Therapeutic Properties: Doxofylline is a bronchodilator classified as a xanthine derivative.
Doxofylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels; main action is bronchodilation and anti-spasmodic; also contains anti-inflammatory properties.
Pharmacology: Pharmacodynamics: Doxofylline did not antagonise adenosine A1, A2B and A3 receptors; there was only a modest inhibition at the highest tested concentration (104 M) against A2A receptors. This may explain the improved tolerability profile of doxofylline in comparison with other xanthine based medicines.
Doxofylline does not inhibit any of the PDE enzyme subtypes, except a modest inhibition at the highest tested concentration (104 M) against PDE2A1. Lacks effect on PDE3, thus no vasodilation and cardiac effects.
Doxofylline does not exert any significant inhibitory effect against any of the 11 HDAC enzymes.
Doxofylline significantly inhibited the migration of neutrophils and the release of IL-6 and TNF-α into the lung lumen, demonstrating the anti-inflammatory action of doxofylline.
Clinical Data: Proven efficacy in Asthma and COPD. In a multicenter, randomized clinical trial, 139 COPD patients received Doxofylline 400 mg b.i.d. or Theophylline 250 mg b.i.d. for 28 days. Doxofylline is as effective as Theophylline in reducing spirometic parameters (p<0.001 for all tests). Doxofylline significantly decreased the daily use of Salbutamol inhaler (p<0.001 for both drugs). Doxofylline had significantly fewer adverse events than patients treated with Theophylline (Melillo et al, 1989).
The pooled-analysis of 483 asthma patients demonstrated that both doxofylline 400 mg and theophylline 250 mg significantly increased FEV1, reduced the rate of asthma events and use of salbutamol to relieve asthma symptoms compared to placebo (p<0.01). No significant differences between doxofylline 400 mg and theophylline 250 mg.
Doxofylline 400 mg did not significantly (p>0.05) increase the risk of AEs compared to placebo, risk of AEs was significantly higher in theophylline 250 mg group (p<0.05) compared to placebo (Calzetta et al, 2018).
In a RCT performed in the USA, 263 patients with chronic reversible bronchial asthma received Doxofylline 400 mg t.i.d., Theophylline 250 mg t.i.d. or placebo for 12 weeks. Doxofylline was as effective as Theophylline. Doxofylline was better tolerated than Theophylline, significantly more patients had to interrupt treatment with Theophylline because of AEs (p=0.001). Doxofylline significantly reduced the number of daily asthma attacks (p<0.05) (Goldstein et al, 2002).
Meta-analysis data obtained from 998 COPD patients. When coupling relative effects for efficacy and safety, doxofylline appeared to be superior in safety and efficacy compared to all other Xanthines (Aminophylline, Bamiphylline and Theophylline) (Cazzola et al, 2018).
Pharmacokinetics: The half-life of Doxofylline is greater than six hours; allows effective constant plasma levels with a t.i.d. dose regimen. ADME principles defined in Single dose pharmacokinetic studies in man after oral and IV administration. Doxofylline followed bi-compartmental model, mean half-life after i.v. was 65 min.
After oral administration, peak plasma levels reached after one hour. Absolute bioavailability is about 62.6%. Less than 4% is excreted through urine unchanged; almost completely metabolized in the liver (<90% drug clearance).
Following repeated administration Doxofylline reaches the steady-state after app. 4 days; the elimination half-life during long-term treatment is 8-10 hours: this allows a twice daily dose regimen. No accumulation of the drug was noted after one week of treatment.