Iclepertin, a selective GlyT1 inhibitor undergoes metabolism mainly via hepatic CYP3A4, with only a small fraction undergoing urinary excretion. Patients with kidney or liver problems can have reduced CYP3A4 levels or activity, which may affect the levels of iclepertin in the blood and, in turn, its safety. Here, we present the results of two studies investigating the safety and pharmacokinetics of iclepertin in participants with various degrees of renal or hepatic impairment. In these two phase I, open-label, non-randomised, parallel studies, a single oral dose of iclepertin 10 mg was administered to participants with mild, moderate or severe renal impairment or mild or moderate hepatic impairment, together with healthy matched participants (based on age, sex, weight and race [only for renal impairment]; n = 8 for each impairment group. Primary and secondary endpoints included maximum plasma concentration (Cmax) and exposure metrics (area under the concentration-time curve [AUC]) of iclepertin. Safety was also assessed (adverse events [AEs]). In the renal impairment study (N = 36), exposure of iclepertin was minimally affected by renal impairment across trial groups except for the severe renal impairment group, which showed increased iclepertin exposure (AUC0–tz and AUC0–∞ geometric mean ratio impaired versus matched participants [90

BACKGROUND:BI 764198 could reduce podocyte injury in focal segmental glomerulosclerosis (FSGS). RESEARCH DESIGN AND METHODS:Four Phase 1 BI 764198 trials: single rising dose (SRD) and multiple rising dose (MRD)/drug-drug interaction trials in healthy volunteers; relative bioavailability (rBA) study (food and formulations effects on pharmacokinetics; PK); and kidney impairment (KI) PK study. RESULTS:SRD trial: 4/54 BI 764198-treated participants (7.4%) had ≥ 1 investigator-defined drug-related adverse event (DRAE): headache (n = 3; 5.6%); diarrhea (n = 1; 16.7%). BI 764198 PK was approximately linear. MRD trial: DRAEs occurred in 5/32 (15.6%) participants receiving BI 764198 and 1/8 (12.5%) receiving placebo. Once-daily BI 764198 80 mg (10 days) did not alter midazolam PK. All BI 764198 formulations tested had similar rBA; food did not affect PK. KI study: geometric mean ratios for area under the plasma concentration-time curve were 147.8% and 177.7% for participants with moderate and severe KI, respectively (vs. without). Limitations include typically small Phase 1 sample sizes and open-label design for the rBA and KI trials. CONCLUSIONS:BI 764198 was well tolerated and could be taken with/without food; evaluation in FSGS is ongoing. CLINICAL TRIAL REGISTRATION:The trials are registered at www.clinicaltrials.gov with codes NCT03854552; NCT04102462; NCT04656288; NCT04176536.

[This corrects the article DOI: 10.1371/journal.pone.0314030.].

BACKGROUND:Fabry disease (FD) is an X-linked lysosomal disorder leading to multiorgan dysfunction, including renal impairment and the risk of significant accumulation for renally excreted drugs. Migalastat, an approved therapy in FD patients with amenable variants, is primarily eliminated in urine; however, its use had not been studied in patients with end-stage renal disease (ESRD) receiving dialysis therapy. This study investigated the pharmacokinetics (PK), dialyzability, and tolerability of 123 mg migalastat in non-FD subjects with ESRD on stable hemodialysis/hemodiafiltration (EudraCT 2018-003684-57). Results were analyzed by population PK and physiologically based PK (PBPK) modeling and intended to propose dose regimens resulting in negligible migalastat trough levels in plasma and comparable concentrations above the threshold in target tissues in FD patients with ESRD. METHODS:Subjects with ESRD received 123 mg migalastat 24 hours before dialysis and, following an 8-day washout, immediately before dialysis. Matched controls with normal renal function (NRF) received migalastat 123 mg. Migalastat concentrations were measured in plasma, urine, and dialysate, and modeled to select regimens providing similar disposition to NRF. RESULTS:Migalastat was extracted by hemodialysis/hemodiafiltration (74%/72%). PBPK modeling predicted that 123 mg every other week (QOW) with regular dialysis 2-3 times weekly in ESRD subjects produced: a fraction of time above EC50 similar to FD patients with NRF; adequate Cmax for intracellular trafficking of mutant α-galactosidase A to the lysosome; and Ctrough levels near the lower limit of quantification (LLOQ) similar to NRF subjects receiving 123 mg every other day. Migalastat 82 mg weekly produced a greater fraction of time above EC50 and longer duration of concentrations above the LLOQ, potentially resulting in accumulation in tissues. CONCLUSION:Migalastat was well extracted by hemodialysis/hemodiafiltration. Migalastat 123 mg QOW is the proposed dose regimen for further evaluation in FD patients with ESRD, which could inform expansion of treatment options. TRIAL REGISTRATION:Trial registration: EU Clinical Trials Register, EudraCT number 2018-003684-57.

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100 mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration-time curve from time 0 to infinity (AUC0- inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA-acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment.

Asundexian is a reversible and selective inhibitor of activated factor XI. It is currently under investigation for the prevention of secondary stroke in at-risk patients; these patients are often characterised by advanced age, impaired organ function and comorbidities. This article summarises results from three Phase I studies that investigated the effects of age and sex (study 1), chronic kidney disease including end-stage kidney disease (ESKD) on dialysis and dialysis-free days (study 2) and Child–Pugh A and B liver disease (study 3) on the safety, pharmacokinetics and pharmacodynamics of a single oral dose of asundexian 25 mg. Study 1 was a multicentre, randomised, single-blind, placebo-controlled group-stratification design; study 2 was a single-centre, non-randomised, non-placebo-controlled, non-blinded group-stratification design; and study 3 had a non-randomised, non-blinded, non–placebo-controlled group-stratification design. Single doses of asundexian 25 mg were generally well tolerated in all three studies, with no asundexian-related bleeding events or treatment-emergent adverse events of special interest. Point estimates (geometric least squares [LS] means) (90

JNJ-73763989 is comprised of 2 short interfering RNAs (siRNAs), JNJ-73763976 and JNJ-73763924, that target hepatitis B virus (HBV) mRNAs for degradation, thereby inhibiting HBV replication. JNJ-56136379 is a capsid assembly modulator that inhibits HBV replication by inducing the formation of empty capsids (CAM-E). In 2 phase 1, open-label, non-randomized, single-center studies, the single-dose pharmacokinetics, safety, and tolerability of JNJ-73763989 or JNJ-56136379 were assessed in participants with moderate hepatic impairment (Child-Pugh Class B) versus participants with normal liver function. Participants in both studies received a single subcutaneous dose of JNJ-73763989 200 mg or oral JNJ-56136379 250 mg, followed by an evaluation of plasma pharmacokinetic parameters and safety assessments. Plasma exposure to JNJ-73763976, JNJ-73763924, and JNJ-56136379 was 1.3- to 1.4-, 1.8- to 2.2-, and 1.1- to 1.3-fold higher in participants with moderate hepatic impairment versus participants with normal liver function; however, these increases were not considered clinically relevant. Both drugs were well tolerated and safe, with 7 (21.9%) participants experiencing 1 or more treatment-emergent adverse events, 3 of which were related to JNJ-56136379. Overall, the plasma exposures of JNJ-73763989 and JNJ-56136379 were higher in participants with moderate hepatic impairment, but both were well tolerated. Further studies are needed to evaluate the effect of hepatic impairment under multiple-dose administration.

Background Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. Main body This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. Conclusion With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.

Abstract Selatogrel is a potent and selective reversible P2Y12 receptor antagonist in development for early treatment of acute myocardial infarction via subcutaneous (s.c.) self‐injection. Selatogrel is almost exclusively eliminated via the hepatobiliary route. Hepatic impairment is associated with reduced drug clearance and primary hemostasis. This single‐center, open‐label study investigated the effect of mild and moderate hepatic impairment on pharmacokinetics (PK) and pharmacodynamics (PD) of a single s.c. dose of selatogrel (16 mg). The study included groups of eight subjects with mild and moderate hepatic impairment, and matched healthy control subjects. Compared to healthy subjects, exposure to selatogrel in subjects with mild and moderate hepatic impairment was 30% and 108% (maximum plasma concentration [Cmax]) and 47% and 212% (area under the concentration‐time curve from zero to infinity [AUC0–∞]) higher, respectively. Hepatic impairment was associated with lower clearance and volume of distribution, whereas plasma protein binding was not affected. Marked inhibition of platelet aggregation (IPA > 80%) was attained within 30 min in all subjects and hepatic impairment prolonged IPA duration. Area under the effect curve was 60% and 160% higher in subjects with mild and moderate hepatic impairment, respectively. PK/PD modeling identified a change in the relationship between exposure and IPA, with a steeper concentration‐effect relationship in healthy subjects compared to subjects with hepatic impairment. The combination of higher exposure and lower half‐maximum inhibitory concentration resulted in longer lasting effect. In conclusion, hepatic impairment alters the PK/PD relationship leading to prolonged effects. Therefore, dose adjustments may be warranted in subjects with moderate hepatic impairment.

The effect of moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of the dual endothelin receptor antagonist aprocitentan was clinically investigated as 25% of aprocitentan is cleared through the liver. Aprocitentan is in clinical development for the treatment of resistant hypertension. This was an open-label, Phase 1 study. Subjects were recruited in two groups (i.e., moderate hepatic impairment (Child–Pugh B; n = 8) and matched healthy subjects (n = 9) and received a single oral dose of 25 mg aprocitentan. Thereafter, they were observed for 14 days. Due to personal reasons one healthy subject discontinued the study. The PK of aprocitentan were similar between subjects with moderate hepatic impairment and healthy subjects, with maximum plasma concentrations (C max ) reached at 4.0 h. There was no difference in C max , indicated by the geometric means ratio (90% confidence interval) of 1.03 (0.86–1.24). There was a lower apparent clearance, a similar apparent volume of distribution, a longer terminal half-life (56.4 h vs 48.3 h in healthy subjects), and an increase in area under the curve from zero to infinity of 23% in moderate hepatically impaired subjects compared to healthy subjects. There were no differences observed in plasma protein binding (range 98.7–99.0%). Aprocitentan was well tolerated, and headache was the only adverse event reported by one subject. In conclusion, there were no clinically relevant differences in PK between subjects with moderate hepatic impairment and healthy subjects. Based on these results, aprocitentan can be administered in subjects with mild and moderate hepatic impairment and dose adjustment is not required. Clinical Trial Registration ClinicalTrials.gov NCT04252495.

Lucerastat is an orally available glucosylceramide synthase inhibitor with a potential to provide substrate reduction therapy for Fabry patients independent of their α-galactosidase A genotype. In humans, lucerastat is mainly eliminated as unchanged parent compound through renal excretion both by active secretion and passive filtration. In vitro studies indicated that lucerastat is a substrate of human organic cation transporter 2 (OCT2) mainly expressed in the kidney. Therefore, this clinical study, conducted in 14 healthy male subjects, investigated the effect of 800 mg twice-daily oral administration of the OCT2 inhibitor cimetidine at steady state on the single-dose pharmacokinetics (PK) of 500 mg lucerastat. The safety and tolerability of lucerastat administered alone and concomitantly with cimetidine were also evaluated. Exposure to lucerastat was slightly higher upon co-administration of cimetidine indicated by geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0–∞) ratio of 1.22 (90% confidence interval [CI] 1.16–1.28). Cimetidine delayed the time to reach maximum lucerastat concentrations (tmax) by 1 h but did not affect its elimination half-life (t½) or maximum plasma concentration (Cmax) as geometric mean ratios were 1.00 (0.91–1.10) and 1.04 (0.92–1.17), respectively, at cimetidine steady state. Lucerastat was safe and well tolerated when given alone and in combination with cimetidine. These results indicate that the single-dose PK of lucerastat are not changed to a clinically relevant extent by cimetidine-mediated OCT2 inhibition, allowing the concomitant use of OCT2 inhibitors with lucerastat without any need for dose adjustment. EudraCT: 2017-003725-14; ClinicalTrials.gov: NCT03380455

Finerenone (BAY 94-8862) is a selective, nonsteroidal mineralocorticoid receptor antagonist. The aim of this study was to assess the effect of mild or moderate hepatic impairment on the pharmacokinetics, safety and tolerability of finerenone. The study was conducted in a single-center, nonrandomized, noncontrolled, nonblinded observational design with group stratification. A single oral 5-mg dose of finerenone was administered as a tablet to participants with mild or moderate hepatic impairment (Child–Pugh A, score 5–6 [n = 9], or Child–Pugh B, score 7–9 [n = 9], respectively) and to age-, weight- and sex-matched healthy participants (n = 9). The pharmacokinetics of finerenone and its metabolites were assessed in plasma and urine, and safety and tolerability were monitored. Finerenone area under the plasma concentration–time curve (AUC) and unbound AUC were 38% and 55% greater, respectively, in participants with moderate hepatic impairment than in healthy participants, whereas maximum plasma concentration (Cmax) was unchanged. No clear effects on AUC or Cmax were seen in participants with mild hepatic impairment. Finerenone was safe and well tolerated in all participants. The effects of mild or moderate hepatic impairment on systemic exposure of finerenone are small, consistent with its low hepatic extraction and preponderance of gastrointestinal over hepatic first-pass clearance. Considering the small increases in AUC and the absence of changes in Cmax, a dose adaptation does not appear to be warranted in patients with mild or moderate hepatic impairment.

AimsThe study objective was to evaluate the pharmacokinetics of the selective progesterone receptor modulator vilaprisan in participants with hepatic impairment. Additionally, the safety and tolerability of vilaprisan were investigated.MethodsIn this phase 1, open‐label, nonrandomised, parallel‐group, pharmacokinetic study, men and women with mild or moderate hepatic impairment (Child–Pugh grade A or B) and control participants with normal hepatic function matched by age, weight and sex received a single oral 2 mg dose of vilaprisan. Key pharmacokinetic parameters, relationships between parameters and safety outcomes were measured.ResultsThirty‐six participants completed the study: 9 with mild hepatic impairment, 9 with moderate hepatic impairment and 18 matched control participants with normal hepatic function. Vilaprisan reached maximum plasma concentrations after 1–2 hours. Unbound vilaprisan exposure was 1.44‐fold higher for participants with mild hepatic impairment vs controls (90% confidence interval: 0.91–2.26), and 1.74‐fold higher for participants with moderate impairment vs controls (90% confidence interval: 1.09–2.78). The maximum observed unbound peak concentrations were similar for participants with hepatic impairment and matched controls. Vilaprisan 2 mg was well tolerated and the incidence of treatment‐emergent adverse events was similar across cohorts.ConclusionOnly mild increases of <1.75‐fold in exposure were observed in participants with mild or moderate hepatic impairment compared with control participants. No safety concern was identified. These data, alongside the excellent safety profile observed in phase 1 and 2 studies, do not indicate that a dose adjustment would be required in patients with mild or moderate hepatic impairment.

Background: According to FDA and EMA guidance for hepatic impairment studies, Child-Pugh classification should be used. In oncology, criteria from the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) are also used to classify hepatic dysfunction. Within a renal and hepatic impairment study on darolutamide, both criteria were used to classify hepatic impairment.

This open-label, nonrandomized, single-dose, phase 1 study evaluated the pharmacokinetics and safety of murepavadin, a novel peptide antibiotic for the treatment of serious Pseudomonas aeruginosa infections. The study was conducted in 32 subjects of either sex in 4 groups (up to 8 per group) with mild (group 1), moderate (group 2), and severe (group 3) renal function impairment or with normal renal function (group 4). The degree of renal impairment of the subjects was classified at screening according to the estimated creatinine clearance (CLCr) according to the Cockcroft-Gault equation. All subjects received a single 2.2-mg/kg of body weight intravenous infusion of murepavadin administered over 3 h. Exposure to murepavadin in plasma increased in subjects with renal function impairment, with the area under the plasma concentration-time curve from zero to infinity (AUC0-∞) increasing about 2.0- to 2.5-fold for subjects with renal function impairment compared to subjects with normal renal function, whereas the increases in maximum observed plasma concentration (Cmax) were about 1.5-fold for subjects with renal function impairment compared to subjects with normal renal function. The total clearance (CL) of murepavadin was lower in all groups of subjects with renal function impairment, with group means ranging from 2.4 liters/h to 3.8 liters/h, compared to 7.0 liters/h in subjects with normal renal function. Accordingly, the terminal elimination half-life (t1/2) prolonged up to 24 h with decreasing renal function compared to 7.7 h in subjects with normal renal function. Murepavadin was well tolerated in all renal function groups. As the elimination of murepavadin is affected by renal function, a dose adjustment is warranted in subjects with impaired renal function. (This paper has been registered at ClinicalTrials.gov under identifier NCT02110459.).

Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib.

AIMS:Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8.METHODS:The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects.RESULTS:Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (Cmax ) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the Cmax of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0-∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its Cmax 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0-∞ by half (90% CI 0.45, 0.59).CONCLUSION:Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged.

AIMS:Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment.METHODS:This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate ≥ 90 ml min-1  1.73m-2 ), moderate (30-59 ml min-1  1.73m-2 ) and severe (<30 ml min-1  1.73m-2 ) impairment. Oral letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses.RESULTS:All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCτ,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCτ,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R2  = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2  = 0.0662, P = 0.2249 and R2  = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2  = 0.3548, P = 0.0021 and R2  = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose letermovir 120 mg was well tolerated across groups.CONCLUSIONS:Renal impairment increased exposure to letermovir, although age was a confounding factor.