Abstract
Background and Objectives
Nerandomilast, a preferential phosphodiesterase 4B inhibitor, is approved for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis in some countries. The objective of this study was to evaluate the safety and pharmacokinetics of nerandomilast in healthy volunteers through single- and multiple-rising-dose studies, and a human mass balance study evaluating absorption, distribution, metabolism, and excretion.
Methods
Healthy participants received oral nerandomilast doses ranging from 0.02 mg to 24 mg in the single-rising-dose trial, 1 mg or 6 mg twice daily for 14 days in the multiple-rising-dose trial, and a single oral dose of 18 mg [14C]-labeled nerandomilast in the mass balance trial. In each trial, pharmacokinetic blood samples were collected for determination of nerandomilast plasma concentrations. In the mass balance study, urine, feces, and blood samples were collected, and [14C]-radioactivity was quantified from these matrices. All pharmacokinetic parameters were calculated via noncompartmental analysis.
Results
Nerandomilast was rapidly absorbed postadministration, with peak plasma concentrations occurring between 0.5 and 1.25 h postdose before declining in a multiphasic manner. Nerandomilast exposure increased dose proportionally following single- and multiple-dose administrations. Steady state was reached by day 7 after twice-daily dosing with up to 1.69-fold drug accumulation. Following a single oral dose administration of [14C]nerandomilast, 58.0% and 36.4% of radioactivity was excreted in feces and urine, respectively. Of the administered dose, 11.9% was excreted as unchanged parent compound in urine. Nerandomilast safety was acceptable across all three studies and nerandomilast was well tolerated in healthy participants.
Conclusions
Nerandomilast exhibited rapid oral absorption, multiphasic elimination profile, dose-proportional exposure, and was excreted via urine and feces.
Trial Registration
NCT01594515 (registered 2012-05-07), NCT01835899 (registered 2013-04-11), and NCT04771286 (registered 2021-02-23).
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s13318-026-01027-9.
Key Points
| This study aimed to characterize the pharmacokinetics of nerandomilast, a preferential PDE4B inhibitor, in healthy volunteers using single- and multiple-rising-doses and assessed mass balance following oral administration of [14C]-labeled nerandomilast. |
| Nerandomilast is rapidly absorbed, exhibits dose-proportional exposure with a multiphasic elimination profile, achieves steady-state by day 7 with up to 1.69-fold accumulation, and is primarily excreted via feces (58.0%) and urine (36.4%). |
| These findings inform dose selection for future clinical trials, characterize nerandomilast’s metabolism and excretion pathways to help predict drug interactions, and support the use of nerandomilast as an approved treatment for pulmonary fibrosis. |
Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease (ILD) characterized by progressive lung fibrosis, declining lung function, and worsening dyspnea [1–3]. In addition to IPF, other types of ILD can also develop a progressive phenotype, termed progressive pulmonary fibrosis (PPF) [3,4]. PPF shares many clinical features with IPF, suggesting potential overlap in pathogenic mechanisms and responsiveness to similar treatments [5].
Until recently, the only two approved treatments for IPF and PPF were nintedanib (IPF and PPF) and pirfenidone (IPF only) [5–10]. These approved treatments slow down the progressive decline in lung function over time but do not stop disease progression [5,11]. Nintedanib and pirfenidone are both associated with gastrointestinal adverse events (AEs) including diarrhea, nausea, and decreased appetite, which may result in treatment discontinuation, and can negatively impact patients’ quality of life [11,12]. Therefore, there was an urgent unmet medical need for more effective treatments with acceptable tolerability that can modify the disease course in patients with IPF and PPF.
Phosphodiesterase 4 (PDE4) enzymes mediate the breakdown of cyclic adenosine monophosphate, a second messenger involved in regulating fibrotic, inflammatory, and immune cell functions [13]. The PDE4 family comprises four subtypes (PDE4A, PDE4B, PDE4C, and PDE4D) with distinct tissue distributions and functional roles [14]. PDE4 has been investigated as a therapeutic target in inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, owing to its ability to modulate inflammation, fibrosis, and immune cells [15–19]. However, pan-PDE4 inhibitors are associated with adverse effects, including diarrhea, nausea, headache, depression, and suicidal ideation, and emetic effects linked to PDE4D inhibition have further limited their use [17,20–23]. Preferential inhibition of PDE4B has been suggested to provide antifibrotic and immunomodulatory effects with reduced risk of side effects, making PDE4B a promising target for treating pulmonary fibrosis [16,24,25].
Nerandomilast is an oral preferential inhibitor of PDE4B with antifibrotic, immunomodulatory, and vascular effects, that has recently been approved for the treatment of IPF and PPF in some countries [25–30]. Nerandomilast has approximately 10-fold selectivity for PDE4B over PDE4D, and 25- to 870-fold selectivity over other PDE4 subtypes, potentially reducing the risk of gastrointestinal events associated with PDE4D inhibition while preserving therapeutic efficacy [25]. In preclinical studies, nerandomilast demonstrated antifibrotic and immunomodulatory properties in pulmonary fibrosis models, with synergistic effects observed with nintedanib in reducing fibroblast proliferation [25]. Phase I and II trials demonstrated its safety, tolerability, and efficacy, with nerandomilast (18 mg twice daily [BID]) preventing forced vital capacity decline over 12 weeks in patients with IPF as a monotherapy and in combination with antifibrotic treatments [31,32]. Nerandomilast was subsequently investigated in two large phase III trials over 52 weeks (FIBRONEERTM-IPF [NCT05321069] and FIBRONEERTM-ILD [NCT05321082]), at doses of 9 mg and 18 mg BID, and was shown to significantly reduce the decline in lung function in patients with IPF and PPF at both dose levels [33,34].
Here, we present data evaluating the pharmacokinetics and safety of nerandomilast in healthy volunteers following oral administration of nerandomilast in studies using single- or multiple-dose administrations. Furthermore, data on absorption, distribution, metabolism, and excretion of nerandomilast were evaluated following a single oral dose of [14C]-labeled nerandomilast.
Materials and Methods
Safety, tolerability, and pharmacokinetics of nerandomilast were evaluated in healthy volunteers following oral administration of nerandomilast in two studies using a single-rising-dose (SRD) (NCT01594515 [registered 2012-05-07]) or multiple-rising-doses (MRD) (NCT01835899 [registered 2013-04-11]). Additionally, the safety, tolerability, metabolism, and excretion pathways of nerandomilast were analyzed in a human absorption, distribution, metabolism, and excretion (hADME) study (NCT04771286 [registered 2021-02-23]).
The SRD study was a partially randomized, placebo-controlled within dose groups, single-blinded, single-center study in healthy male participants aged 18–45 years. Participants were divided into nine dose groups (0.02 mg, 0.06 mg, 0.2 mg, 0.6 mg, 2 mg, 4 mg, 8 mg, 16 mg, and 24 mg), with each dose group comprising two cohorts of four participants each (three receiving active treatment and one receiving placebo). The dose range was selected on the basis of preclinical pharmacology and toxicology data, and model-predicted human exposure. Based on these data, 0.5 mg was chosen as a starting dose for human studies. In addition, the human equivalent of the no observed adverse effect level (NOAEL) derived from 4-week rat toxicity studies was 28.8 mg/day, supporting evaluation of doses up to 24 mg, while a low starting dose was selected to provide an additional safety margin. The first cohort in each dose group was not randomized and underwent staggered administration of treatments (active-placebo-active-active) with intervals of at least 1 h between the first three participants; the fourth participant received the active treatment 10 min after the third participant. Upon confirmation of tolerability, the second cohort received treatments 2 days later, with participants randomly assigned to active treatment or placebo and a minimum interval of 10 min between participants. The remaining dose groups were investigated sequentially in ascending order, with a minimum interval of 5 days between the initiation of successive groups. Progression to the next dose group was contingent upon the absence of dose-limiting events, and a favorable safety and tolerability profile in the preceding dose group.
The MRD study was a randomized, double-blinded, and placebo-controlled within dose groups study in healthy male participants aged 18–50 years. Participants were included in two sequential dose groups of 12 participants each. Within each dose group, nine participants received nerandomilast and three received placebo for up to 14 days. The dose groups were investigated sequentially in ascending order, starting with the lowest dose and allowing sufficient time for data evaluation between groups. Progression to the next dose group was based on the safety and tolerability of the preceding dose group. Based on preclinical pharmacology and toxicology data, findings from the SRD study, and model-predicted exposure, dose levels of 1 mg BID, 6 mg BID, 12 mg BID, and 18 mg once daily were initially planned. BID dosing was proposed to reduce peak–trough fluctuations and mitigate the risk of suboptimal trough exposure that could occur with once-daily dosing. However, dose escalation was stopped after the second dose group (6 mg BID) because interim pharmacokinetic evaluation predicted that doses above 6 mg BID would exceed the predefined NOAEL established in the 4-week rat toxicity study. Consequently, only the 1 mg BID and 6 mg BID dose levels were evaluated in the MRD study. Subsequent longer-term repeat-dose toxicology studies in multiple species supported higher NOAELs, which informed later clinical dose selection.
The hADME study was an open-label, single-dose, single-arm, single-period study (NCT04771286) in healthy male participants aged 18–65 years, in which six participants received a single oral dose of 18 mg [14C]nerandomilast, consisting of 17.16 mg nonlabeled nerandomilast mixed with 0.84 mg radiolabeled nerandomilast. The 18-mg dose selected for the hADME study was on the basis of phase II data demonstrating that nerandomilast 18 mg BID was safe and efficacious in patients with IPF over 12 weeks of treatment. This dose was subsequently carried forward into the phase III FIBRONEERTM-IPF and FIBRONEERTM-ILD studies, where 18 mg BID was evaluated over 52 weeks.
In each clinical trial, intensive pharmacokinetic blood samples were collected to accurately quantify nerandomilast or [14C]nerandomilast equivalent (EQ) plasma concentrations over time, enabling a detailed pharmacokinetic analysis including characterization of its absorption, distribution, metabolism, and elimination. Concentrations of nerandomilast and its metabolites were determined by a validated liquid chromatography–mass spectrometry tandem assay.
For the hADME study, excretion pathways were evaluated in samples of urine and feces, with [14C]-radioactivity measured in blood samples to assess systemic exposure and overall drug distribution. Pharmacokinetic parameters, including maximum concentration (Cmax), area under the concentration–time curve (AUC), and terminal half-life, were determined using noncompartmental analysis to provide a robust understanding of the drug’s kinetic characteristics.
Safety and tolerability were assessed on the basis of analysis of AEs, clinical laboratory tests (hematology, clinical chemistry, urinalysis, and fecal occult blood test), vital signs, 12-lead electrocardiogram, physical examinations, and tolerability as assessed by the investigator. A significant AE was defined as a marked hematologic or other laboratory abnormality, or any event that led to an intervention, including withdrawal of test drug/investigational product treatment, dose reduction, or significant additional concomitant therapy (from International Council for Harmonisation E3) [35].
Descriptive statistical analyses were applied to all pharmacokinetic and safety end points across the trials to summarize the data and identify trends in drug behavior and tolerability.
The trials were carried out in accordance with the principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation—Good Clinical Practice guidelines, and in accordance with applicable regulatory requirements and Boehringer Ingelheim standard operating procedures.
Results
Participant Characteristics
The participant characteristics in each study are shown in Table 1. The SRD study included 70 male participants who were all White, with a mean age of 35.3 years and a mean body mass index (BMI) of 26.0 kg/m2. The MRD study included 24 male participants with a mean age of 42.0 years and a mean BMI of 25.4 kg/m2. Most participants (23/24, 95.8%) in the MRD study were White. The hADME study included six male participants (four White, two Asian) with a mean age of 44.3 years and a mean BMI of 24.5 kg/m2.
Table 1.
Participant characteristics
| SRD study | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Nerandomilast (mg) | Placebo | Total | |||||||||
| 0.02 | 0.06 | 0.2 | 0.6 | 2 | 4 | 8 | 16 | 24 | |||
| n = 6 | n = 6 | n = 6 | n = 6 | n = 6 | n = 6 | n = 6 | n = 6 | n = 6 | n = 16 | N = 70 | |
| Gender, n (%) | |||||||||||
| Male | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 16 (100) | 70 (100) |
| Race, n (%) | |||||||||||
| Asian | – | – | – | – | – | – | – | – | – | – | – |
| Black | – | – | – | – | – | – | – | – | – | – | – |
| White | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 16 (100) | 70 (100) |
| Age, mean (SD) [years] | 33.5 (5.1) | 29.5 (4.8) | 38.2 (6.5) | 35.0 (5.5) | 35.5 (5.9) | 32.7 (5.9) | 36.3 (6.3) | 40.5 (3.3) | 33.5 (8.4) | 36.6 (5.6) | 35.3 (6.1) |
| BMI, mean (SD) [kg/m2] | 25.8 (3.0) | 26.9 (1.5) | 24.9 (2.5) | 26.9 (1.5) | 24.8 (2.9) | 26.9 (1.6) | 26.9 (2.9) | 26.3 (2.7) | 26 (0.9) | 25.6 (2.6) | 26.0 (2.3) |
| Smoking status, n (%) | |||||||||||
| Never smoked | 5 (83.3) | 3 (50) | 4 (66.7) | 4 (66.7) | 4 (66.7) | 4 (66.7) | 3 (50.0) | 6 (100) | 4 (66.7) | 10 (62.5) | 47 (67.1) |
| Ex-smoker | 1 (16.7) | 2 (33.3) | 1 (16.7) | 1 (16.7) | 2 (33.3) | – | 2 (33.3) | – | 1 (16.7) | 3 (18.8) | 13 (18.6) |
| Current smoker | – | 1 (16.7) | 1 (16.7) | 1 (16.7) | – | 2 (33.3) | 1 (16.7) | – | 1 (16.7) | 3 (18.8) | 10 (14.3) |
| MRD study | hADME study | ||||
|---|---|---|---|---|---|
| Nerandomilast | Placebo | Total | [14C]nerandomilast | ||
| 1 mg BID | 6 mg BID | 18 mg | |||
| n = 9 | n = 9 | n = 6 | N = 24 | N = 6 | |
| Gender, n (%) | |||||
| Male | 9 (100) | 9 (100) | 6 (100) | 24 (100) | 6 (100) |
| Race, n (%) | |||||
| Asian | – | – | – | – | 2 (33.3) |
| Black | 1 (11.1) | – | – | 1 (4.2) | – |
| White | 8 (88.9) | 9 (100) | 6 (100) | 23 (95.8) | 4 (66.7) |
| Age, mean (SD) [years] | 38.7 (8.5) | 44.3 (8.3) | 43.5 (9.9) | 42.0 (8.8) | 44.3 (17.7) |
| BMI, mean (SD) [kg/m2] | 26.2 (2.1) | 24.6 (2.6) | 25.4 (2.4) | 25.4 (2.4) | 24.5 (2.9) |
| Smoking status, n (%) | |||||
| Never smoked | 6 (66.7) | 4 (44.4) | 5 (83.3) | 15 (62.5) | 1 (16.7) |
| Ex-smoker | 3 (33.3) | 5 (55.6) | 1 (16.7) | 9 (37.5) | 3 (50.0) |
| Current smoker | – | – | – | – | 2 (33.3) |
BID twice daily, BMI body mass index, hADME human absorption, distribution, metabolism, and excretion, MRD multiple-rising-dose, SD standard deviation, SRD single-rising-dose
All participants in the SRD and hADME studies completed the trial, whereas two participants withdrew prematurely from the MRD study: one on day 14 after 23 doses of nerandomilast, owing to urgent private reasons, and one on day 12 after 20 doses of nerandomilast owing to AEs.
Pharmacokinetics
The geometric mean (gMean) plasma concentration–time profiles of nerandomilast after single-dose and multiple-dose administration are shown in Fig. 1, and a summary of the pharmacokinetic parameters is provided in Table 2. In both the SRD and MRD studies, nerandomilast was rapidly absorbed, with Cmax occurring between 0.5 and 1.25 h postadministration, and showed a multiphasic decline in plasma concentration (Fig. 2; Table 2).
Fig. 1.
Concentration–time profiles of nerandomilast after a single dose in the SRD study (a) and multiple BID doses of nerandomilast in the MRD study (b). BID twice daily, MRD multiple-rising-dose, SRD single-rising-dose
Table 2.
Selected pharmacokinetic parameters after a single oral dose administration of nerandomilast (0.06 mg to 24 mg) in the SRD study, post single dose and at steady state after administration of 1 mg BID and 6 mg BID nerandomilast in the MRD study, and pharmacokinetic parameters for [14C]nerandomilast-EQ, nerandomilast, and metabolite BI 764333 in plasma following a single oral dose of 18 mg [14C]nerandomilast in the hADME study
| SRD study | ||||||||
|---|---|---|---|---|---|---|---|---|
| Nerandomilast | ||||||||
| 0.06 mga | 0.2 mga | 0.6 mga | 2 mg | 4 mg | 8 mg | 16 mg | 24 mg | |
| AUC0–∞, nmol·h/L | 7.44 (12.7) | 24.1 (13.9) | 67.9 (15.6) | 287 (14.9) | 679 (32.0) | 1210 (18.3) | 2180 (19.9) | 3650 (22.6) |
| Cmax, nmol/L | 1.42 (23.2) | 5.02 (20.1) | 13.7 (14.2) | 46.9 (38.9) | 113 (20.4) | 176 (12.6) | 292 (22.2) | 542 (12.1) |
| tmaxb, h | 0.750 (0.500, 1.00) | 0.750 (0.500, 1.52) | 1.00 (0.483, 1.03) | 0.517 (0.500, 1.00) | 0.709 (0.500, 1.03) | 1.01 (0.500, 1.50) | 1.25 (1.00, 2.48) | 1.00 (1.00, 1.50) |
| t½, h | 3.93 (27.0) | 4.21 (25.6) | 6.13 (54.8) | 20.0 (59.6) | 29.2 (31.2) | 19.6 (21.2) | 20.7 (31.5) | 26.1 (41.6) |
| CL/F, mL/min | 299 (12.7) | 308 (13.9) | 328 (15.6) | 259 (14.9) | 219 (32.0) | 245 (18.3) | 273 (19.9) | 244 (22.6) |
| Vz/F, L | 102 (28.6) | 112 (22.9) | 174 (44.4) | 447 (57.0) | 552 (33.4) | 415 (24.4) | 490 (24.3) | 551 (34.8) |
| MRTpo, h | 5.96 (20.7) | 5.84 (16.2) | 7.39 (33.4) | 15.5 (40.7) | 19.7 (22.9) | 14.8 (16.5) | 15.3 (33.8) | 15.8 (42.9) |
| Ae0–24, nmol | 18.6 (12.9) | 58.5 (25.2) | 192 (21.7) | 516 (19.7) | 1110 (28.2) | 2220 (19.3) | 3540 (17.1) | 6310 (20.4) |
| fe0–24, % | 13.9 (12.9) | 13.1 (25.2) | 14.3 (21.7) | 11.6 (19.7) | 12.5 (28.2) | 12.5 (19.3) | 9.94 (17.1) | 11.8 (20.4) |
| CLR0–24, mL/min | 43.0 (16.7) | 41.3 (20.6) | 50.2 (18.2) | 37.0 (24.8) | 36.4 (24.1) | 36.1 (25.1) | 33.5 (23.4) | 35.4 (11.5) |
| MRD study | |||||
|---|---|---|---|---|---|
| Post single dose | At steady state | ||||
| 1 mg | 6 mg | 1 mg BID | 6 mg BID | ||
| AUC0–∞, nmol·h/L | 131 (18.6) | 958 (20.9) | |||
| AUCτ,1, nmol·h/L | 94.9 (10.3) | 622 (20.7) | AUCτ,ss, nmol·h/L | 148 (10.7) | 1090 (19.6) |
| Cmax, nmol/L | 24 (25.1) | 133 (14.9) | Cmax,ss, nmol/L | 28.6 (15.3) | 199 (14.5) |
| Cmin,ss, nmol/L | 5.47 (25.2) | 42 (30) | |||
| tmaxb, h | 0.5 (0.50, 1.00) | 0.75 (0.50, 1.50) | tmax,ssb, h | 0.88 (0.50, 1.00) | 0.75 (0.50, 1.50) |
| t½, h | 10.9 (46.4) | 20.5 (34.8) | t½,ss, h | 24.3 (17.7) | 25.2 (43.3) |
| CL/F, mL/min | 283 (18.6) | 232 (20.9) | CL/Fss, mL/min | 251 (10.7) | 204 (19.6) |
| Vz/F, L | 268 (28.1) | 412 (43.7) | Vz/Fss, L | 528 (22.1) | 444 (54.1) |
| MRTpo, h | 10.6 (34.2) | 16.6 (24.9) | MRTpo,ss, h | 19.5 (12.3) | 20.1 (40.7) |
| RA,AUC | 1.6 (11.3) | 1.69 (17.8) | |||
| RA,Cmax | 1.19 (24.6) | 1.45 (14.9) | |||
| LI | 1.18 (14.7) | 1.1 (21.7) | |||
| hADME study | |||
|---|---|---|---|
| [14C]nerandomilast-EQ | Nerandomilast | BI 764333 | |
| AUC0–tz, h∙nmol/L | 10,600 (25.6) | 2850 (19.5) | 672 (32.9) |
| Cmax, nmol/L | 606 (12.4) | 544 (11.8) | 13 (29.2) |
| tmaxb, h | 0.75 (0.50 to 1.00) | 0.625 (0.50 to 1.00) | 4 (2.00 to 12.0) |
All values displayed are gMean (gCV%) except for tmax
aFor the 0.06-mg, 0.2-mg, and 0.6-mg dose groups, terminal phase λz-related pharmacokinetic parameters (t1/2, CL/F, Vz/F, and MRTpo) were unreliable owing to incomplete plasma concentration–time profiles at these lower doses
bData for tmax are presented as median with minimum, maximum
Ae cumulative amount of drug excreted unchanged, AUC area under the concentration–time curve, BID twice daily, CL/F apparent oral clearance, CLR renal clearance, Cmax maximum concentration, EQ equivalent, fe fraction of drug excreted unchanged, gCV geometric coefficient of variation, gMean geometric mean, hADME human absorption distribution metabolism and excretion, LI linearity index, MRD multiple-rising-dose, MRTpo oral mean residence time, RA accumulation ratio, SRD single-rising-dose, t1/2 terminal half-life, tmax time to maximum drug concentration, Vz/F apparent volume of distribution
Fig. 2.
Nerandomilast exposure versus dose after single oral doses of 0.06–24 mg; a AUC0–∞ versus dose, b Cmax versus dose in the SRD study. AUC area under the concentration–time curve, Cmax maximum concentration, gMean geometric mean
In the SRD study, nerandomilast exposure (Cmax and AUC0–∞) increased dose proportionally over the dose range of 0.06–24 mg following single-dose administration (Table 2; Fig. 2). The gMean Cmax values ranged from 1.42 nmol/L for the 0.06-mg dose to 542 nmol/L for the 24-mg dose. The gMean AUC0–∞ ranged from 7.44 nmol⋅h/L for the 0.06-mg dose to 3650 nmol⋅h/L for the 24-mg dose. The gMean terminal half-life was between 19.6 h and 29.2 h at doses 2 mg and above (Table 2). The amount of unchanged drug excreted in urine over 24 h ranged from 9.94% to 15.8% of the administered dose (Table 2; Online Resource, Supplementary Fig. S1).
In the MRD study, nerandomilast reached Cmax within approximately 1 h postdosing, and steady state was achieved by day 7 following BID dosing. AUCτ and Cmax values were up to 1.69-fold higher after the multiple administrations compared with a single administration, indicating some accumulation of nerandomilast at steady state (Table 2). Nerandomilast exposure was approximately dose proportional at steady state from 1 mg BID to 6 mg BID (Online Resource, Supplementary Table S1); higher doses were not evaluated in this study.
In the hADME study, the gMean of cumulative fractions (% of dose) excreted in urine and feces, and total recovery of [14C]nerandomilast-EQ after single oral administration are shown in Fig. 3 and summarized in Table 3. The gMean total recovery of [14C]nerandomilast-EQ in urine and feces (no vomiting was reported) was 95.0%, and individual values ranged from 89.9% to 98.0% of the administered dose. The gMean contribution of urinary excretion was 36.4%, whereas 58.0% was excreted in feces. The amount of unchanged drug excreted in urine was 11.9% (Online Resource, Supplementary Table S2).
Fig. 3.
Geometric mean of cumulative fractions (% of dose) excreted in urine and feces, and total recovery of [14C]nerandomilast-EQ, after a single oral administration of 18 mg [14C]nerandomilast in the hADME study. EQ equivalent, hADME human absorption, distribution, metabolism, and excretion
Table 3.
Fractions of [14C]-radioactivity excreted in urine and feces following a single oral dose administration of 18 mg [14C]nerandomilast in the hADME study
| fe0–tz, % | |
|---|---|
| Urine | 36.4 (11.8) |
| Feces | 58 (12.7) |
| Total in urine and feces | 95 (2.99) |
All values displayed are gMean (gCV%)
fe fraction of drug excreted unchanged, hADME human absorption, distribution, metabolism, and excretion
For the hADME study, key pharmacokinetic parameters of [14C]nerandomilast-EQ, nerandomilast, and the major circulating metabolite BI 764333 in plasma are summarized in Table 2 and Supplementary Table S2. Key pharmacokinetic parameters for [14C]nerandomilast-EQ in whole blood are listed in Supplementary Table S3 (Online Resource). Additional pharmacokinetic parameters analyzed for nerandomilast and the major circulating metabolite BI 764333 are shown in Supplementary Table S4 (Online Resource). Assessment of pharmacokinetic parameters for [14C]nerandomilast-EQ and nerandomilast in plasma showed a similar Cmax for both analytes, although the area under the plasma concentration–time curve from time zero to the last measurable concentration at time tz. (AUC0–tz) was 3.7-fold higher for [14C]nerandomilast-EQ compared with unlabeled nerandomilast (Table 2; Online Resource, Supplementary Fig. S2). This difference likely reflects the contribution of circulating metabolites to total plasma radioactivity. The gMean blood concentration–time profiles of [14C]nerandomilast-EQ after a single oral administration were similar to the plasma concentration–time profiles of [14C]nerandomilast-EQ (Online Resource, Supplementary Fig. S2). Concentrations of the major circulating metabolite BI 764333 and the minor metabolite BI 764334 were also measurable in plasma. BI 764333 showed a Cmax of 13.0 nmol/L (gMean; 29.2% geometric coefficient of variation; Table 2) after 4 h, while BI 764334 was only measurable between 12 h and 36 h for most participants (Online Resource, Supplementary Fig. S2). For the major circulating metabolite BI 764333, AUC0–tz and Cmax were substantially lower than those observed for nerandomilast (Table 2; Online Resource, Supplementary Fig. S2).
Safety
The AE profile following single doses of nerandomilast, multiple doses of nerandomilast, and [14C]nerandomilast administration is summarized in Table 4.
Table 4.
Safety summary after a single dose of nerandomilast in the SRD study, after multiple BID dosing in the MRD study, and after single-dose administration of [14C]nerandomilast in the hADME study
| SRD study | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Nerandomilast | Placebo | Total | |||||||||
| 0.02 mg | 0.06 mg | 0.2 mg | 0.6 mg | 2 mg | 4 mg | 8 mg | 16 mg | 24 mg | |||
| Any adverse event | 2 (33.3) | 2 (33.3) | 3 (50.0) | 3 (50.0) | 1 (16.7) | 3 (50.0) | 3 (50.0) | 2 (33.3) | 3 (50.0) | 5 (31.1) | 27 (38.6) |
| Severe adverse events | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Drug-related adverse events | 0 (0) | 2 (33.3) | 1 (16.7) | 0 (0) | 0 (0) | 2 (33.3) | 1 (16.7) | 1 (16.7) | 1 (16.7) | 1 (6.3) | 9 (12.9) |
| Other significant adverse events (according to ICH E3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Adverse events leading to discontinuation | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Significant adverse events (prespecified) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Serious adverse events | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| MRD study | hADME study | ||||
|---|---|---|---|---|---|
| Nerandomilast | Placebo | Total | [14C]nerandomilast | ||
| 1 mg BID | 6 mg BID | 18 mg | |||
| Any adverse event | 4 (44.4) | 1 (11.1) | 1 (16.7) | 6 (25.0) | 4 (66.7)a |
| Severe adverse events | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Drug-related adverse events | 4 (44.4) | 1 (11.1) | 1 (16.7) | 6 (25.0) | 2 (33.3) |
| Other significant adverse events (according to ICH E3) | 0 (0) | 1 (11.1) | 0 (0) | 1 (4.2) | 0 (0) |
| Adverse events leading to discontinuation | 0 (0) | 1 (11.1) | 0 (0) | 1 (4.2) | 0 (0) |
| Significant adverse events (prespecified) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0)b |
| Serious adverse events | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
All values are n (%)
hADME human absorption distribution metabolism and excretion, ICH International Council for Harmonisation, MRD multiple-rising-dose, SRD single-rising-dose
aDefined as treatment-emergent adverse events
bDefined as treatment-emergent adverse events of special interest
In the SRD study, 27/54 participants reported AEs with nerandomilast and 5/16 with placebo. Headache was the most common AE, reported by 8/54 participants in the nerandomilast groups and 1/16 in the placebo group (Online Resource, Supplementary Table S5). However, none of those receiving the highest doses of nerandomilast (16 mg and 24 mg) reported headache. Overall, 9/70 participants reported AEs that were considered treatment-related by the investigator (8 receiving nerandomilast and 1 receiving placebo). No serious AEs or other significant AEs were reported. Most events were of mild intensity, and all had resolved by the end of the study.
In the MRD study, 5/18 participants reported AEs with nerandomilast and 1/6 participants with placebo. A total of 4 participants (4/9) reported treatment-emergent AEs in the 1 mg BID treatment group, 1/9 in the 6 mg BID treatment group, and 1/6 in the placebo group. Participants’ most frequently reported AEs were headache (1/18 participants with nerandomilast and 1/6 participants with placebo) and gastrointestinal disorders (3 participants with nerandomilast and none with placebo; Online Resource, Supplementary Table S6). A total of 6/24 participants reported AEs that were considered treatment-related by the investigator (5 receiving nerandomilast and 1 receiving placebo). One participant was reported to have a significant AE, which the investigator assessed as treatment-related (elevated C-reactive protein) and which led to discontinuation of the trial medication. No severe AEs, significant AEs (prespecified events), or serious AEs were reported. All AEs had resolved by the end of the study.
In the hADME study, treatment-emergent AEs were reported for 4/6 participants who received [14C]nerandomilast. Investigator-defined drug-related AEs were reported for 2/6 participants. The most frequently reported treatment-related AE was headache (2/6 participants), with abdominal discomfort, diarrhea, and epistaxis reported in one participant each (Online Resource, Supplementary Table S7). All treatment-emergent AEs were of mild intensity and were reported to be resolved by the end of the trial. No serious AEs, AEs leading to discontinuation of trial drug, protocol-specified AEs of special interest, or other significant AEs were reported.
Discussion
The results of the SRD, MRD, and hADME studies demonstrated that nerandomilast was rapidly absorbed, showed a multiphasic decline in plasma concentration, had a dose-proportional increase in exposure, was excreted via both urine and feces, and had acceptable tolerability in healthy participants.
Results obtained in this study were similar to previously published pharmacokinetic data. In healthy male participants, a dose-proportional increase in AUC of nerandomilast in plasma was observed for the dose ranges from 36-mg to 48-mg single doses and from 6 mg to 12 mg twice-daily. A steady state was reached by day 6 [31].
Two antifibrotic drugs routinely used in IPF are nintedanib and pirfenidone [5–10]. Pirfenidone reaches peak plasma concentration approximately 4 h after oral administration with food, and exhibits a half-life of about 2.4 h [36]. After oral administration, nintedanib reaches peak plasma concentrations within 2–4 h and exhibits a half-life of approximately 10–15 h [37]. Similarly, nerandomilast reached peak plasma concentration between 0.5 h and 1.25 h postdose administration and exhibited a half-life of 20.5 h.
The most common AEs (headache and gastrointestinal disorders) are known for pan-PDE4 inhibitors, and no new or unexpected AEs were observed [17]. Overall, the safety profile of nerandomilast was acceptable across all three studies and nerandomilast was well tolerated in healthy participants, although these were small sample sizes with a short study duration.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
The authors acknowledge the investigators and clinical trial leads for their contributions to the design, execution, and analysis of the three trials included in this study. Shivani Singh, PhD of Nucleus Global, provided writing, editorial support and formatting assistance, which was contracted and funded by Boehringer Ingelheim. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
Funding
This trial was supported and funded by Boehringer Ingelheim International GmbH & Co. KG, Biberach an der Riss, Germany. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment related to the development of the manuscript.
Declarations
Conflict of interest
Yichao Yu, Dilara Jappar, Jing Wu, Ashish Sharma, and Donald Zoz are employees of Boehringer Ingelheim Pharmaceuticals, Inc. Ute Burkard is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. Carl Coeck is an employee of Boehringer Ingelheim SComm.
Availability of Data and Material
To ensure independent interpretation of clinical trial results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to clinical study data pertinent to the development of the publication. In adherence with the Boehringer Ingelheim policy on transparency and publication of clinical study data, scientific and medical researchers can request access to clinical study data, typically, 1 year after the approval has been granted by major regulatory authorities or after termination of the development programme. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.
Ethics Approval
The trials were carried out in accordance with the principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation—Good Clinical Practice guidelines, and in accordance with applicable regulatory requirements and Boehringer Ingelheim standard operating procedures. All subjects were informed about the trial, both verbally and in writing, by the investigator. All participants provided signed and dated informed consent forms according to the local regulatory and legal requirements. For SRD study, the Institutional Review Board (IRB) was the Ethikkommission bei der Landesärztekammer Rheinland-Pfalz, located at Deutschhausplatz 3, 55116 Mainz, Germany, with approval granted on 24 April 2012; for MRD study, the IRB was the Ethik-Kommission bei der Landesärztekammer Baden-Württemberg, Jahnstraße 40, 70597 Stuttgart, Germany, with approval on 12 March 2013; and for ADME study, the IRB was the Medisch Ethische Toetsings Commissie van de Stichting Beoordeling Ethiek Bio-Medisch Onderzoek, Dr. Nassaulaan 10, 9401 HK Assen, The Netherlands, with approval on 11 March 2021.
Consent to Participate
All subjects were informed about the trial, both verbally and in writing, by the investigator. All participants provided signed and dated informed consent forms according to the local regulatory and legal requirements.
Consent for Publication
Not applicable.
Code Availability
Not applicable.
Author Contributions
YY and DZ designed the research, UB performed the research, JW and UB analyzed the data, and all authors wrote the manuscript.
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