the 12-week, randomized OTEMTO 1 and 2 studies in patients with moderate to severe COPD (Table 1; coprimary endpoints) [33].
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24-Hour Lung Function 4.1.1
Tiotropium/olodaterol provided greater improvements in the lung function profile over 24 h than the monotherapies or placebo in the 6-week, randomized, double-blind, multicentre, incomplete crossover, phase III VIVACITO study in patients with moderate to very severe COPD [32]. At week 6, the adjusted mean FEV1 AUC from 0–24 h (primary endpoint), FEV1 AUC from 0–12 h and FEV1 AUC from 12–24 h responses were significantly greater with tiotropium/olodaterol 5/5 μg/day than with tiotropium 5 μg/day, olodaterol 5 μg/day or placebo (Fig. 1). Likewise, peak0–3 FEV1 (i.e. maximum FEV1 within the first 3 h post-dose) and trough FEV1 responses were significantly greater with tiotropium/olodaterol than with the individual components or placebo (p < 0.0001 for adjusted means), with the improvement in trough FEV1 versus placebo (0.207 L) considered clinically relevant (i.e. >0.1 L [38]). Significant improvements in peak0–3 FEV responses, and significant and clinically relevant improvements in trough FEV1 responses were also seen with tiotropium and olodaterol monotherapies relative to placebo (all p < 0.0001 for adjusted means) [32].
Functional residual capacity and residual volume responses at 2.5 and 22.5 h post-dose (measured by plethysmography in a subset of 143 patients) were also improved to a significantly greater extent with tiotropium/olodaterol than with the monotherapies or placebo at week 6 (all p < 0.05 for adjusted means) [32].
The lung-function profile of tiotropium/olodaterol was also compared with that of the fluticasone propionate/salmeterol fixed-dose combination in the 6-week, randomized, double-blind, 4-period, crossover ENERGITO study in patients with moderate to severe COPD (GOLD 2–3) [34]. Results showed that tiotropium/olodaterol 5/5 μg once daily improved lung function to a significantly greater extent than fluticasone propionate/salmeterol 250/50 or 500/50 μg twice daily, as assessed by FEV1 AUC0–12 response at 6 weeks (adjusted mean treatment difference 0.125 and 0.129 L, respectively; both p < 0.0001; primary endpoint). Significant improvements with tiotropium/olodaterol 5/5 μg twice daily over fluticasone propionate/salmeterol 250/50 and 500/50 μg twice daily were also seen for the FEV1 AUC0–24 (adjusted mean treatment difference 0.082 and 0.086 L, respectively), FEV1 AUC12–24 (0.039 and 0.043 L), and trough FEV1 (0.047 and 0.058 L) responses (all p < 0.001) [34].
Health-Related Quality of Life 4.2
Tiotropium/olodaterol 5/5 μg/day fixed-dose combination was associated with clinically meaningful improvements in HR-QOL in patients with moderate to very severe COPD [31, 33].
In a combined analysis of the TOnado 1 and 2 studies, the St George’s Respiratory Questionnaire (SGRQ) total score at week 24 was significantly improved with tiotropium/olodaterol relative to the monotherapies (coprimary endpoint; Table 2) [31], with improvements seen in all SGRQ domains [5]. Although clinically meaningful improvements (i.e. a decrease of ≥4 units from baseline) in SGRQ total scores were seen in all three treatment groups (−6.8, −5.6 and −5.1 with tiotropium/olodaterol, tiotropium and olodaterol, respectively), the difference between the tiotropium/olodaterol and tiotropium or olodaterol groups did not meet the threshold of clinical relevance (Table 2). However, the responder rate (i.e. the proportion of patients with clinically relevant improvements) was significantly higher with tiotropium/olodaterol than with tiotropium or olodaterol (Table 2).
The TOnado studies did not include a placebo arm because of the long treatment duration (52 weeks) and inclusion of patients with very severe COPD [33]. In order to compare HR-QOL benefits between tiotropium/olodaterol and placebo recipients, the OTEMTO 1 and 2 studies were designed with a shorter treatment duration (12 weeks) and excluded patients with very severe COPD [33]. At week 12, statistically and clinically significant improvements in HR-QOL were seen with tiotropium/olodaterol relative to placebo in OTEMTO 1 and 2, as assessed by SGRQ total scores (Table 2). In addition, responder rates were significantly higher with tiotropium/olodaterol than with tiotropium and placebo in both studies (Table 2). These results indicate that the improvement in lung function with
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tiotropium/olodaterol (Sect. 4.1) translated to a clinically significant improvement in health status relative to placebo [33]. Tiotropium monotherapy also improved SGRQ total scores to a statistically (p < 0.05), but not clinically significant extent relative to placebo (between-group difference −2.40 and −2.85 in OTEMTO 1 and 2, respectively); responder rates were significantly higher with tiotropium than placebo in OTEMTO 1, but not in OTEMTO 2 (Table 2).
Dyspnoea 4.3
Tiotropium/olodaterol 5/5 μg/day fixed-dose combination improved dyspnoea to a greater extent than the individual components (tiotropium 5 μg/day or olodaterol 5 μg/day) or placebo in patients with moderate to very severe COPD [31, 33]. In the combined analysis of TOnado 1 and 2, the Mahler Transition Dyspnoea Index (TDI) focal score at week 24 with tiotropium/olodaterol (mean score 1.98) was significantly (p < 0.05) improved relative to tiotropium (mean treatment difference of 0.36) and olodaterol (mean treatment difference of 0.42) [31]. In addition, significantly (p = 0.003) more tiotropium/olodaterol than olodaterol recipients experienced clinically meaningful improvements (i.e. increase of ≥1 unit) in these scores (54.9 vs. 48.2 % of olodaterol recipients); there was no significant difference between tiotropium/olodaterol and tiotropium recipients for these rates (54.9 vs. 50.6 %) [5]. Similarly, in the OTEMTO 1 and 2 studies, the TDI focal scores at week 12 with tiotropium/olodaterol (mean scores 1.94 and 1.53, respectively) were significantly (p < 0.05) improved relative to placebo (mean differences of 2.05 and 1.2) and tiotropium (mean differences of 0.61 and 0.58), with the differences between tiotropium/olodaterol and placebo considered clinically relevant [33]. Significant improvements in TDI focal scores were also seen with tiotropium relative to placebo in OTEMTO 1 and 2 (mean differences 1.45 and 0.61, respectively), with the treatment difference in OTEMTO 1 considered clinically relevant [33].
Rescue Medications and Exacerbations 4.4
Tiotropium/olodaterol fixed-dose combination reduced the need for rescue medication relative to the monotherapies in patients with moderate to very severe COPD in the combined analysis of the TOnado 1 and 2 studies [31]. Tiotropium/olodaterol 5/5 μg/day recipients required significantly (p < 0.0001) less daytime (mean 0.76 vs. 0.97 and 0.87 occasions/day) and night-time (1.24 vs. 1.69 and 1.52 occasions/day) rescue salbutamol than tiotropium 5 μg/day and olodaterol 5 μg/day recipients [5]. In addition, the risk of moderate/severe COPD exacerbation (as assessed by Kaplan-Meier estimates) was significantly lower with tiotropium/olodaterol than with olodaterol [risk ratio (RR) 0.83; 95 % CI 0.71–0.99; p = 0.033], but no significant difference was seen between the tiotropium/olodaterol and tiotropium groups (RR 0.92; 95 % CI 0.78–1.09) [31]. It should be noted that the TOnado studies were not designed to assess the effect of treatments on COPD exacerbations [31].
Inspiratory Capacity and Exercise Endurance 4.5
Two replicate, 6-week, randomized, double-blind, 4-period, incomplete crossover, phase III studies (MORACTO 1 and 2) [35] and a 12-week, randomized, double-blind, parallel group, phase III study (TORRACTO) [36] assessed the effect of tiotropium/olodaterol 5/5 μg/day on inspiratory capacity, breathing discomfort and symptom-linked exercise endurance versus that of tiotropium 5 μg/day, olodaterol 5 μg/day and/or placebo in patients with moderate to severe COPD (GOLD 2–3).
Tiotropium/olodaterol fixed-dose combination significantly improved inspiratory capacity at rest relative to tiotropium, olodaterol and placebo, following up to 12 weeks’ treatment in the MORACTO and TORRACTO studies (Table 3) [35, 36]. Endurance time during constant work-rate cycling was also significantly improved with tiotropium/olodaterol relative to placebo in MORACTO 1 and 2, and relative to olodaterol in MORACTO 2 [35, 36].
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5 Tolerability of Tiotropium/Olodaterol
The tolerability profile of tiotropium/olodaterol 5/5 μg/day fixed-dose combination was generally similar to that of tiotropium 5 μg/day and olodaterol 5 μg/day alone in patients with moderate to very severe COPD [31]. In the combined analysis of the 52-week TOnado 1 and 2 studies, treatment-emergent adverse events (AEs) were reported in 74.0, 73.3 and 76.6 % of tiotropium/olodaterol, tiotropium and olodaterol recipients, respectively, most of which were of mild or moderate severity. Treatment-related AEs occurred in 7.1, 6.1 and 6.6 % of patients in the tiotropium/olodaterol, tiotropium and olodaterol groups, serious adverse events (SAEs) in 16.4, 16.7 and 17.4 % of patients, and 7.4, 9.0 and 9.9 % of patients withdrew from therapy because of adverse events. The incidence of fatal AEs was low in the three treatment groups (1.7, 1.6 and 1.3 %, respectively) [31].
The most common AEs (incidence >10 % in any group) in tiotropium/olodaterol, tiotropium and olodaterol recipients were respiratory, thoracic and mediastinal disorders (39.4, 42.7 and 45.3 % in the respective groups), infections and infestations (36.3, 33.7 and 37.9 %), gastrointestinal disorders (13.9, 14.9 and 15.9 %) and musculoskeletal and connective tissue disorders (15.2, 11.3 and 11.9 %) [31]. Of the respiratory events, COPD was the most common event, occurring in 32.3, 32.9 and 35.6 % of tiotropium/olodaterol, tiotropium and olodaterol recipients, respectively; AEs reported at an incidence of >3 % and more commonly with tiotropium/olodaterol than either comparator are summarized in Fig. 2 [31].
As expected in patients with moderate to very severe COPD, the most common SAEs in tiotropium/olodaterol, tiotropium and olodaterol recipients were respiratory in nature (8.8, 8.1 and 8.2 %, respectively), with COPD (6.9, 6.3 and 6.5 %) and pneumonia (1.7, 0.9 and 1.4 %) the most common events, as assessed by an independent adjudication committee [39]. The incidence of cardiovascular (CV) SAEs was 1.8, 1.8 and 1.4 % and that of cerebrovascular SAEs was 0.5, 0.5 and 0.6 % in the respective groups [39]. There were no significant differences between tiotropium/olodaterol and tiotropium or olodaterol for the incidence of any major adverse cardiac adverse event (MACE) or any cardiac event, indicating that tiotropium/olodaterol did not increase the risk for these AEs [31]. The overall incidence of treatment-emergent AEs in tiotropium/olodaterol, tiotropium and olodaterol recipients in the subgroup of patients with cardiac history (78.1, 80.6 and 79.7 %, respectively) was generally similar to that in the overall population [31].
Like other inhaled medicines, tiotropium/olodaterol may cause paradoxical bronchospasm, which could be life-threatening in some cases; treatment with tiotropium/olodaterol should be discontinued immediately and substituted with alternative therapy if this AE is reported [4, 5]. The most common anticholinergic AE with tiotropium/olodaterol during the 52-week period was dry mouth, which was reported in approximately 1.7 % of patients (vs. 2.7 % of tiotropium and 1 % of olodaterol recipients) and led to treatment discontinuation in one (0.1 %) patient [5]. Serious anticholinergic AEs associated with the use of tiotropium/olodaterol include glaucoma, constipation, intestinal obstruction (including ileus paralytic) and urinary retention [5]. The most common β2-adrenergic AEs with tiotropium/olodaterol were palpitations, tachycardia and hypertension [5], occurring at incidences of ≤3 % [4]. β2-adrenergic agonists like olodaterol have also been associated with AEs such as arrhythmia, myocardial ischaemia, tremor, muscle spasms, hypokalaemia (which has the potential to produce adverse CV effects) and hyperglycaemia, which should be taken into consideration when treating patients with the tiotropium/olodaterol fixed-dose combination [4, 5].
The tolerability profile of tiotropium/olodaterol in other phase III trials was generally similar to that seen in the TOnado trials, with no new safety concerns identified [32-36].
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6 Dosage and Administration of Drug
Tiotropium/olodaterol fixed-dose combination is indicated in the USA [4] and EU [5] for the maintenance treatment of airflow obstruction in adult patients with COPD [4, 5], including chronic bronchitis and/or emphysema [4]. The recommended dosage is 5 μg of tiotropium and 5 μg of olodaterol administered once daily as two puffs from the Respimat® inhaler. Each actuation from the Respimat® inhaler delivers 2.5 μg of tiotropium and 2.5 μg olodaterol from the mouthpiece. Tiotropium/olodaterol is not indicated for the treatment of acute deterioration of COPD or for the treatment of asthma [4, 5].
Local prescribing information should be consulted for details regarding dosage and administration, contraindications, potential drug interactions, warnings and precautions.
7 Place of Drug in the Management of Disease
The goal of treatment in patients with stable COPD is to reduce existing symptoms and the risk of future events [2]. Current GOLD treatment guidelines recommend a patient-specific approach to pharmacotherapy, with the choice of treatment based on factors such as the severity of symptoms, risk of exacerbations, drug availability and the patient’s response. By combining the patient’s symptomatic assessment, spirometric classification (GOLD 1–4; mild to very severe) and/or risk of exacerbations, patients with COPD are classified into four groups: group A (low risk, less symptoms), group B (low risk, more symptoms), group C (high risk, less symptoms) and group D (high risk, more symptoms) [2].
In low-risk patients (groups A and B), single-agent bronchodilators are recommended as first-choice therapy, with combination treatment with bronchodilators recommended if patients do not experience sufficient improvement in symptoms with single agents [2]. For high-risk patients (groups C and D), treatment options include dual or triple combination therapy with ICS, bronchodilators (LABA or LAMA) and/or PDE4 inhibitors [2]. However, combination therapy is limited by the need for separate inhalers and, often, different dosing schedules for the individual agents [40]. This led to the development of fixed-dose combinations, such as the LABA plus LAMA combinations of umeclidinium plus vilanterol (approved in the USA, EU and several other countries) and aclidinium bromide plus formoterol fumarate (approved in the EU).
Recently, a fixed-dose combination of the well-established once-daily LAMA tiotropium and the novel once-daily LABA olodaterol, was approved for use in patients with COPD (Sect. 6). It targets COPD-associated bronchoconstriction via two different mechanisms, direct smooth muscle relaxation by the stimulation of β2-adrenergic receptors (olodaterol) and indirect smooth muscle relaxation by inhibiting the action of acetylcholine at muscarinic receptors (tiotropium) (Sect. 2).
Once-daily tiotropium/olodaterol improved lung function and provided symptomatic benefits in patients with moderate to very severe (GOLD 2–4) or moderate to severe (GOLD 2–3) COPD in several well-designed, phase III studies of 6–52 weeks’ duration (Sect. 4). Greater improvements in lung function were seen with the fixed-dose combination than with the component monotherapies or placebo, with the benefit over the monotherapies seen regardless of factors such as baseline ICS therapy, prior treatment with a LABA or LAMA, or disease severity (Sect. 4). However, lung function improvements in patients with less severe disease were numerically greater than those seen in patients with more severe disease (Sect. 4). Tiotropium/olodaterol provided consistently greater lung function benefits over the 24 h dosage interval than the component monotherapies, placebo or twice-daily fixed-dose fluticasone propionate/salmeterol (Sect. 4.1). In addition, tiotropium/olodaterol improved HR-QOL (Sect. 4.2) and dyspnoea (Sect. 4.3) to a clinically relevant extent, reduced the need for rescue medication (Sect. 4.4), and improved inspiratory capacity and exercise endurance (Sect. 4.5).
Tiotropium/Olodaterol: A Review 11
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Although none of the phase III studies were designed to assess exacerbations, in one study (Sect. 4.4), the risk of moderate/severe exacerbation was lower with tiotropium/olodaterol than with olodaterol, but not relative to tiotropium. The ongoing 52-week DYNAGITO study (NCT02296138) is designed specifically to compare the effect of tiotropium/olodaterol on exacerbations versus that of tiotropium in patients with severe to very severe COPD; the estimated completion date for primary endpoint data collection is early 2017. In addition, the ongoing 12-week PHYSACTO (NCT02085161) study is evaluating the effect of tiotropium/olodaterol (plus exercise and activity training) versus tiotropium (plus exercise and activity training) on exercise capacity and daily activities in patients with COPD; primary endpoint data collection is expected to be completed in late 2015.
The tolerability profile of tiotropium/olodaterol in the phase III studies was generally similar to that of the component monotherapies, with most treatment-emergent AEs of mild or moderate severity (Sect. 5). The most common AEs and serious AEs during 52 weeks’ therapy were respiratory in nature, of which COPD, as expected in patients with moderate to very severe disease, occurred most frequently with the fixed-dose combination and the comparators (Sect. 5). Anticholinergic and β2-adrenergic AEs were reported in few tiotropium/olodaterol recipients, with the most common events (e.g. dry mouth, hypertension) reported at incidences of ≤3 % (Sect. 5). Tiotropium/olodaterol therapy did not increase the risk of CV events relative to treatment with the component monotherapies (Sect. 5).
Tiotropium/olodaterol is delivered via the Respimat® Soft Mist™ inhaler that delivers a metered dose of the agents as a slow-moving mist, which is expected to improve lung deposition and reduce oropharyngeal deposition relative to delivery via pressurized metered dose inhalers (MDI) or dry-powder inhalers (DPI) [3]. As drug delivery is not dependent on the patient’s inspiratory capacity or effort, the Respimat® inhaler allows consistent lung deposition regardless of lung function and even patients with poor technique are expected to have higher lung deposition than that achieved with other inhaler types [3]. Although some concerns have been raised in the literature regarding increased CV risk with the Respimat® inhaler (for example in a Dutch database study [41]), the large (n = 17,135) randomized, double-blind TIOSPIR study assessing tiotropium monotherapy did not show an increased risk of death or of MACE with Respimat® relative to the DPI HandiHaler® [42].
To conclude, maintenance treatment with tiotropium/olodaterol fixed-dose combination improves lung function and health status and provides symptomatic benefits in patients with moderate to very severe COPD. The tolerability profile of the fixed-dose combination is generally similar to that of the component monotherapies. Although further studies assessing the effect of tiotropium/olodaterol on exacerbations and comparative studies with other combination therapies, including other fixed-dose combinations, are needed to definitively place tiotropium/olodaterol relative to other recommended therapies, current evidence indicates that tiotropium/olodaterol is a useful treatment option for patients with COPD, with potential advantages including once-daily administration and the convenience of a single inhaler.
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Data selection sources: Relevant medical literature (including published and unpublished data) on tiotropium/olodaterol was identified by searching databases including MEDLINE (from 1946), PubMed (from 1946) and EMBASE (from 1996) [searches last updated 18 September 2015], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Tiotropium, Spiriva, BA-679, olodaterol, Striverdi, BI-1744, chronic obstructive lung disease, chronic obstructive pulmonary disease, COPD. Study selection: Studies in patients with COPD who received tiotropium/olodaterol. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Acknowledgments
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any external funding.
Conflicts of interest Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
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Tables and Figures
Table 1 Efficacy of inhaled tiotropium/olodaterol 5/5 μg/day fixed-dose combination in patients with moderate to very severe [31] or moderate to severe [33] COPD in randomized, double-blind, multicentre, phase III trials
BL values for FEV1 AUC0–3 were 1.158 and 1.150 L (TOnado 1 and 2), and 1.296 and 1.323 L (OTEMTO 1 and 2); BL values for trough FEV1 were 1.161 and 1.150 L (TOnado 1 and 2) and 1.298 and 1.329 L (OTEMTO 1 and 2) AUC0–3 area under the curve from 0–3 h, BL baseline, diff difference, FEV1 forced expiratory volume in 1 s, OLO olodaterol, pt patient, TIO tiotropium, TIO/OLO tiotropium/olodaterol * p < 0.05, ** p ≤0.0001 vs. TIO/OLO
a No. of pts evaluable for FEV1 AUC0–3 response b Coprimary endpoints; response was defined as the adjusted mean change from baseline c In OTEMTO 1 and 2, TIO 5 recipients also had significantly (p < 0.0001) greater improvement in FEV1 AUC0–3 response (between-group difference 0.219 and 0.194 L) and trough FEV1 response (0.134 and 0.127 L) than PL recipients
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Fig. 1 Lung function responses over 24 h with inhaled tiotropium/olodaterol in the VIVACITO study [32]. Values in the bars are the differences between the tiotropium/olodaterol and comparator groups. FEV1 AUCx–y forced expiratory volume in 1 s area under the curve from x–y h, OLO olodaterol, PL placebo TIO tiotropium, TIO/OLO tiotropium/olodaterol. * p < 0.0001 versus all comparators.
-0.1
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Adju
sted
mea
n re
spon
se (L
)
TIO/OLO 5/5 μg/day
TIO 5 μg/day
OLO 5 μg/day
PL
0.28
0
0.11
5
0.11
0
*
0.11
9
0.12
6
0.10
2
0.10
3
0.31
9
0.24
3
*
*
FEV1 AUC
0–24
(primary endpoint) FEV
1 AUC
0–12 FEV
1 AUC
12–24
Tiotropium/Olodaterol: A Review 17
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Table 2 Health-related quality of life with inhaled tiotropium/olodaterol 5/5 μg/day fixed-dose combination in patients with moderate to very severe [31] or moderate to severe [33] COPD
Study Treatment (μg/day) Pt no. SGRQ total scorea SGRQ (duration) Mean values Diff from TIO/OLO 5/5 respondersb (%) TOnado combined TIO/OLO 5/5 979 36.67 57.5†‡‡
SGRQ total score at BL in the TOnado combined analysis was 43.51, in OTEMTO 1 was 42.43 and in OTEMTO 2 was 42.70 BL baseline, diff difference, OLO olodaterol, PL placebo, pt(s) patient(s), SGRQ St George’s Respiratory Questionnaire, TIO tiotropium, TIO/OLO tiotropium/olodaterol * p < 0.05, ** p < 0.005, *** p < 0.0001 vs TIO/OLO 5/5; † p < 0.0001 vs. OLO 5; ‡p < 0.05, ‡‡ p = 0.0001 vs TIO 5; ¶ p < 0.05, ¶¶ p < 0.0001 vs. PL
a Coprimary endpoint (a decrease in score indicates improvement) b Proportion of pts with a decrease of ≥4-units from baseline in SGRQ total score c In OTEMTO 1 and 2, TIO 5 recipients also had significantly greater improvements in SGRQ total scores than PL recipients (between-group differences −2.40 and −2.85; both p < 0.05)
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Table 3 Effect of inhaled tiotropium/olodaterol 5/5 μg/day fixed-dose combination on inspiratory capacity and exercise endurance in patients with moderate to severe COPD [5, 35, 36]
Study (duration) Comparisons Adjusted mean treatment diff Percentage improvement in inspiratory capacitya (L) in endurance timeb (%) MORACTO 1 [35] (6 weeks) TIO/OLO 5/5 vs. TIO 5 0.114** −0.7
OLO 5 0.119** 0.2 PL 0.244** 20.9**
MORACTO 2 [35] (6 weeks) TIO/OLO 5/5 vs. TIO 5 0.088* 4.3
OLO 5 0.080* 11.1* PL 0.265** 13.4**
TORRACTO [36] (12 weeks) TIO/OLO 5/5 vs. PL 0.234** 13.8*
Diff difference, OLO 5 olodaterol 5 μg/day, PL placebo, TIO 5 tiotropium 5 μg/day, TIO/OLO 5/5 tiotropium/olodaterol 5/5 μg/day * p < 0.05, ** p ≤ 0.0001 for all comparisons
a Inspiratory capacity at rest (pre-exercise) at 2 h post-dose; coprimary endpoint (MORACTO 1 and 2) b During constant work-rate cycle ergometry to symptom limitation; coprimary (MORACTO 1and 2) and primary (TORRACTO) endpoint
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Fig. 2 Adverse events occurring at an incidence of >3 % and more often with inhaled tiotropium/olodaterol fixed-dose combination than with tiotropium or olodaterol in the combined analysis of TOnado 1 and 2 [31]. OLO olodaterol, TIO tiotropium, TIO/OLO tiotropium/olodaterol
