Effect of Hepatic Impairment on Trilaciclib Pharmacokinetics.

Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in adult patients with extensive-stage small cell lung cancer receiving a platinum/etoposide-containing or topotecan-containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open-label, parallel-group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child-Pugh B, n = 8) and severe (Child-Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m2. The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration-time curve) in participants with moderate and severe HI was ∼40% and ∼60% higher, respectively, compared with healthy matched controls based on Child-Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration-approved trilaciclib dose of 240 mg/m2 should be reduced by ∼30%, to 170 mg/m2, for patients with moderate or severe HI.

Venetoclax pharmacokinetics in participants with end-stage renal disease undergoing haemodialysis.

AIMS: Renal insufficiency is a common comorbidity in patients with haematological malignancies. This study aimed to assess how end-stage renal disease (ESRD) might affect the pharmacokinetics of venetoclax, a Bcl-2 inhibitor, in participants with ESRD undergoing haemodialysis. METHODS: Venetoclax was administered as a single 100-mg dose to 6 female participants with ESRD (estimated glomerular filtration rate <15 mL/min) both prior to haemodialysis and between haemodialysis days and 7 healthy female participants with normal renal function (estimated glomerular filtration rate >90 mL/min). Intensive pharmacokinetic and protein binding samples were collected from all participants. Arterial and venous samples were collected from ESRD participants during haemodialysis to assess the effect of haemodialysis on venetoclax pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. RESULTS: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that haemodialysis did not affect the pharmacokinetics of venetoclax. The fraction unbound (fu ) of venetoclax was ~2-fold higher for participants with ESRD compared to participants with normal renal function. The unbound maximum plasma concentration and area under the plasma concentration-time curve from time 0 to 48 h were comparable between ESRD and normal function groups. The mean half-life ranged from 10.4 to 12.2 h across groups, demonstrating that ESRD did not affect the half-life of venetoclax. No new safety signals were observed during this study. CONCLUSION: ESRD and dialysis do not alter unbound venetoclax plasma concentrations. No pharmacokinetics driven dose adjustment is needed for patients with renal insufficiency.

Safety, Pharmacokinetics, and Exposure-Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease.

Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30 mL/min/1.73 m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10 participants with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2 ; Group 3) received a single dose of subcutaneous nedosiran sodium 170 mg. Group 1a received nedosiran 8 hours before beginning hemodialysis, Group 1b received nedosiran 2 hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.

A phase I, open-label, single-dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib.

Futibatinib is a covalently binding FGFR1-4 inhibitor that received US Food and Drug Administration approval for the treatment of patients with previously treated, advanced intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements. This phase I trial evaluated the pharmacokinetics (PKs), safety, and tolerability of futibatinib in subjects with impaired hepatic function and matched healthy volunteers. Twenty-two subjects with hepatic impairment (8 mild [Child-Pugh 5-6], 8 moderate [7-9], and 6 severe [10-15]) and 16 matched healthy control subjects received a single oral dose of futibatinib 20 mg. Futibatinib PKs were compared between subjects with mild/moderate/severe hepatic impairment and each corresponding control cohort and the overall control cohort. Relationships between futibatinib PKs and Child-Pugh scores and liver function tests were examined via scatter/regression plots. Compared with matched controls, the area under the plasma concentration-time curve from time zero to infinity increased by 21%/20%/18% and the maximum plasma concentration (Cmax ) increased by 43%/15%/10% in subjects with mild/moderate/severe hepatic impairment, respectively. Changes were not considered clinically relevant: geometric mean ratios were within 80%-125%, except for Cmax in subjects with mild hepatic impairment (143%). No obvious trends were observed among futibatinib PK parameters versus Child-Pugh scores, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase (all p > 0.05). Futibatinib was well-tolerated, with only four grade 1 treatment-emergent adverse events (mild hepatic impairment = 2 and control = 2). The results demonstrate that futibatinib dose adjustments due to mild/moderate/severe hepatic impairment are not necessary in patients receiving futibatinib 20 mg daily.

Pharmacokinetics and Safety of Multiple-Dose Alpelisib in Participants with Moderate or Severe Hepatic Impairment: A Phase 1, Open-Label, Parallel Group Study.

The pharmacokinetics (PK) and safety of single-dose alpelisib (300 mg) were assessed in participants with moderate to severe hepatic impairment (n = 6 each) compared with their matching healthy controls (n = 11). Blood samples were collected upto 144 hours post-dose and evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary PK parameters (maximum plasma concentration [Cmax], area under the curve [AUC]inf and AUClast) and secondary PK parameters (AUC0-t, apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [Tmax], and half-life [T1/2]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non­compartmental analysis. Cmax of alpelisib decreased by approximately 17% in the moderate hepatic impairment group vs. the healthy control group (geometric mean ratio; GMR [90% confidence interval; CI], 0.833 [0.530, 1.31]). Cmax in the severe hepatic impairment group was comparable to that of the healthy control group (GMR [90% CI], 1.00 [0.636, 1.58]). AUClast for alpelisib decreased by approximately 27% in the moderate hepatic impairment group vs. the healthy control group (GMR [90% CI], 0.726 [0.487, 1.08]). AUClast was 26% higher in the severe hepatic impairment group compared with the healthy control group (GMR [90% CI], 1.26 [0.845, 1.87]). Overall, 3 participants (13.0%) experienced at least 1 adverse event which were either grade 1 or 2. Adverse events did not lead to study drug discontinuation. No grade 3 or 4 adverse events, serious adverse events or deaths were reported. The results indicate that a single dose of alpelisib was well tolerated in this study population. There was no significant impact of moderate or severe hepatic impairment on the exposure of alpelisib.

Brigatinib pharmacokinetics in patients with chronic hepatic impairment.

Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. This open-label, parallel-group study investigated the effect of chronic hepatic impairment on the pharmacokinetics (PK) of brigatinib to inform dosing recommendations for these patients. Participants with hepatic impairment classified according to Child-Pugh categories of mild (A), moderate (B), or severe (C) and matched-healthy participants with normal hepatic function received a single oral dose of 90-mg brigatinib. Plasma samples were collected for the determination of brigatinib plasma protein binding and estimation of plasma PK parameters. Twenty-seven participants were enrolled (Child-Pugh A-C, n = 6 each; matched-healthy participants, n = 9). The mean fraction of free plasma brigatinib was comparable for the Child-Pugh A (11.1%), Child-Pugh B (10.8%), and healthy participant groups (8.5%); free brigatinib was higher in the Child-Pugh C group (23.1%). There were no clinically meaningful effects of mild or moderate hepatic impairment on unbound systemic exposures (area under the plasma concentration-time curve [AUC]) of brigatinib (geometric least-squares mean ratios [90% CI] of 89.32% [69.79%-114.31%] and 99.55% [77.78%-127.41%], respectively). In the severe hepatic impairment group, brigatinib unbound AUC was approximately 37% higher (geometric least-squares mean ratio [90% CI] of 137.41% [107.37%-175.86%]) compared with healthy participants with normal hepatic function. Brigatinib was well tolerated in healthy participants and in participants with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. The brigatinib dose should be reduced by approximately 40% for patients with severe hepatic impairment.

Safety and Pharmacokinetics of Taniborbactam (VNRX-5133) with Cefepime in Subjects with Various Degrees of Renal Impairment.

Taniborbactam, an investigational ß-lactamase inhibitor that is active against both serine- and metallo-ß-lactamases, is being developed in combination with cefepime to treat serious infections caused by multidrug-resistant Gram-negative bacteria. Anticipating the use of cefepime-taniborbactam in patients with impaired renal function, an open-label, single-dose clinical study was performed to examine the pharmacokinetics of both drugs in subjects with various degrees of renal function. Hemodialysis-dependent subjects were also studied to examine the amounts of cefepime and taniborbactam dialyzed. Single intravenous infusions of 2 g cefepime and 0.5 g taniborbactam coadministered over 2 h were examined, with hemodialysis-dependent subjects receiving doses both on- and off-dialysis. No subjects experienced serious adverse events or discontinued treatment due to adverse events. The majority of adverse events observed were mild in severity, and there were no trends in the safety of cefepime-taniborbactam related to declining renal function or the timing of hemodialysis. Clinically significant and similar decreases in drug clearance with declining renal function were observed for both cefepime and taniborbactam. The respective decreases in geometric mean clearance for subjects with mild, moderate, and severe renal impairment compared to subjects with normal renal function were 18%, 63%, and 78% for cefepime and 15%, 63%, and 81% for taniborbactam, respectively. Decreases in clearance were similar for both drugs and were shown to be proportional to decreases in renal function. Both cefepime and taniborbactam were dialyzable, with similar amounts removed during 4 h of hemodialysis. This study is registered at ClinicalTrials.gov as NCT03690362.

Effects of Renal Impairment on the Pharmacokinetics of Gefapixant, a P2X3 Receptor Antagonist.

Gefapixant, a P2X3 receptor antagonist, has demonstrated efficacy in patients with refractory or unexplained chronic cough. We investigated the effect of renal impairment (RI) on the pharmacokinetics (PK) of gefapixant 50 mg in an open-label, single-dose study enrolling participants with moderate (n = 6) or severe (n = 6) RI, end-stage renal disease (ESRD; n = 6) under hemodialysis (HD) and non-HD conditions, and healthy matched controls (n = 6). Serial plasma and urine samples for gefapixant concentrations were collected at selected time points over 72 and 48 hours after dosing, respectively. Linear regression analysis predicted a 1.87-, 2.79-, and 3.76-fold higher exposure (area under the plasma concentration-time curve) for participants with mild, moderate, and severe RI, respectively, than that for healthy matched control participants. Categorical analysis exhibited a 2.98-, 4.43-, and 4.74-fold higher exposure for participants with moderate RI, severe RI, and ESRD, respectively, than that for healthy matched control participants. Apparent oral clearance and renal clearance was lower in participants with various degrees of RI, by 66% to 90%, compared with healthy matched control participants, explaining the increased gefapixant exposure with increasing degrees of renal impairment. Gefapixant area under the plasma concentration-time curve and maximum plasma concentration decreased by ≈25% under HD conditions compared to non-HD conditions. Single-dose administration of gefapixant was generally well tolerated in this study. The data from this trial informed the enrollment of phase 3 clinical trials that evaluated the efficacy and safety of gefapixant in >2000 participants with refractory or unexplained chronic cough. Those efficacy and safety data, combined with analysis of population pharmacokinetics from across the entire development program, will be used to evaluate the magnitude of the renal impairment effect in the refractory or unexplained chronic cough population and to determine any dose adjustment recommendations.

Effect of mild or moderate hepatic impairment on the pharmacokinetics of risdiplam.

AIM: This phase I, multicentre, open-label, nonrandomised, parallel-group, two-part study aimed to evaluate the effect of mild to moderate hepatic impairment on the pharmacokinetics (PK), safety and tolerability of a single oral dose of risdiplam. METHODS: Adult subjects (aged 18-70 years) with mild (Child-Pugh Class A; Part 1) or moderate (Child-Pugh Class B; Part 2) hepatic impairment were matched with subjects with normal hepatic function on sex, age, body mass index and smoking status. Each subject received a single oral dose of 5 mg of risdiplam. Plasma concentrations of risdiplam and its metabolite M1 were measured and PK parameters were compared. Adverse events, laboratory abnormalities, vital signs and electrocardiogram measurements were assessed. RESULTS: After a single dose (5 mg) of risdiplam, the risdiplam PK parameters area under the plasma concentration-time curve from time zero to infinity and maximum observed plasma concentration were approximately 20% and 5% lower, respectively, in subjects with mild hepatic impairment and approximately 8% and 20% higher, respectively, in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. These differences were not statistically significant; all 90% confidence intervals for geometric least squares-means ratios spanned unity. No new risdiplam-related safety findings were observed in subjects with mild or moderate hepatic impairment. CONCLUSION: Mild or moderate hepatic impairment did not have a clinically relevant impact on the PK of risdiplam. Therefore, no dose adjustment is required in patients with mild or moderate hepatic impairment when receiving risdiplam.

Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics.

Pexidartinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the colony-stimulating factor 1 receptor. Pexidartinib undergoes extensive hepatic metabolism via multiple cytochrome P450 and uridine 5'-diphospho-glucuronosyl transferase enzymes, with ZAAD-1006a as the only major metabolite in human plasma. As pexidartinib is extensively metabolized, hepatic impairment (HI) could lead to increased exposure to pexidartinib. The objective of the two phase 1, open-label studies was to determine the pharmacokinetics of pexidartinib after a single 200-mg dose in subjects with mild and moderate HI, based on Child-Pugh classification (PL3397-A-U123: 8 mild HI and 8 moderate HI vs 16 matched healthy controls) and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (PL3397-A-U129: 8 moderate HI versus 8 matched healthy controls [NCT04223635]). Based on Child-Pugh classification, exposure to pexidartinib (maximum observed concentration [Cmax ], area under the plasma concentration-time curve up to the last measurable concentration [AUClast ], and extrapolated to infinity [AUCinf ]) was similar in subjects with mild and moderate HI and in respective matched healthy controls, whereas ZAAD-1006a exposure (AUC) was approximately 27% to 28% and 41% to 48% higher in mild and moderate HI, respectively. According to NCI-ODWG criteria, total pexidartinib exposure was 42% to 46% higher in subjects with moderate HI, compared with healthy controls, and total ZAAD-1006a exposure was 70% to 79% higher for subjects with moderate HI, compared with matched healthy controls with normal hepatic function. These findings were used to develop appropriate dose recommendations in patients with hepatic impairment.

Pharmacokinetics and Safety of Intravenous Ferric Pyrophosphate Citrate: Equivalence to Administration via Dialysate.

Ferric pyrophosphate citrate (FPC) is indicated to maintain hemoglobin in patients with stage 5 hemodialysis-dependent chronic kidney disease on chronic hemodialysis by addition to the dialysate. An intravenous (IV) FPC presentation containing 6.75 mg of iron in 4.5 mL was developed. The objective was to establish the equivalence of iron delivery via dialysate and IV infusion using a pharmacokinetic approach. An open-label, randomized, multiple-period, single-dose, crossover study was conducted in 27 patients with CKD-5HD. Each patient received (1) a basal iron profile over 12 hours, (2) FPC 6.75 mg Fe IV predialyzer, (3) FPC 6.75 mg Fe IV postdialyzer, and (4) FPC 2 µM (110 µg Fe/L of hemodialysate). Serum and plasma iron was analyzed for total Fe and transferrin bound iron (TBI). Equivalence was determined by comparing maximum observed concentration and area under the concentration-time curve from time 0 to the last observation of 110 µg Fe/L of hemodialysate (reference) and test treatments Fe predialyzer and postdialyzer iron profiles. The main outcome measure was the measurement of bioequivalence between the reference and test treatments. Bioequivalence parameters showed that infusion of FPC iron IV, predialyzer and postdialyzer delivered equivalent iron as via hemodialysate. The increment in serum total Fe from predialysis to postdialysis was the same as observed in the long-term clinical studies of FPC. FPC IV was well tolerated. IV infusion of 6.75 mg iron as FPC during 3 hours of HD delivers an equivalent amount of iron as when Triferic is delivered via hemodialysate. The IV presentation of FPC extends the ability to provide FPC iron to all patients receiving hemodialysis or hemodiafiltration.

Evaluation of the Pharmacokinetics and Safety of a Single Dose of Acalabrutinib in Subjects With Hepatic Impairment.

Acalabrutinib received approval for the treatment of adult patients with mantle cell lymphoma who received at least 1 prior therapy and adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. This study investigated the impact of hepatic impairment (HI) on acalabrutinib pharmacokinetics (PK) and safety at a single 50-mg dose in fasted subjects. This study was divided into 2 parts: study 1, an open-label, parallel-group study in Child-Pugh class A or B subjects and healthy subjects; and study 2, an open-label, parallel-group study in Child-Pugh class C subjects and healthy subjects. Baseline characteristics and safety profiles were similar across groups. Acalabrutinib exposure (area under the plasma concentration-time curve) increased slightly (1.90- and 1.48-fold) in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment compared with healthy subjects. In severe hepatic impairment (Child-Pugh class C), acalabrutinib exposure (area under the plasma concentration-time curve and maximum plasma concentration) increased ≈5.0- and 3.6-fold, respectively. Results were consistent across total and unbound exposures. Severe hepatic impairment did not impact total/unbound metabolite (ACP-5862) exposures; the metabolite-to-parent ratio decreased to 0.6 to 0.8 (vs 3.1-3.6 in healthy subjects). In summary, single oral dose of 50-mg acalabrutinib was safe and well tolerated in subjects with mild, moderate, and severe hepatic impairment and in healthy control subjects. In subjects with severe hepatic impairment, mean acalabrutinib exposure increased by up to 5-fold and should be avoided. Acalabrutinib does not require dose adjustment in patients with mild or moderate hepatic impairment.

Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study.

AIMS: Capmatinib, a mesenchymal-epithelial transition factor tyrosine kinase inhibitor, is metabolized by cytochrome P450 (CYP) 3A4 and aldehyde oxidase. In individuals with hepatic impairment, alterations in hepatobiliary excretion and metabolism could lead to higher capmatinib exposure. We compared the pharmacokinetics of a single oral dose of capmatinib 200 mg administered to participants with varying degrees of hepatic impairment vs. matched controls with normal hepatic function. METHODS: This phase 1, multicentre, open-label, parallel-group study enrolled adult participants with normal hepatic function and mild, moderate and severe hepatic impairments. Eligible participants received a single oral dose of 200 mg capmatinib. The pharmacokinetic parameters of capmatinib were analysed and compared across participants with impaired and normal hepatic function. RESULTS: Of 31 enrolled participants, 29 had an evaluable pharmacokinetic profile: normal (n = 9); mild (n = 6); moderate (n = 8); severe (n = 6). Compared with the normal group, geometric mean (GM) maximum (peak) observed plasma drug concentration after single-dose administration decreased by 27.6% in the mild group (GM ratio [GMR] = 0.724; 90% confidence interval [CI]: 0.476-1.10), by 17.2% in the moderate group (GMR = 0.828; 90% CI: 0.563-1.22) and remained unchanged in the severe group (GMR = 1.02; 90% CI: 0.669-1.55). Compared with the normal group, GM area under the plasma concentration-time curve from time zero to infinity decreased by 23.3% in the mild group (GMR = 0.767; 90% CI: 0.532-1.11), by 8.6% in the moderate group (GMR = 0.914; 90% CI: 0.652-1.28) and increased by 24% in the severe group (GMR = 1.24; 90% CI: 0.858-1.78). CONCLUSION: Mild, moderate and severe hepatic impairment did not have a clinically relevant impact on capmatinib pharmacokinetics. No new safety findings are reported in this study.

Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired renal function and those requiring hemodialysis.

STUDY OBJECTIVE: Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed. DESIGN: Open-label, Phase-1 pharmacokinetic study. SETTING: Research Study Center. PATIENTS: Twenty-three matched subjects were included, seven with "Normal" renal function (creatinine clearance >90 ml/min), eight with "Severe" renal impairment (glomerular filtration rate <30 ml/min/1.73 m2 ), and eight subjects requiring hemodialysis. MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On dialysis), as well as, on a non-dialysis day (Off dialysis). Plasma, urine, and dialysate fluid were collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during on and off dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment-emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate. CONCLUSION: No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing.

Pharmacokinetics and safety of lefamulin after single intravenous dose administration in subjects with impaired-hepatic function.

STUDY OBJECTIVE: Lefamulin is a novel pleuromutilin recently approved by the FDA for the treatment of community-acquired bacterial pneumonia. Given that, lefamulin is primarily metabolized by CYP450 Phase-1 reactions, this study evaluated the pharmacokinetics of IV lefamulin in subjects with various degrees of hepatic impairment as compared with matched healthy subjects. DESIGN: Open-label, Phase-1 clinical pharmacokinetic study. SETTING: Research Study Center. PATIENTS: Twenty-seven subjects; comprised of 11 individuals with normal hepatic function and eight each with moderate or severe hepatic impairment were included, as classified by Child-Pugh scores. MEASUREMENTS AND MAIN RESULTS: Subjects were administered a single dose of IV lefamulin 150 mg over 1 h. Plasma was collected for 48 h and analyzed for lefamulin and its major metabolite, BC-8041, concentrations in addition to assessing lefamulin plasma protein binding. Pharmacokinetics were evaluated by noncompartmental analysis. Pharmacokinetic parameters were compared using least square geometric mean ratios. Lefamulin was well tolerated in all hepatic function groups. Statistical analyses revealed reductions in Cmax and increases in renal clearance for Moderate and Severe groups, as well as, the increased volume of distribution for the Severe group. Lefamulin plasma AUC mean (SD) was similar across groups at 7615 (1554), 8233 (2286), and 8938 (1640) h.ng/mL for Normal, Moderate, and Severe groups, respectively, despite decreased clearance observed primarily during terminal elimination phases. Decreased plasma-protein binding was seen in hepatically-impaired versus normal subjects. CONCLUSION: Lefamulin was generally well tolerated. Differences in lefamulin and BC-8041 pharmacokinetics were small, relative to the overall variability, and any changes appear to be compensated by increases in renal clearance and decreased protein binding.

NaPi-IIb Inhibition for Hyperphosphatemia in CKD Hemodialysis Patients.

INTRODUCTION: Chronic kidney disease (CKD) has a prevalence of 9.1% globally, and frequently results in elevated serum phosphate, increasing cardiovascular morbidity and mortality risk in hemodialysis (HD) patients. DS-2330b, an oral NaPi-IIb inhibitor, reduced intestinal phosphate absorption in preclinical studies, but its effect in patients with CKD is unknown. This 2-part, randomized, placebo- and active-controlled, single- and repeated-dose, phase 1b study evaluated safety and efficacy of DS-2330b in patients with CKD on HD. METHODS: Part A, a 2-period, 2-way study, evaluated safety and pharmacokinetics of DS-2330b 250 mg in solution and tablet formulations. Part B assessed the safety of DS-2330b in solution (chosen based on results of part A) and its effect on serum phosphate. Patients were randomized to placebo 3 times daily (TID), DS-2330b 400 mg TID, DS-2330b 400 mg with sevelamer 1.6 g TID, and sevelamer 1.6 g with placebo TID for 14 days. Safety endpoints included adverse event (AE) monitoring. RESULTS: Six patients completed part A. Two patients experienced serious AEs considered unrelated to DS-2330b treatment. Thirty-two patients enrolled and completed part B. Serum phosphate mean change from baseline ± SD was -2.2±1.5 mg/dl versus -1.9 ± 1.1 mg/dl for DS-2330b monotherapy versus placebo. Patients receiving DS-2330b with sevelamer or sevelamer with placebo experienced the greatest serum phosphate decrease from baseline. Nine patients (28.1%) experienced ≥1 treatment-emergent AE (TEAE); 7 patients experienced drug-related TEAEs. The TEAE incidence was comparable between DS-2330b and control groups. CONCLUSIONS: DS-2330b, alone or in combination with sevelamer, was safe and well tolerated but did not demonstrate clinically meaningful efficacy in HD patients.

Effect of severe renal impairment on the pharmacokinetics of brigatinib.

Background Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non-small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.

Pharmacokinetics of Gepotidacin in Subjects With Normal Hepatic Function and Hepatic Impairment.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. This phase 1 nonrandomized, open-label, multicenter, 2-part study evaluated the pharmacokinetics, safety, and tolerability of oral gepotidacin 1500 mg in 3 different hepatic settings (normal, moderate impairment, and severe impairment). Gepotidacin was safe and generally tolerated in all subjects. Compared to subjects with normal hepatic function, gepotidacin plasma area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) and maximum concentration significantly increased by 1.7- and 1.9-fold, respectively, in severe hepatic impairment; increases in moderate impairment were not statistically significant. No significant effect was observed for gepotidacin plasma elimination half-life (geometric mean range, 8.2-9.1 hours) across hepatic groups. Renal clearance increased in moderate (16%) and severe (52%) hepatic impairment vs normal. The mean fraction of gepotidacin dose excreted in urine increased with increasing hepatic impairment (normal, 7.5%; moderate, 11.2%; and severe, 19.9%). Urine gepotidacin concentrations remained high for 12 hours in all hepatic groups after dosing. Saliva gepotidacin concentrations displayed a linear relationship with plasma concentrations (R2 = 0.76). The ratio of saliva AUC to unbound plasma AUC and elimination half-life were not affected by hepatic impairment. These data indicate that gepotidacin dose adjustment is not required in mild to moderate hepatic impairment; severe hepatic impairment may require increases in dosing interval or dose reduction.

Glucosuric, renal and haemodynamic effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2, in patients with chronic kidney disease: A randomized trial.

AIM: To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, in patients with chronic kidney disease (CKD). METHODS: This multiple-dose, parallel-group, phase II mechanistic study randomized 53 participants (aged 18-78 years, body mass index ≤ 50 kg/m2 ) with varying degrees of CKD or normal renal function to treatment with licogliflozin (50 mg once daily) or placebo for 7 days. The effects of licogliflozin on 24-h urinary glucose excretion (UGE24 ), renal function, haemodynamics, pharmacokinetics and safety were assessed. RESULTS: Licogliflozin treatment for 7 days significantly (p < .01) increased UGE24 from baseline in participants with normal renal function (adjusted mean change: 41.8 [33.6, 49.9] g) or with mild (32.6 [24.1, 41.0] g), moderate A (35.7 [28.6, 42.9] g) or moderate B (20.3 [13.1, 27.5] g) CKD, but not in severe (6.2 [-0.71, 13.18] g) CKD. Licogliflozin reduced urinary electrolytes (sodium, potassium and chloride), blood pressure and urinary volume to varying extents among different groups. Significant increases in renin (p < .05), angiotensin II (p < .05) and aldosterone (p < .01) levels were observed. Adverse events were generally mild, and most commonly included diarrhoea (94%), flatulence (68%) and abdominal pain (21%). CONCLUSION: Licogliflozin treatment results in significantly increased UGE and favourable changes in urinary electrolytes and haemodynamics in patients with varying degrees of CKD (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 ).

Pharmacokinetics of Voxelotor in Patients With Renal and Hepatic Impairment.

Two open-label studies assessed the safety, tolerability, and pharmacokinetics of Oxbryta (voxelotor) in subjects with hepatic or renal impairment. Eight subjects with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2 ) and 8 healthy age-, sex-, and body mass index-matched controls were administered a single oral dose of voxelotor 900 mg. Seven patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment and healthy age-, sex-, and body mass index-matched controls (7:7:7:7) were administered a single oral dose of voxelotor 1500 mg, except those with severe hepatic impairment (600 mg). There was no apparent effect of renal function on the excretion of voxelotor based on comparable half-life values between subjects with severe renal impairment and healthy matched controls. Mean area under the concentration-time curve from time 0 to infinity (AUC0-inf ) values were lower by approximately 50% (plasma) and 25% (whole blood) in subjects with severe renal impairment compared with controls. Accordingly, dose adjustment is not required in patients with severe renal impairment. Voxelotor plasma and whole-blood exposures were slightly increased in subjects with mild and moderate hepatic impairment. Mean AUC0-inf values were approximately 9% to 18% higher compared with those of healthy matched controls. Dose adjustment is therefore not required in patients with mild or moderate hepatic impairment. Voxelotor mean AUC0-inf values were approximately 90% higher in subjects with severe hepatic impairment. A lower voxelotor dose (1000 mg) is recommended for patients with severe hepatic impairment. Voxelotor was well tolerated in all treatment groups.