Trimbow Mechanism of Action

Pharmacotherapeutic group: Drugs for obstructive airway diseases, adrenergics in combinations with anticholinergics. ATC code: R03AL09.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Trimbow contains beclometasone dipropionate, formoterol and glycopyrronium in a solution formulation resulting in an aerosol with extrafine particles with an average mass median aerodynamic diameter (MMAD) of around 1.1 micrometres and co-deposition of the three components. The aerosol particles of Trimbow are on average much smaller than the particles delivered in non-extrafine formulations. For beclometasone dipropionate, this results in a more potent effect than formulations with a non-extrafine particle size distribution (100 micrograms of beclometasone dipropionate extrafine in Trimbow are equivalent to 250 micrograms of beclometasone dipropionate in a non-extrafine formulation).
Beclometasone dipropionate: Beclometasone dipropionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases of the airways such as COPD. Their action is mediated by the binding to glucocorticoid receptors in the cytoplasm resulting in the increased transcription of genes coding for anti-inflammatory proteins.
Formoterol: Formoterol is a selective beta2-adrenergic agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1-3 minutes after inhalation, and has a duration of 12 hours after a single dose.
Glycopyrronium: Glycopyrronium is a high-affinity, long-acting muscarinic receptor antagonist (anticholinergic) used for inhalation as bronchodilator treatment of COPD. Glycopyrronium works by blocking the bronchoconstrictor action of acetylcholine on airway smooth muscle cells, thereby dilating the airways. Glycopyrronium bromide is a high affinity muscarinic receptor antagonist with a greater than 4-fold selectivity for the human M3 receptors over the human M2 receptor as it has been demonstrated.
Clinical efficacy and safety: The Phase III clinical development programme in COPD included two 52-week active-controlled studies. Study TRILOGY compared Trimbow with a fixed combination of beclometasone dipropionate and formoterol 100/6 micrograms two inhalations twice daily (1,368 randomised patients). Study TRINITY compared Trimbow with tiotropium 18 micrograms inhalation powder, hard capsule, one inhalation once daily; in addition, effects were compared with an extemporary triple combination made of a fixed combination of beclometasone dipropionate and formoterol 100/6 micrograms two inhalations twice daily plus tiotropium 18 micrograms inhalation powder, hard capsule, one inhalation once daily (2,691 randomised patients). Both studies were conducted in patients with a clinical diagnosis of COPD with severe to very severe airflow limitation (FEV₁ less than 50% predicted), with symptoms assessed as a COPD Assessment Test (CAT) score of 10 or above, and with at least one COPD exacerbation in the previous year. The two studies included approximately 20% of patients who used the AeroChamber Plus spacer.
Reduction of COPD exacerbations: Compared with a fixed combination of beclometasone dipropionate and formoterol, Trimbow reduced the rate of moderate/severe exacerbations over 52 weeks by 23% (rate: 0.41 versus 0.53 events per patient/year; p = 0.005). Compared with tiotropium, Trimbow reduced the rate of moderate/severe exacerbations over 52 weeks by 20% (rate: 0.46 versus 0.57 events per patient/year; p = 0.003). Compared with tiotropium, Trimbow also reduced the rate of severe exacerbations (i.e. excluding moderate exacerbations) by 32% (rate: 0.067 versus 0.098 events per patient/year; p = 0.017). No differences were observed when comparing Trimbow and the extemporary triple combination (moderate/severe exacerbation rate: 0.46 versus 0.45 events per patient/year).
In addition, compared with both a fixed combination of beclometasone dipropionate and formoterol and with tiotropium, Trimbow significantly prolonged the time to first exacerbation (hazard ratio 0.80 and 0.84 respectively; p = 0.020 and 0.015 respectively), with no differences between Trimbow and the extemporary triple combination (hazard ratio 1.06).
Effects on lung function: Pre-dose FEV₁: Compared with a fixed combination of beclometasone dipropionate and formoterol, Trimbow improved pre-dose FEV₁ by 81 mL after 26 weeks of treatment and by 63 mL after 52 weeks of treatment. Compared with tiotropium, Trimbow improved pre-dose FEV₁ by 51 mL after 26 weeks of treatment and by 61 mL after 52 weeks of treatment. These improvements were statistically significant (p < 0.001).
No differences were observed when comparing Trimbow and the extemporary triple combination (difference of 3 mL in pre-dose FEV₁ after 52 weeks of treatment).
2-hour post-dose FEV₁: Compared with a fixed combination of beclometasone dipropionate and formoterol, Trimbow significantly improved 2-hour post dose FEV₁ by 117 mL after 26 weeks of treatment and by 103 mL after 52 weeks of treatment (p < 0.001). This endpoint was only measured in study TRILOGY.
Inspiratory Capacity (IC): Compared with tiotropium, Trimbow significantly improved IC by 39 mL (p = 0.025) and 60 mL (p = 0.001) after 26 and 52 weeks of treatment respectively. Similar effects were seen when comparing Trimbow with the extemporary triple combination. This endpoint was only measured in study TRINITY.
Symptomatic outcomes: Trimbow significantly improved dyspnoea (measured as the Transition Dyspnoea Index - TDI - focal score) after 26 weeks of treatment compared with baseline (by 1.71 units; p < 0.001), but the adjusted mean difference versus a fixed combination of beclometasone dipropionate and formoterol was not statistically significant (0.21 units; p = 0.160). A responder analysis showed that a significantly greater percentage of patients had a clinically significant improvement (focal score greater than or equal to 1) after 26 weeks with Trimbow than with a fixed combination of beclometasone dipropionate and formoterol (57.4% versus 51.8%; p = 0.027). TDI was only measured in study TRILOGY.
Trimbow was also statistically significantly superior to both a fixed combination of beclometasone dipropionate and formoterol and to tiotropium in terms of improvement in quality of life (measured by the Saint George Respiratory Questionnaire - SGRQ - total score). A responder analysis showed that a significantly greater percentage of patients had a clinically significant improvement (reduction versus baseline of greater than or equal to 4) after 26 and 52 weeks with Trimbow than with a fixed combination of beclometasone dipropionate and formoterol and with tiotropium.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Trimbow in all subsets of the paediatric population in COPD (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Related to Trimbow: The systemic exposure to beclometasone dipropionate, formoterol and glycopyrronium has been investigated in a pharmacokinetic study conducted in healthy subjects. The study compared data obtained after treatment with a single dose of Trimbow (4 inhalations of 100/6/25 micrograms, a non-marketed formulation containing twice the approved strength of glycopyrronium) or a single dose of the extemporary combination of beclometasone dipropionate/formoterol (4 inhalations of 100/6 micrograms) plus glycopyrronium (4 inhalations of 25 micrograms). The maximum plasma concentration and systemic exposure of beclometasone dipropionate main active metabolite (beclometasone 17-monopropionate) and formoterol were similar after administration of the fixed or extemporary combination.
For glycopyrronium, the maximum plasma concentration was similar after administration of the fixed or extemporary combination, while the systemic exposure was slightly higher after administration of Trimbow than with the extemporary combination. This study also investigated the potential pharmacokinetic interaction between the active components of Trimbow by comparing the pharmacokinetic data obtained after a single dose of the extemporary combination or after a single dose of the single components beclometasone dipropionate/formoterol or glycopyrronium. There was no clear evidence of pharmacokinetic interaction, however the extemporary combination showed formoterol and glycopyrronium levels transiently slightly higher immediately after dosing compared with the single components. It is noted that single component glycopyrronium, formulated as pressurised metered dose inhaler, which was used in the PK studies, is not available on the market.
A comparison across studies showed that the pharmacokinetics of beclometasone 17-monopropionate, formoterol and glycopyrronium is similar in COPD patients and in healthy subjects.
Effect of a spacer: The use of Trimbow with the AeroChamber Plus spacer in COPD patients increased the lung delivery of beclometasone 17-monopropionate, formoterol and glycopyrronium (maximum plasma concentration increased by 15%, 58% and 60% respectively). The total systemic exposure (as measured by AUC_0-t) was slightly reduced for beclometasone 17-monopropionate (by 37%) and formoterol (by 24%), while it was increased for glycopyrronium (by 45%). See also Precautions.
Effect of renal impairment: Systemic exposure (AUC_0-t) to beclometasone dipropionate, to its metabolite beclometasone 17-monopropionate and to formoterol was not affected by mild to severe renal impairment. For glycopyrronium, there was no impact in subjects with mild and moderate renal impairment. However, an increase in total systemic exposure of up to 2.5-fold was observed in subjects with severe renal impairment (glomerular filtration rate below 30 mL/min/1.73 m²), as a consequence of a significant reduction of the amount excreted in urine (approximately 90% reduction of glycopyrronium renal clearance). Simulations performed with a pharmacokinetic model showed that even when covariates had extreme values (body weight less than 40 kg and concomitant glomerular filtration rate below 27 mL/min/1.73 m²), exposure to Trimbow active substances remains in approximately a 2.5-fold range compared to the exposure in a typical patient with median covariate values.
Related to beclometasone dipropionate: Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclometasone 17-monopropionate which has a more potent topical anti-inflammatory activity compared with the pro-drug beclometasone dipropionate.
Absorption, distribution and biotransformation: Inhaled beclometasone dipropionate is rapidly absorbed through the lungs; prior to absorption there is extensive conversion to beclometasone 17-monopropionate via esterase enzymes that are found in most tissues. The systemic availability of the active metabolite arises from lung (36%) and from gastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasone dipropionate is negligible; however, pre-systemic conversion to beclometasone 17-monopropionate results in 41% of the dose being absorbed as the active metabolite. There is an approximately linear increase in systemic exposure with increasing inhaled dose. The absolute bioavailability following inhalation is approximately 2% and 62% of the nominal dose for unchanged beclometasone dipropionate and beclometasone 17-monopropionate, respectively. Following intravenous dosing, the disposition of beclometasone dipropionate and its active metabolite is characterised by high plasma clearance (150 and 120 L/h, respectively), with a small volume of distribution at steady-state for beclometasone dipropionate (20 L) and larger tissue distribution for its active metabolite (424 L). Plasma protein binding is moderately high.
Elimination: Faecal excretion is the major route of beclometasone dipropionate elimination mainly as polar metabolites. The renal excretion of beclometasone dipropionate and its metabolites is negligible.
The terminal elimination half-lives are 0.5 hours and 2.7 hours for beclometasone dipropionate and beclometasone 17-monopropionate, respectively.
Patients with hepatic impairment: The pharmacokinetics of beclometasone dipropionate in patients with hepatic impairment has not been studied, however, as beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver to form the more polar products beclometasone 21-monopropionate, beclometasone 17-monopropionate and beclometasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclometasone dipropionate.
Related to formoterol: Absorption and distribution: Following inhalation, formoterol is absorbed from both the lung and the gastrointestinal tract. The fraction of an inhaled dose that is swallowed after administration with a metered dose inhaler may range between 60% and 90%. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Peak plasma concentrations of the unchanged active substance occur within 0.5 to 1 hour after oral administration. Plasma protein binding of formoterol is 61-64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. The elimination half-life determined after oral administration is 2-3 hours. Absorption of formoterol is linear following inhalation of 12 to 96 micrograms of formoterol.
Biotransformation: Formoterol is widely metabolised and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. Liver appears to be the primary site of metabolism. Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations.
Elimination: The cumulative urinary excretion of formoterol after single inhalation from a dry powder inhaler increased linearly in the 12-96 micrograms dose range. On average, 8% and 25% of the dose was excreted as unchanged and total formoterol, respectively. Based on plasma concentrations measured following inhalation of a single 120 micrograms dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged active substance excreted in the urine, respectively.
The relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing. After oral administration (40 to 80 micrograms), 6% to 10% of the dose was recovered in urine as unchanged active substance in healthy subjects; up to 8% of the dose was recovered as the glucuronide. A total 67% of an oral dose of formoterol is excreted in urine (mainly as metabolites) and the remainder in the faeces. The renal clearance of formoterol is 150 mL/min.
Patients with hepatic impairment: The pharmacokinetics of formoterol has not been studied in patients with hepatic impairment; however, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe hepatic impairment.
Related to glycopyrronium: Absorption and distribution: Glycopyrronium has a quaternary ammonium structure which limits its passage across biological membranes and produces slow, variable and incomplete gastrointestinal absorption. Following glycopyrronium inhalation, the lung bioavailability was 10.5% (with activated charcoal ingestion) while the absolute bioavailability was 12.8% (without activated charcoal ingestion) confirming the limited gastrointestinal absorption and indicating that more than 80% of glycopyrronium systemic exposure was from lung absorption. After repeated inhalation of twice daily doses ranging from 12.5 to 50 micrograms via pressurised metered dose inhaler in COPD patients, glycopyrronium showed linear pharmacokinetics with little systemic accumulation at steady-state (median accumulation ratio 2.2-2.5).
The apparent volume of distribution (V_z) of inhaled glycopyrronium was increased compared to intravenous (i.v.) infusion (6420 L versus 323 L), reflecting the slower elimination after inhalation.
Biotransformation: The metabolic pattern of glycopyrronium in vitro (humans, dogs, rats, mice and rabbits liver microsomes and hepatocytes) was similar among species and the main metabolic reaction was the hydroxylation on the phenyl or ciclopentyl rings. CYP2D6 was found to be the only enzyme responsible for glycopyrronium metabolism.
Elimination: The mean elimination half-life of glycopyrronium in healthy volunteers was approximately 6 hours after i.v. injection while after inhalation in COPD patients it ranged from 5 to 12 hours at steady-state. After a glycopyrronium single i.v. injection, 40% of the dose was excreted in the urine within 24 hours. In COPD patients receiving repeated twice daily administration of inhaled glycopyrronium, the fraction of the dose excreted in urine ranged from 13.0% to 14.5% at steady-state. Mean renal clearance was similar across the range of doses tested and after single and repeated inhalation (range 281-396 mL/min).
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity and toxicity to reproduction and development.
Safety pharmacology: In an inhalation study in telemetered dogs, the cardiovascular system was a major target system for acute effects of Trimbow (increase in heart rate, decrease in blood pressure, ECG changes at higher doses), effects probably mainly related to the beta2-adrenergic activity of formoterol and the antimuscarinic activity of glycopyrronium. There was no evidence for overadditive effects of the triple combination when compared with the single components.
Repeat dose toxicity: In repeat dose inhalation studies with Trimbow in rats and dogs of up to 13 weeks duration, the main observed alterations were related to effects on the immune system (probably due to systemic corticosteroid effects of beclometasone dipropionate and its active metabolite beclometasone 17-monopropionate) and on the cardiovascular system (probably related to the beta2-adrenergic activity of formoterol and the anti-muscarinic activity of glycopyrronium). The toxicological profile of the triple combination reflected that of the single active components without a relevant increase in toxicity and without unexpected findings.
Reproductive and development toxicity: Beclometasone dipropionate/beclometasone 17-monopropionate was considered responsible for reproductive toxicity effects in rats such as reduction of the conception rate, fertility index, early embryonic development parameters (implantation loss), delay in ossification and increased incidence of visceral variations; while tocolytic and anti-muscarinic effects, attributed to the beta2-adrenergic activity of formoterol and the anti-muscarinic activity of glycopyrronium, affected pregnant rats in the late phase of gestation and/or early phase of lactation, leading to loss of pups.
Genotoxicity: Genotoxicity of Trimbow has not been evaluated, however, the single active components were devoid of genotoxic activity in the conventional test systems.
Carcinogenicity: Carcinogenicity studies have not been performed with Trimbow. However, in a 104-week rat inhalation carcinogenicity study and an oral 26-week carcinogenicity study in transgenic Tg.rasH2 mice, glycopyrronium bromide showed no carcinogenic potential and published data concerning long-term studies conducted with beclometasone dipropionate and formoterol fumarate in rats do not indicate a clinically relevant carcinogenic potential.