PubChem compound: 166177189
Nerandomilast is a selective inhibitor of phosphodiesterase 4 (PDE4) with preferential inhibition of the PDE4B isoenzyme over PDE4A, C and D. There is a 9-fold selectivity over PDE4D, 24-fold selectivity over PDE4A and 870-fold selectivity over PDE4C based on in vitro data. At the recommended doses, inhibition of PDE4B and weaker inhibition of PDE4D can be expected. PDE4 hydrolyses and inactivates cyclic adenosine monophosphate (cAMP). Nerandomilast exerts both anti-fibrotic and immunomodulatory effects as preferential PDE4B inhibition elevates intracellular cAMP levels and reduces the expression of pro-fibrotic growth factors and inflammatory cytokines, which are overexpressed in fibrotic lung disease.
At single doses of nerandomilast up to 48 mg (2.2-times the estimated Cmax,ss exposure at the maximum recommended human dose), clinically significant QTc interval prolongation was not observed.
The pharmacokinetics of nerandomilast have been characterised in healthy volunteers, patients with IPF and patients with PPF. No clinically relevant differences in pharmacokinetics of nerandomilast were noted between these populations.
Nerandomilast reached peak plasma concentrations (Cmax) at a median time (Tmax) of 1.00-1.25 h (range between 0.5-4 hours) after oral administration of 9 mg and 18 mg doses. The absolute oral bioavailability of nerandomilast was 73% (90% CI: 67-79%).
Administration of 18 mg nerandomilast with a high-fat and high caloric meal did not change nerandomilast exposure to a clinically relevant extent (AUC increased by approximately 15% while Cmax decreased by approximately 14%).
After single intravenous administration of nerandomilast, the geometric mean volume of distribution Vss was approximately 94 L (gCV 32.0%). In vitro, nerandomilast was a substrate of the transporter protein P-gp, but not of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2.
In vitro human plasma protein binding of nerandomilast was 77% with no concentration dependence.
In healthy volunteers, nerandomilast was preferentially distributed in plasma with a blood-to-plasma ratio of 0.6-0.8.
Nerandomilast is mainly metabolised via oxidation by CYP3A and glucuronidation by multiple uridine-5′-diphospho-glucuronosyltransferase enzymes.
Following single oral administration, nerandomilast was the primary circulating component representing approximately 50% of circulating radioactivity.
After multiple oral administrations of 12 mg nerandomilast twice daily, the only major metabolite identified in plasma at steady state was the di-oxidative metabolite BI 764333/M480(4). This pharmacologically inactive metabolite represented 12% of the total plasma material at steady state consisting of both parent compound and all its metabolites.
Nerandomilast has a chiral sulfur atom and the oral pharmaceutical form predominantly contains chirally pure nerandomilast (R-enantiomer). After oral administration of nerandomilast, chiral inversion from R-enantiomer to S-enantiomer occurs via metabolism. The S-enantiomer was identified as a minor (3% of total circulating radioactivity) metabolite of nerandomilast and is pharmacologically inactive. The pharmacologically active R-enantiomer remained as the predominant circulating enantiomer.
Following multiple oral doses of 18 mg nerandomilast twice daily, the terminal half-life was approximately 10 to 17 h and the geometric mean apparent plasma clearance at steady state was 274 mL/min with inter-individual variability (gCV%) of 23.6%. After oral administration of a single 18 mg dose of radiolabelled nerandomilast, approximately 95% of the dose was recovered within 9 days after dosing, with 58% recovered in faeces (13% unchanged) and 36% recovered in urine (12% unchanged).
Nerandomilast exhibited dose proportional pharmacokinetics following oral administration of both, single doses (0.06 to 48 mg) and multiple doses (1 to 18 mg twice daily). Following oral administration of 18 mg nerandomilast twice daily, steady state was achieved within 4 days with an accumulation ratio of up to 1.38 based on AUC and Cmax.
No clinically significant differences in the pharmacokinetics of nerandomilast were observed based on age (18-90 years), sex, ethnicity (Hispanic/Latino or not Hispanic/Latino), mild, moderate, and severe renal impairment (eGFR ≥15 and <90 mL/min based on CKD-EPI formula), or mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Subjects with end stage renal disease and subjects with severe hepatic impairment (Child Pugh C) have not been studied.
Asian patients have up to 47% higher nerandomilast trough concentration compared to White patients. This effect is not expected to be clinically meaningful.
A population PK analysis indicated higher nerandomilast exposure in patients with lower body weight and lower exposure in patients with higher body weight. The impact of body weight on nerandomilast plasma concentrations is not expected to be clinically meaningful.
Increases in nerandomilast steady state trough concentrations were associated with better efficacy in patients with IPF and PPF, as indicated by a smaller reduction in absolute Forced Vital Capacity (FVC) from baseline over 52 weeks.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity. There is no evidence of phototoxic potential.
Repeat-dose toxicity studies were conducted in rats, minipigs, and monkeys. Vasculopathy (inflammation, haemorrhage, and blood vessel necrosis) was the primary finding observed in the rat and minipig. No adverse vascular effects were observed in monkeys administered up to 30 mg/kg/day (10-times human exposure based on AUC at the maximum recommended human dose (MRHD)). Adverse vascular effects observed in rats and in minipigs affected various tissues (i.e., mesentery and GI tract in rats, heart and lung in minipigs). In long-term studies, no adverse vascular changes were observed in rats at 2 mg/kg/day, and vascular changes were observed in one minipig at 3 mg/kg/day (both equivalent to human exposure, based on AUC at the MRHD). The exposure margin in monkeys, considered the most relevant species to humans, suggests that primates are less sensitive to vascular effects than other species.
In toxicology studies in monkeys at exposures higher than 10-times human exposure based on AUC at the MRHD, emesis and heart findings (focal degeneration or necrosis not accompanied by vascular changes) were observed.
In a fertility study in male rats, nerandomilast administration at a dose of 6 mg/kg/day (approximately 4-times human exposure based on AUC at the MRHD) showed no effect on mating, fertility, or sperm indices.
In female rats, decreased indices for mating and fertility were observed at the highest tested dose of 9 mg/kg/day (approximately 9-times human exposure based on AUC at the MRHD) and were related to general toxicity. No such effects were observed at the No Observed Adverse Effects Level (NOAEL) dose of 6 mg/kg/day (approximately 4-times human exposure at the MRHD). In the fertility and early embryonic development and the embryo-foetal development studies, an increase in early resorptions was observed in rats at doses ≥6 mg/kg/day. No such effects were observed at the NOAEL dose of 3 mg/kg/day (approximately 3-times human exposure at the MRHD).
Sexually mature female monkeys administered nerandomilast for 39 weeks showed sporadic menstrual cycle prolongation at dose levels of 10 mg/kg/day and 30 mg/kg/day (approximately 3- or 10-times human exposure based on AUC at the MRHD). Menstrual cycles were not affected in monkeys at 3 mg/kg/day (equivalent to human exposure based on AUC at the MRHD). No changes in oestrous cycles were observed in rats.
Following administration of radiolabelled nerandomilast to pregnant rats, radioactivity was detected in placenta, embryo-foetal blood and tissues, suggesting transfer across the placental barrier.
Embryo-foetal development studies in rats and rabbits showed no teratogenicity, no skeletal variations and no fetotoxicity up to the highest tested dose levels of 9 mg/kg/day and 15 mg/kg/day, equivalent to 7- and 4-times human exposure based on AUC at the MRHD, respectively. Embryo-foetal lethality due to post-implantation loss related to an increase in early resorptions was observed in rats at the dose of 6 mg/kg/day (5-times human exposure based on AUC at the MRHD) administered from gestation day 6 to 17. No embryo-foetal lethality was observed in rats and rabbits at the NOAEL dose of 3 mg/kg/day and 15 mg/kg/day (approximately 3- and 4-times human exposure based on AUC at the MRHD, respectively).
In a dose range-finding pre- and postnatal development study in rats, a maternal dose of 6 mg/kg/day (approximately 5- to 6-times human exposure at the MRHD) from gestation day 6 to lactation day 6 resulted in lower pup weights. In the pivotal pre- and postnatal development study, nerandomilast administered to pregnant female rats from gestation day 6 to lactation day 20, had no adverse effects on maternal performance or toxicity or on F1 generation (offspring) development, behaviour, and reproductive performance up to the highest tested dose of 3 mg/kg/day (approximately 2-times human exposure based on AUC at the MRHD). In this study, nerandomilast was present in the plasma of rat pups during the lactation period.
In a single dose milk secretion study in lactating rats dosed with radiolabelled nerandomilast by the oral route, similar concentrations of total radioactivity were observed in the milk and plasma of lactating females, with the maximum radioactive concentration observed at 1 hour post dose that was significantly reduced by 24 hours post dose. The concentration of total radioactivity in animal milk does not necessarily predict the concentration of the active substance in human milk.
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