Impact of Renal Impairment on the Pharmacokinetics of Apremilast and Metabolite M12

Abstract

The pharmacokinetics of apremilast and its major metabolite M12 were evaluated in subjects with varying degrees of renal impairment. Men and women with renal impairment (estimated glomerular filtration rate, 60‒89 mL/min [mild, n = 8], 30‒59 mL/min [moderate, n = 8], or <30 mL/min [severe, n = 8]) or demographically healthy matched (control) subjects (n = 24) received a single oral dose of apremilast 30 mg. Plasma apremilast and metabolite M12 concentrations were determined, and pharmacokinetic parameters were calculated from samples obtained predose and up to 72 hours postdose. In subjects with mild to moderate renal impairment, apremilast pharmacokinetic profiles were similar to healthy matched subjects. In subjects with severe renal impairment, apremilast elimination was significantly slower, and exposures based on area under the plasma concentration‐versus‐time curve from time zero extrapolated to infinity and maximum observed plasma concentration were increased versus healthy matched subjects. Metabolite M12 pharmacokinetic profiles for subjects with mild renal impairment were similar to those of the healthy matched subjects; however, they were increased in both the moderate and severe renally impaired subjects. Dose reduction of apremilast is recommended in individuals with severe renal impairment, but not in those with mild to moderate renal impairment.

Characterization of LY2775240, a selective phosphodiesterase‐4 inhibitor, in nonclinical models and in healthy subjects

“…The oral PDE4 inhibitor apremilast is approved to treat psoriasis and other inflammatory conditions, and is given as a twice daily 30 mg dose. While there are reported values of PDE4 inhibition following apremilast treatment (20) the time course of PDE4 inhibition over the course of dosing duration is not well understood. In this study we utilized a novel PD assay to directly compare the PDE4 inhibition achieved by LY2775240 with that achieved by apremilast, over the course of a 24-hour duration.…”

Innovative rheumatologische und osteologische Medikation im Kontext der chronischen Niereninsuffizienz – Was ist möglich?

“…Apremilast wird als Hemmer der Phosphodiesterase 4 in der Therapie der Psoriasis-Arthritis sowie bei der Psoriasis eingesetzt. 3 % der applizierten Dosis wird renal eliminiert [28]. Bei einer gering oder mild eingeschränkten Nierenfunktion ist keine Dosisanpassung von Apremilast notwendig.…”

“…Bei einer gering oder mild eingeschränkten Nierenfunktion ist keine Dosisanpassung von Apremilast notwendig. Bei einer Einschränkung der GFR < 30 ml/min wurde eine Anstieg der Apremilast-Metaboliten im Serum im Vergleich zu gesunden Probanden nachgewiesen [28]. Demzufolge wird eine Dosisreduktion auf die Hälfte der täglichen Dosis in der Fachinformation empfohlen und während der Titrationsphase sollte auf die Abenddosen verzichtet werden [29].…”

Technological advances in current metabolomics and its application in tradition Chinese medicine

“…28,29 The efficacy of MS in the study of endogenous metabolites stems from its proven success in disease studies, 30-32 pharmacokinetics 33,34 and drugmetabolite analysis. 35 MS (especially Q-TOF) also helps to identify previously uncharacterized metabolites. 13,36,37 MS in quantitative analysis of small molecules has been established, unlike its application to proteomics.…”