PubChem compound: 166177189
Nerandomilast is an inhibitor of phosphodiesterase 4 (PDE4) with at least nine-fold preferential inhibition of the PDE4B isoenzyme over PDE4A, PDE4C and PDE4D based on in vitro data. PDE4 hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP). Nerandomilast exerts both anti-fibrotic and immunomodulatory effects as PDE4B inhibition elevates intracellular cAMP levels and reduces the expression of pro-fibrotic growth factors and inflammatory cytokines, which are overexpressed in IPF.
Increases in nerandomilast steady state trough concentrations were associated with better efficacy, as indicated by a smaller reduction in forced vital capacity (FVC) from baseline over 52 weeks.
At 2.1 times the maximal concentration provided by the maximum recommended dose of nerandomilast, clinically significant QTc interval prolongation was not observed.
Nerandomilast exposure increased in a dose proportional manner following administration of single doses of 0.0032 to 2.6 times a single dose of 18 mg and multiple doses of 0.056 to 1 times the maximum recommended dose of 18 mg twice daily.
Following administration of multiple doses of 18 mg twice daily, Cmax increases 1.3-fold and AUCtau increases 1.38-fold. Nerandomilast steady state is reached in approximately 4 days.
No clinically relevant differences in nerandomilast pharmacokinetics were observed between healthy subjects and patients with IPF.
The absolute oral bioavailability of nerandomilast is 73%. Nerandomilast median (min, max) time to maximum plasma concentration (Tmax) is 1 to 1.25 hours (range 0.5 to 4 hours).
No clinically relevant differences in nerandomilast pharmacokinetics were observed following administration with a high-fat meal (1000 calories, 50% fat).
Nerandomilast steady state apparent (oral) central volume of distribution is 93 L (CV 37%). In vitro, nerandomilast plasma protein binding is 77% and is not concentration dependent. Nerandomilast blood-to-plasma ratio is approximately 0.6 to 0.8.
The geometric mean (CV%) elimination half-life of nerandomilast is 17 hours (46%) with an apparent (oral) clearance of 15.2 L/h.
Nerandomilast is primarily metabolized by CYP3A and to a lesser extent by multiple UGT enzymes.
After oral administration of nerandomilast, chiral inversion from the pharmacologically active R-enantiomer to the pharmacologically inactive S-enantiomer occurs via metabolism. The S-enantiomer was identified as a minor metabolite of nerandomilast. The R-enantiomer is the predominant circulating enantiomer.
After a single oral dose of radiolabeled nerandomilast, approximately 58% of the dose was recovered in feces (14% as unchanged nerandomilast) and 36% of the dose was recovered in urine (13% as unchanged nerandomilast).
No clinically significant differences in the pharmacokinetics of nerandomilast were observed based on age (range: 18 to 90 years), body weight (range: 34 to 136 kg), sex, race (66% White and 32.5% Asian), mild (eGFR ≥60 to <90 mL/min/1.73 m² [calculated according to Chronic Kidney Disease Epidemiology Collaboration]), moderate (eGFR ≥30 to <60 mL/min/1.73 m²), or severe renal impairment (eGFR ≥15 to <30 mL/min/1.73 m²), or mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Subjects with end stage renal disease or severe hepatic impairment (Child-Pugh Class C) have not been studied.
Nerandomilast Cmax increased by 1.3-fold and AUC increased by 2.2-fold following concomitant administration with itraconazole (a strong CYP3A and P-gp inhibitor) 200 mg oral solution once daily for 4 days.
Nerandomilast trough concentrations at steady state (Ctrough,ss) decreased by approximately 50% following concomitant administration with pirfenidone in patients with IPF.
No clinically significant differences in nerandomilast Ctrough,ss were observed when used concomitantly with nintedanib. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with nerandomilast: oral midazolam (CYP3A4 substrate), pirfenidone, and nintedanib.
CYP450 Enzymes: Nerandomilast is a CYP3A4 substrate. Nerandomilast does not inhibit CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
Transporter Systems: Nerandomilast is a P-glycoprotein (P-gp) substrate, but is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2. Nerandomilast is an inhibitor of P-gp, MATE1, MATE2-K, but is not expected to cause clinically significant interactions. Nerandomilast is not an inhibitor of BCRP, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.
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