Combined bronchodilators (tiotropium plus olodaterol) for patients with chronic obstructive pulmonary disease

Figures & data

Table 1 Pharmacokinetics of tiotropium and olodaterol

	Absorption	Distribution	Metabolism	Elimination
Tiotropium	Tmax 5 minutes Bioavailability 19.5% (inhalation)	72% bound to plasma proteins	Hepatic (minimal), via CYP2D6 and CYP3A4	Excretion: urine (16%); feces (primarily nonabsorbed drug)
Olodaterol	Tmax 10–20 minutes Bioavailability 30% (inhalation)	60% bound to plasma proteins	Direct glucuronidation (UGT2B7, UGT1A1, 1A7, and 1A9) and O-demethylation (primarily CYP2C9 and 2C8)	Excretion: urine (9% unchanged); majority in feces

Abbreviations: T_max, time to peak plasma concentration; CYP, cytochrome P450.

Table 2 Special populations and Stiolto™ respimat

Special populations	Comments
Pediatric (aged <18 years)	Safety and efficacy of olodaterol and tiotropium has not been established in this population
Geriatric population	Tiotropium: monitoring patients with moderate-to-severe renal impairment due to increased plasma drug levels
	Olodaterol: no differences in effectiveness or adverse effects were noted in geriatric patients compared to younger adults
Pregnancy/lactation	Pregnancy category C
	Excretion in breast milk unknown/use caution
Renal impairment	Tiotropium: caution in moderate-to-severe renal impairment; monitor closely
	Olodaterol: no dosage adjustment necessary
Hepatic impairment	No dosage adjustment necessary for both tiotropium and olodaterol

Notes: Pregnancy category C: animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans.

Table 3 Clinical trial results of tiotropium and olodaterol combination

Study	Arms	Efficacy endpoints	Findings
TONADO 1 and 2^Citation50	Tiotropium plus olodaterol FDC 5/5 μg or 2.5/5 μg versus monocomponents (olodaterol 5 μg or Tiotropium 5 μg or 2.5 μg) Respimat	AUC0–3 of FEV1, trough FEV1, and SGRQ total score over 52 weeks	Improvements in FEV1 AUC0–3 with tiotropium plus olodaterol FDC 5/5 μg and 2.5/5 μg over individual components were SS (P<0.0001 for all comparisons) Improvements in trough FEV1 with combination were SS (P<0.05 for all comparisons) SS improvements in SGRQ for FDC 5/5 μg over monocomponents (versus olodaterol 5 μg: −1.693±0.553*, P<0.01; versus tiotropium 5 μg: −1.233±0.551*, P<0.05) but not for tiotropium plus olodaterol FDC 2.5/5 μg
VIVACITO^Citation51	Tiotropium plus olodaterol FDC (2.5/5 μg, 5/5 μg) versus tiotropium (2.5 μg or 5 μg) and olodaterol (5 μg) monotherapy via Respimat	24-hour FEV1 time profile over 6 weeks	Significant improvement in FEV1 with the FDC versus monocomponents
ANTHELTO 1 and 2^Citation52	Olodaterol 5 μg once daily (via Respimat^®) combined with tiotropium 18 μg once daily (via HandiHaler^®) versus tiotropium 18 μg once daily (via HandiHaler^®) combined with placebo (via Respimat^®)	AUC0–3 of FEV1, trough FEV1, and SGRQ total score over 12 weeks	Significant improvements with the FDC over tiotropium + placebo in: FEV1 AUC0–3 (treatment differences: 0.117 L [P<0.001], ANHELTO 1; 0.106 L [P<0.001], ANHELTO 2) Trough FEV1 (treatment differences: 0.062 L [P<0.001]), ANHELTO 1; 0.040 L [P=0.0029], ANHELTO 2 Improvements in SGRQ total scores (treatment difference −1.85; P<0.0001)
TORRACTO^Citation53	Tiotropium plus olodaterol (5/5 μg or 2.5/5 μg) once daily via Respimat Soft Mist inhaler, or placebo	Exercise ET at 12 weeks	ET significantly increased (21% increase, P=0.06) Significantly increased pre-exercise IC (P<0.0005)

Notes:

* Data are presented as adjusted mean ± standard error.

Abbreviations: ET, endurance time; FDC, fixed-dose combination; FEV₁, forced expiratory volume in 1 second; IC, inspiratory capacity; SGRQ, St George’s Respiratory Questionnaire; SS, statistically significant.

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