Pharmacokinetics of JNJ-73763989 and JNJ-56136379 (Bersacapavir) in Participants With Moderate Hepatic Impairment.

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.

Single-dose pharmacokinetics, safety, and tolerability of the dual endothelin receptor antagonist aprocitentan 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 (Cmax) reached at 4.0 h. There was no difference in Cmax, 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.

New strategies to improve clinical outcomes for diabetic kidney disease.

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.

Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of the P2Y12 receptor antagonist selatogrel.

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.

Impact of the organic cation transporter 2 inhibitor cimetidine on the single-dose pharmacokinetics of the glucosylceramide synthase inhibitor lucerastat in healthy subjects.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. TRIAL REGISTRATION: EudraCT: 2017-003725-14; ClinicalTrials.gov: NCT03380455.

Effect of hepatic impairment on the pharmacokinetics of vilaprisan: An open-label, single-dose, parallel-group study.

AIMS: The 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. METHODS: In 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. RESULTS: Thirty-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. CONCLUSION: Only 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.

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals with Mild or Moderate Hepatic Impairment.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Pharmacokinetics, Tolerability, and Safety of Murepavadin, a Novel Antipseudomonal Antibiotic, in Subjects with Mild, Moderate, or Severe Renal Function 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.).

Effect of gemfibrozil and rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects.

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.

Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment.

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.

Pharmacokinetics and safety of nifedipine GITS/candesartan fixed-dose combination in subjects with hepatic impairment
.

OBJECTIVE: To investigate the pharmacokinetic (PK) profiles and safety of nifedipine and candesartan after a single oral dose of nifedipine gastrointestinal therapeutic system (GITS) 30 mg/candesartan cilexetil 8 mg (N30/C8 mg) fixed-dose combination (FDC) in adults with mild to moderate hepatic impairment. METHODS: A phase I, single-center, non-randomized, non-controlled, non-blinded, observational study (N = 32). PK profiles for nifedipine and candesartan were assessed in patients with mild (Child-Pugh A; group 1) or moderate (Child-Pugh B; group 2) hepatic impairment and compared with age- and gender-matched healthy controls (groups 3 and 4) following a single dose of N30/C8 FDC. Safety and tolerability were assessed throughout the study. RESULTS: On average, area under the plasma concentration vs. time curves (AUC) for nifedipine increased 93% and 253% in mild and moderate hepatic impairment, while maximum plasma concentrations (Cmax) increased 64% and 171%, respectively. AUC values for candesartan increased 19% and 92%, while Cmax values increased 3% and 11%, respectively. In subjects with or without liver impairment, adverse event rates were similar and consistent with the known side-effect profiles of nifedipine GITS and candesartan as monotherapies. CONCLUSIONS: Careful monitoring, and, if necessary, dose adjustment according to response and tolerability may be required for nifedipine GITS/candesartan FDC in patients with mild and moderate hepatic impairment.
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Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

BACKGROUND AND OBJECTIVE: 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. METHODS: This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30-59 mL/min/1.73 m2 and 15-29 mL/min/1.73 m2, respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (C max) between subjects with renal impairment and healthy matched controls. RESULTS: Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUClast and C max, was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUClast for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3-213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28-39 % for moderate impairment, 34-42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. CONCLUSION: Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals With Renal Impairment.

Finerenone (BAY 94-8862) is a nonsteroidal mineralocorticoid receptor antagonist in development for the treatment of diabetic kidney disease. This observational trial compared the pharmacokinetics of a single oral dose of finerenone 10 mg (immediate-release tablet) in adults with mild (creatinine clearance [CLCR ] 50-80 mL/min; n = 8), moderate (CLCR 30 to < 50 mL/min; n = 8), or severe (CLCR < 30 mL/min; n  =  9) renal impairment with those in adults with normal renal function (CLCR > 80 mL/min; n  = 8) over 96 hours postdose. Exposure to finerenone was not affected by mild renal impairment. In participants with moderate or severe renal impairment, exposure to finerenone was increased compared with those with normal renal function (increase in area under the curve for unbound finerenone, 57.1% [outlier excluded] and 46.5%, respectively), with moderate to high interindividual variability. Renal impairment had no consistent effect on the maximum plasma concentration, Cmax (differences in Cmax for unbound finerenone of +12% and -7% with moderate [outlier excluded] and severe impairment vs normal renal function, respectively). Renal elimination of finerenone is minimal. However, changes in exposure may occur because of the effects of renal impairment on nonrenal routes of elimination.

Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment.

AIM: The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS: Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with mild, moderate and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 µg or 400 µg was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS: Exposure increased with the severity of hepatic impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with mild hepatic impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate hepatic impairment when compared with healthy subjects. The two subjects with severe hepatic impairment showed similar dose-normalized exposure to that of subjects with moderate hepatic impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS: Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment.

Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function.

PURPOSE: In two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled ß2-agonist for treatment of COPD, were investigated. SUBJECTS AND METHODS: The first trial included eight subjects with mild hepatic function impairment (Child-Pugh A), eight subjects with moderate impairment (Child-Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min(-1)) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 µg olodaterol administered with the Respimat Soft Mist inhaler. RESULTS: Olodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0-4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%-125%) and 105% (79%-140%), respectively. Corresponding values for dose-normalized maximum concentration (C max) were 112% (84%-151%) (mild impairment) and 99% (73%-135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0-4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%-195%), and for C max was 137% (84%-222%). There was no significant relationship between creatinine clearance and AUC0-4 or C max. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment. CONCLUSION: Mild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose.

Pharmacokinetics of serelaxin in patients with severe renal impairment or end-stage renal disease requiring hemodialysis: A single-dose, open-label, parallel-group study.

Serelaxin, a recombinant human relaxin-2 hormone, is in clinical development for treating acute heart failure. This open-label, parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-hour intravenous infusion (10 µg/kg) in patients with severe renal impairment (n = 6) or end-stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n = 6] or during dialysis-free interval [n = 6]), compared with matched healthy subjects (n = 18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with mean terminal elimination half-life of 6.5-8.8 hours. Compared with healthy subjects, a moderate decrease in serelaxin systemic clearance (37%-52%) and increase in its exposure (30%-115%) were observed in all patients. During the 4-hour hemodialysis in ESRD patients, 30% serelaxin was removed, with hemodialysis clearance constituting approximately 52% of total systemic clearance. Serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. Antiserelaxin antibodies were not detected in any participant. Given the shallow dose-response relationship observed with serelaxin in clinical studies and its wide therapeutic window, the observed PK differences in patients with severe renal impairment compared with healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients.

Pharmacokinetics of bound and unbound telaprevir in cirrhotic patients with moderate and severe hepatic impairment.

This study aimed to characterize the pharmacokinetic parameters of telaprevir (TVR) in patients with moderate and severe hepatic impairment, measure the unbound (pharmacologically active) plasma concentrations of TVR, and determine if any changes in TVR exposure were of clinical relevance. Ten patients with moderate (Child-Pugh B) hepatic impairment, 10 matched healthy control volunteers, and 4 nonmatched patients with severe (Child-Pugh C) hepatic impairment received 750 mg TVR every 8 hours for 6 days. Venous blood samples were collected at various times throughout the study. Single-dose and steady-state pharmacokinetics of total and unbound TVR were calculated. Safety and tolerability of TVR were also assessed. The mean maximum plasma concentration and area under the curve values of total and unbound TVR were lower in patients with moderate hepatic impairment compared with matched healthy controls following a single dose and at steady state but did not consistently meet statistical significance. This trend was also present when patients with severe hepatic impairment were compared with the nonmatched healthy controls. However, the safety profile of TVR in the patient and healthy volunteer groups was comparable with previously published data. These results indicate that reduced plasma concentrations of total and unbound TVR in patients with hepatic impairment are unlikely to be clinically relevant.

Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects.

AIMS: This study investigated the effect of a fixed dose combination of lopinavir/ritonavir on the pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679. METHODS: This was an open label, randomized, single centre, two way, crossover study. Twenty healthy male subjects were treated with a single dose of 400 µg selexipag alone and in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily. RESULTS: The results showed that lopinavir/ritonavir approximately doubled the exposure to selexipag. The area under the plasma concentration-time curve from time zero to infinity (AUC(0,∞) and the maximum plasma concentration (Cmax) of selexipag were 2.2- and 2.1-fold higher, respectively, than under selexipag alone, with a 90% confidence interval (CI) of the geometric mean ratio (GMR) of 1.9, 2.7 and 1.7, 2.6, respectively. For ACT-333679, the clinically more relevant component of selexipag, systemic exposure was increased by 8% (GMR of AUC(0,∞) 1.1, 90% CI 0.9, 1.3), when lopinavir/ritonavir was co-administered with selexipag. The most frequently reported adverse event (AE) was headache. A single dose of selexipag, administered either alone or together with multiple doses of lopinavir/ritonavir, was safe and well tolerated. CONCLUSIONS: Lopinavir/ritonavir does not affect the PK parameters of selexipag and ACT-333679 to a clinically relevant extent. Therefore, adaptation of the selexipag dose is not required when co-administered with inhibitors of the organic anion-transporting polypeptide (OATP) 1B1/ 1B3, P-glycoprotein (P-gp) and/or CYP3A4.

Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist.

PURPOSE: Setipiprant, a selective oral CRTH2 antagonist, has been investigated for the treatment of allergic rhinitis and asthma. In vitro data showed that setipiprant has a weak induction potential on CYP3A4. An interaction at the hepatic level between setipiprant and CYP3A4 substrates was not expected even at the dosing regimen of 1,000 mg setipiprant b.i.d. due to the high plasma protein binding. However, at this dosing regimen, interactions at the gut level could not be excluded. METHODS: In this single-center, open-label study, 40 mg of simvastatin was administered orally on Day 1, and then concomitantly with setipiprant on Day 10 following 9 days of setipiprant 1,000 mg b.i.d. to 22 healthy male subjects. RESULTS: In the presence of setipiprant, the simvastatin concentration-time profile was similar to that of simvastatin alone. The concentrations of simvastatin were, however, slightly lower, resulting in a 9 % decrease in C max (geometric mean ratio (GMR) 0.91, 90 % confidence interval (CI) (0.73, 1.13)) and in a 16 % lower AUC0-∞ (GMR 0.84, 90 % CI (0.72, 0.99)). Exposure to simvastatin acid was similar when comparing simvastatin with or without setipiprant. The GMR and 90 % CI for AUC0-∞ were within the 0.8 to 1.25 limits, whereas those for C max were outside (GMR 2.73, 90 % CI (2.11, 3.53)). Moreover, the median t max of simvastatin acid occurred earlier (1.8 h) when combined compared to 3.0 h when administered alone. CONCLUSIONS: As setipiprant has little impact on simvastatin pharmacokinetics, it does not modulate CYP3A4 in a clinically relevant manner.

Pharmacokinetics, safety, and tolerability of faldaprevir in patients with renal impairment.

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.).