Chemical formula: C₁₇H₁₄Cl₂F₂N₂O₃ Molecular mass: 403.207 g/mol PubChem compound: 449193
Roflumilast is a PDE4 inhibitor, a non-steroid, anti-inflammatory active substance designed to target both the systemic and pulmonary inflammation associated with COPD. The mechanism of action is the inhibition of PDE4, a major cyclic adenosine monophosphate (cAMP)-metabolizing enzyme found in structural and inflammatory cells important to the pathogenesis of COPD. Roflumilast targets the PDE4A, 4B and 4D splicing variants with similar potency in the nanomolar range. The affinity to the PDE4C splicing variants is 5 to 10-fold lower. This mechanism of action and the selectivity also apply to roflumilast N-oxide, which is the major active metabolite of roflumilast.
Inhibition of PDE4 leads to elevated intracellular cAMP levels and mitigates COPD-related malfunctions of leukocytes, airway and pulmonary vascular smooth muscle cells, endothelial and airway epithelial cells and fibroblasts in experimental models. Upon in vitro stimulation of human neutrophils, monocytes, macrophages or lymphocytes, roflumilast and roflumilast N-oxide suppress the release of inflammatory mediators e.g. leukotriene B4, reactive oxygen species, tumour necrosis factor α, interferon γ and granzyme B.
In patients with COPD, roflumilast reduced sputum neutrophils. Furthermore, roflumilast attenuated influx of neutrophils and eosinophils into the airways of endotoxin challenged healthy volunteers.
Roflumilast is extensively metabolised in humans, with the formation of a major pharmacodynamically active metabolite, roflumilast N-oxide. Since both roflumilast and roflumilast N-oxide contribute to PDE4 inhibitory activity in vivo, pharmacokinetic considerations are based on total PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast N-oxide).
The absolute bioavailability of roflumilast following a 500 micrograms oral dose is approximately 80%. Maximum plasma concentrations of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state. Maximum concentrations of the N-oxide metabolite are reached after about eight hours (ranging from 4 to 13 hours). Food intake does not affect the total PDE4 inhibitory activity, but delays time to maximum concentration (tmax) of roflumilast by one hour and reduces Cmax by approximately 40%. However, Cmax and tmax of roflumilast N-oxide are unaffected.
Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single dose of 500 micrograms roflumilast is about 2.9 l/kg. Due to the physico-chemical properties, roflumilast is readily distributed to organs and tissues including fatty tissue of mice, hamster and rat. An early distribution phase with marked penetration into tissues is followed by a marked elimination phase out of fatty tissue most probably due to pronounced break-down of parent compound to roflumilast N-oxide. These studies in rats with radiolabelled roflumilast also indicate low penetration across the blood-brain barrier. There is no evidence for a specific accumulation or retention of roflumilast or its metabolites in organs and fatty tissue.
Roflumilast is extensively metabolised via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the major metabolite observed in the plasma of humans. The plasma AUC of the N-oxide metabolite on average is about 10-fold greater than the plasma AUC of roflumilast. Thus, the N-oxide metabolite is considered to be the main contributor to the total PDE4 inhibitory activity in vivo.
In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human hepatic microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low probability of relevant interactions with substances metabolised by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.
The plasma clearance after short-term intravenous infusion of roflumilast is about 9.6 l/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabelled roflumilast, about 20% of the radioactivity was recovered in the faeces and 70% in urine as inactive metabolites.
The pharmacokinetics of roflumilast and its N-oxide metabolite are dose-proportional over a range of doses from 250 micrograms to 1,000 micrograms.
In older people, females and in non-Caucasians, total PDE4 inhibitory activity was increased. Total PDE4 inhibitory activity was slightly decreased in smokers. None of these changes were considered to be clinically meaningful. No dose adjustment is recommended in these patients. A combination of factors, such as in black, non-smoking females, might lead to an increase of exposure and persistent intolerability. In this case, roflumilast treatment should be reassessed.
In Study RO-2455-404-RD when compared with the overall population, the total PDE4 inhibitory activity determined from ex vivo unbound fractions was found to be 15% higher in patients ≥75 years of age, and 11% higher in patients with baseline body weight <60 kg.
Total PDE4 inhibitory activity decreased by 9% in patients with severe renal impairment (creatinine clearance 10-30 ml/min). No dose adjustment is necessary.
The pharmacokinetics of roflumilast 250 micrograms once-daily was tested in 16 patients with mild to moderate hepatic impairment classified as Child-Pugh A and B. In these patients, the total PDE4 inhibitory activity was increased by about 20% in patients with Child-Pugh A and about 90% in patients with Child-Pugh B. Simulations suggest dose proportionality between roflumilast 250 and 500 micrograms in patients with mild and moderate hepatic impairment. Caution is necessary in Child-Pugh A patients. Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C should not take roflumilast.
There is no evidence for an immunotoxic, skin sensitising or phototoxic potential.
A slight reduction in male fertility was seen in conjunction with epididymal toxicity in rats. No epididymal toxicity or changes in semen parameters were present in any other rodent or non-rodent species including monkeys in spite of higher exposures.
In one of two rat embryofetal development studies, a higher incidence of incomplete skull bone ossification was seen at a dose producing maternal toxicity. In one of three rat studies on fertility and embryofetal development, post-implantation losses were observed. Post-implantation losses were not seen in rabbits. Prolongation of gestation was seen in mice.
The relevance of these findings to humans is unknown.
Most relevant findings in safety pharmacology and toxicology studies occurred at higher doses and exposure than that intended for clinical use. These findings consisted mainly of gastrointestinal findings (i.e. vomiting, increased gastric secretion, gastric erosions, intestine inflammation) and cardiac findings (i.e. focal haemorrhages, haemosiderin deposits and lympho-histiocytic cell infiltration in the right atria in dogs, and decreased blood pressure and increased heart rate in rats, guinea pigs and dogs).
Rodent-specific toxicity in the nasal mucosa was observed in repeat-dose toxicity and carcinogenicity studies. This effect seems to be due to an ADCP (4-Amino-3,5-dichloro-pyridine) N-oxide intermediate specifically formed in rodent olfactory mucosa, with special binding affinity in these species (i.e. mouse, rat and hamster).
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