Chemical formula: C₂₂H₂₄N₂O₇S Molecular mass: 460.5 g/mol PubChem compound: 11561674
Apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, IL-17 and other inflammatory cytokines. Cyclic AMP also modulates levels of anti-inflammatory cytokines such as IL-10. These pro- and anti-inflammatory mediators have been implicated in psoriatic arthritis and psoriasis.
In clinical studies in patients with psoriatic arthritis, apremilast significantly modulated, but did not fully inhibit, plasma protein levels of IL-1α, IL-6, IL-8, MCP-1, MIP-1β, MMP-3, and TNF-α. After 40 weeks of treatment with apremilast, there was a decrease in plasma protein levels of IL-17 and IL-23, and an increase in IL-10. In clinical studies in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes, including those for inducible nitric oxide synthase (iNOS), IL-12/IL-23p40, IL-17A, IL-22 and IL-8. In clinical studies in patients with Behçet Disease treated with apremilast, there was a significant positive association between the change in plasma TNF-alpha and clinical efficacy as measured by the number of oral ulcers.
Apremilast administered at doses of up to 50 mg twice daily did not prolong the QT interval in healthy subjects.
Apremilast is well absorbed with an absolute oral bioavailability of approximately 73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of approximately 2.5 hours. Apremilast pharmacokinetics are linear, with a dose-proportional increase in systemic exposure in the dose range of 10 to 100 mg daily. Accumulation is minimal when apremilast is administered once daily and approximately 53% in healthy subjects and 68% in patients with psoriasis when administered twice daily. Co-administration with food does not alter the bioavailability therefore, apremilast can be administered with or without food.
Human plasma protein binding of apremilast is approximately 68%. The mean apparent volume of distribution (Vd) is 87 L, indicative of extravascular distribution.
Apremilast is extensively metabolised by both CYP and non-CYP mediated pathways including oxidation, hydrolysis, and conjugation, suggesting inhibition of a single clearance pathway is not likely to cause a marked drug-drug interaction. Oxidative metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. Apremilast is the major circulating component following oral administration. Apremilast undergoes extensive metabolism with only 3% and 7% of the administered parent compound recovered in urine and faeces, respectively. The major circulating inactive metabolite is the glucuronide conjugate of O-demethylated apremilast (M12). Consistent with apremilast being a substrate of CYP3A4, apremilast exposure is decreased when administered concomitantly with rifampicin, a strong inducer of CYP3A4.
In vitro, apremilast is not an inhibitor or inducer of cytochrome P450 enzymes. Hence, apremilast co-administered with substrates of CYP enzymes is unlikely to affect the clearance and exposure of active substances that are metabolised by CYP enzymes.
In vitro, apremilast is a substrate, and a weak inhibitor of P-glycoprotein (IC50 >50 μM), however clinically relevant drug interactions mediated via P-gp are not expected to occur.
In vitro, apremilast has little to no inhibitory effect (IC50 >10 μM) on Organic Anion Transporter (OAT)1 and OAT3, Organic Cation Transporter (OCT)2, Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP) and is not a substrate for these transporters. Hence, clinically relevant drug-drug interactions are unlikely when apremilast is co-administered with drugs that are substrates or inhibitors of these transporters.
The plasma clearance of apremilast is on average about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 9 hours. Following oral administration of radiolabelled apremilast, about 58% and 39% of the radioactivity is recovered in urine and faeces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and faeces, respectively.
Apremilast was studied in young and elderly healthy subjects. The exposure in elderly subjects (65 to 85 years of age) is about 13% higher in AUC and about 6% higher in Cmax for apremilast than that in young subjects (18 to 55 years of age). There is limited pharmacokinetic data in subjects over 75 years of age in clinical trials. No dose adjustment is necessary for elderly patients.
The pharmacokinetics of apremilast were evaluated in a clinical trial in subjects 6 to 17 years of age with moderate to severe plaque psoriasis at the recommended paediatric dose regimen. Population pharmacokinetic analysis indicated that steady-state exposure (AUC and Cmax) of apremilast in paediatric patients receiving the paediatric dose regimen (20 mg or 30 mg twice daily, based on body weight) was similar to steady-state exposure in adult patients at the 30 mg twice daily dose.
There is no meaningful difference in the PK of apremilast between mild or moderate renally impaired adult subjects and matched healthy subjects (N=8 each). The results support that no dose adjustment is needed in patients with mild and moderate renal impairment.
In 8 adult subjects with severe renal impairment to whom a single dose of 30 mg apremilast was administered, the AUC and Cmax of apremilast increased by approximately 89% and 42%, respectively. The dose of apremilast should be reduced to 30 mg once daily in adult patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m² or CLcr <30 mL/min). In paediatric patients 6 years of age and older with severe renal impairment, the dose of apremilast should be reduced to 30 mg once daily for children who weigh at least 50 kg and to 20 mg once daily for children who weigh 20 kg to less than 50 kg.
The pharmacokinetics of apremilast and its major metabolite M12 are not affected by moderate or severe hepatic impairment. No dose adjustment is necessary for patients with hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. There is no evidence of immunotoxic, dermal irritation, or phototoxic potential.
In a male mouse fertility study, apremilast at oral doses of 1, 10, 25, and 50 mg/kg/day produced no effects on male fertility; the No Observed Adverse Effect Level (NOAEL) for male fertility was greater than 50 mg/kg/day 3-fold clinical exposure.
In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral doses of 10, 20, 40, and 80 mg/kg/day, a prolongation of oestrous cycles and increased time to mating were observed at 20 mg/kg/day and above; despite this, all mice mated and pregnancy rates were unaffected. The No Observed Effect Level (NOEL) for female fertility was 10 mg/kg/day (1.0-fold clinical exposure).
In a combined female mouse fertility and embryo-foetal developmental toxicity study with oral doses of 10, 20, 40, and 80 mg/kg/day, absolute and/or relative heart weights of maternal animals were increased at 20, 40, and 80 mg/kg/day. Increased numbers of early resorptions and reduced numbers of ossified tarsals were observed at 20, 40, and 80 mg/kg/day. Reduced foetal weights and retarded ossification of the supraoccipital bone of the skull were observed at 40 and 80 mg/kg/day. The maternal and developmental NOEL in the mouse was 10 mg/kg/day (1.3-fold clinical exposure).
In a monkey embryo-foetal developmental toxicity study, oral doses of 20, 50, 200, and 1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) at doses of 50 mg/kg/day and above; no test article-related effect in prenatal loss was observed at 20 mg/kg/day (1.4-fold clinical exposure).
In a pre- and postnatal study, apremilast was administered orally to pregnant female mice at doses of 10, 80 and 300 mg/kg/day from Gestation Day (GD) 6 to day 20 of lactation. Reductions in maternal body weight and weight gain, and one death associated with difficulty in delivering pups were observed at 300 mg/kg/day. Physical signs of maternal toxicity associated with delivering pups were also observed in one mouse at each of 80 and 300 mg/kg/day. Increased peri- and post-natal pup deaths and reduced pup body weights during the first week of lactation were observed at ≥80 mg/kg/day (≥4.0-fold clinical exposure). There were no apremilast-related effects on duration of pregnancy, number of pregnant mice at the end of the gestation period, number of mice that delivered a litter, or any developmental effects in the pups beyond postnatal day 7. It is likely that pup developmental effects observed during the first week of the postnatal period were related to the apremilast-related pup toxicity (decreased pup weight and viability) and/or lack of maternal care (higher incidence of no milk in the stomach of pups). All developmental effects were observed during the first week of the postnatal period; no apremilast-related effects were seen during the remaining pre- and post-weaning periods, including sexual maturation, behavioural, mating, fertility and uterine parameters. The NOEL in the mouse for maternal toxicity and F1 generation was 10 mg/kg/day (1.3-fold clinical AUC).
Carcinogenicity studies in mice and rats showed no evidence of carcinogenicity related to treatment with apremilast.
Apremilast is not genotoxic. Apremilast did not induce mutations in an Ames assay or chromosome aberrations in cultured human peripheral blood lymphocytes in the presence or absence of metabolic activation. Apremilast was not clastogenic in an in vivo mouse micronucleus assay at doses up to 2,000 mg/kg/day.
There is no evidence of immunotoxic, dermal irritation, or phototoxic potential.
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