Pharmacokinetics and Safety of Pemafibrate in Patients with both Dyslipidemia and Severe Renal Impairment: A Phase 4 Study

Abstract

Aims: Per the package insert, pemafibrate was contraindicated for use in patients with severe renal impairment despite its biliary excretion. To validate this, we evaluated the pharmacokinetics and safety of pemafibrate for 12 weeks in patients with hypertriglyceridemia and renal impairment.

Methods: In this phase 4, multicenter, placebo-controlled, double-blind, parallel-group, comparative study, 21 patients were randomly assigned to pemafibrate 0.2 mg/day or placebo within Groups A (estimated glomerular filtration rate [eGFR] ＜30 mL/min/1.73m² without hemodialysis; pemafibrate n=4; placebo, n=2), B (hemodialysis; pemafibrate, n=4; placebo, n=1), and C (eGFR ≥ 30 and ＜60 mL/min/1.73m² without hemodialysis; pemafibrate, n=8; placebo, n=2) for 12 weeks. Area under the concentration vs time curve within the dosing interval (τ) (AUC_τ) of pemafibrate was measured after 12-week administration.

Results: The AUC_τ (geometric mean) of pemafibrate was 7.333 and 7.991 ng·h/mL in Groups A+B and C, respectively; in Groups A+B to C at 12 weeks, the geometric mean ratio of pemafibrate AUC_τ was 0.92 (90% confidence interval [CI]: 0.62, 1.36). The upper limit of the 90% CI was ≤ 2.0 (predetermined criterion). There was no consistent trend in the AUC_τ and maximum plasma concentration of pemafibrate with/without statin use. Renal impairment degree did not affect the incidence of adverse events. No safety concerns were observed.

Conclusion: Pemafibrate repeated administration in patients with severe renal impairment did not increase pemafibrate exposure.

Clinical trial registration: jRCT2031200177

List of abbreviations: ADR, adverse drug reaction, AE, adverse event, AUC_τ, area under the concentration vs time curve within the dosing interval (τ), C, cholesterol, CI, confidence interval, CK, creatine kinase, CKD, chronic kidney disease, CL_ss/F, apparent clearance at steady state, C_max, maximum plasma concentration, C_trough, trough concentration, eGFR, estimated glomerular filtration rate, HDL, high-density lipoprotein, Kel, elimination rate constant, LDL, low-density lipoprotein, MedDRA/J, Medical Dictionary for Regulatory Activities/J, MRT_ss, mean residence time at steady state, PPARα, peroxisome proliferator-activated receptor α, SPPARMα, selective PPARα modulator, TC, total cholesterol, TG, triglyceride, tmax, time to maximum plasma concentration, t_1/2, terminal elimination half-life, Vd_ss/F, apparent volume of distribution at steady state

Introduction

The number of patients with chronic kidney disease (CKD) is increasing worldwide. It is estimated that one in eight people in Japan and one in 10 people worldwide have CKD^{1, 2)}. High triglyceride (TG) and low high-density lipoprotein (HDL)-cholesterol (C) levels associated with qualitative abnormalities of low-density lipoprotein (LDL) and HDL are frequently observed in patients with CKD. In contrast, LDL-C levels are not necessarily elevated^3-5). High TG levels in patients with CKD have been reported as a risk factor for developing atherosclerosis^6-8). High TG levels are attributed to the pro-inflammatory effects of remnant lipoproteins and TG‐rich lipoproteins accumulated in the arterial wall^{9, 10)}.

Lipid management is required for patients with CKD. Fibrates (fenofibrate and bezafibrate), peroxisome proliferator-activated receptor α (PPARα) agonists, exhibit TG-lowering and HDL-C-raising effects and may be useful in lipid management of patients with CKD. Sub-analyses limited to patients with CKD in the large time-to-event trials, such as VA-HIT¹¹⁾ and FIELD¹²⁾, suggest that fibrates may be useful in cardiovascular disease risk control in patients with CKD. However, there are limitations in the use of fibrates in patients with severe renal impairment. For instance, fenofibrate and bezafibrate, widely used for treating hypertriglyceridemia, are excreted primarily by the kidney. With decreased renal function (decreased creatinine clearance), bezafibrate kidney excretion likely decreases, leading to increased plasma concentrations of the drugs^{13, 14)}; thus, bezafibrate is contraindicated in patients with moderate to severe renal impairment (serum creatinine ＞1.5 mg/100 mL)^{15, 16)}. Moreover, the use of fibrates is associated with an increased risk of rhabdomyolysis^{17, 18)}. While the underlying mechanism is unclear, the increased risk is attributed to a destabilization of the myocyte membranes from cholesterol depletion and cellular damage caused by increased intracellular Ca^2＋ levels^{19, 20)}. Notably, cases of rhabdomyolysis with bezafibrates in Japan have been reported frequently when bezafibrate was administered to patients with severe renal impairment²¹⁾, presumably because of reduced drug excretion and increased drug concentration in the plasma, thus increasing the risk of fibrate-induced rhabdomyolysis.

Pemafibrate is a novel selective PPARα modulator (SPPARMα) approved in Japan in 2017 for treating hyperlipidemia. It improves lipid metabolism by binding to the nuclear receptor PPARα and selectively regulating the expression of a group of genes involved in lipid metabolism, mainly in the liver^22-24). It is used primarily in patients with dyslipidemia to lower TG levels. Because it has less effect on the liver and kidneys, SPPARMα is considered safer than fibrates^25-28). Unlike fibrates, pemafibrate is primarily excreted in the bile. It has been shown that plasma concentrations of pemafibrate after a single 0.2 mg dose are not affected by renal function level in patients not receiving a statin without hypertriglyceridemia²⁹⁾. In a long-term study of the safety and efficacy of pemafibrate, including 11 patients with severe renal impairment and patients on dialysis, patients with CKD did not exhibit increased pemafibrate concentration in plasma following repeated 0.2 mg dosing; however, pharmacokinetics was not investigated in detail³⁰⁾. The pharmacokinetic profile of pemafibrate differs from that of fibrates; however, a list of restrictions on its use in patients with severe renal impairment is written on the label of packages marketed in Japan because fenofibrate was used as the control drug in some clinical trials for approval. Detailed information on the pharmacokinetics of pemafibrate during repeated dosing in hypertriglyceridemic patients with severe renal impairment is lacking.

We hypothesized that the systemic exposure of pemafibrate does not increase to the point of concern regarding rhabdomyolysis development in patients with severe renal impairment and that it may be used for treating dyslipidemia in patients with severe renal impairment. Thus, we conducted this post-marketing study to evaluate the pharmacokinetics and safety of pemafibrate for 12 weeks in patients with dyslipidemia who have high TG levels and renal impairment (with and without statin treatment) and to verify that the degree of renal impairment does not have a clinically problematic effect on the pharmacokinetics of pemafibrate.

Methods

Study Design

This study was a phase 4, multicenter, placebo-controlled, randomized, double-blind, parallel-group, comparative study conducted from September 2020 to June 2021 at six sites in Japan. The study was reviewed and approved by the Institutional Review Board at all participating sites and was conducted in compliance with ethical principles based on the Declaration of Helsinki, Good Clinical Practice, and Good Post-marketing Study Practice. The study was registered at the Japan Registry for Clinical Trials under the identifier number jRCT2031200177.

Patients

Patients with high TG levels and renal impairment were enrolled according to the inclusion and exclusion criteria. At enrollment, all patients provided informed consent for participation in this study.

Men or postmenopausal women with dyslipidemia whose age at the time of obtaining consent was ≥ 20 years and with fasting serum TG level ≥ 150 mg/dL in the screening test were included in this study. Patients with estimated glomerular filtration rate (eGFR) ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis were included in Group A, patients undergoing hemodialysis were included in Group B, and those with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis were included in Group C.

The main exclusion criteria were as follows: patients with severe hepatic disorder, liver cirrhosis, biliary obstruction, or gallstones; kidney transplant recipients; with poorly controlled nephrotic syndrome; receiving or previously treated with pemafibrate; with at least one liver function test value (aspartate aminotransferase, alanine aminotransferase) exceeding 2.5 times and creatine kinase (CK) level exceeding 5 times the upper limit of the reference range in the screening test; with history of serious drug allergy (e.g., anaphylactic shock); participating in other clinical trials or studies at the time of obtaining consent; and deemed inappropriate for study participation by the investigator. Detailed inclusion and exclusion criteria are listed in the Supplementary Materials.

Randomization and Blinding

Randomization and double blinding were used to avoid bias in patient selection and evaluation. Patients were randomized to pemafibrate 0.2 mg/day or placebo in a 3:1 ratio within Groups A, B, and C and received the study drug for 12 weeks. An independent allocation manager performed blinding, which was maintained throughout the study period for patients, investigators, and study sponsors. For blinding, the pemafibrate 0.1-mg tablets had an indistinguishable appearance from the placebo tablets.

Procedures and Interventions

The study periods were a maximum screening period of 8 weeks and a follow-up period of 12 weeks. No diet and exercise regimen changes were to be made during the study period. In hemodialysis patients, the interval between hemodialysis sessions was not changed whenever possible. In addition, the timing of hemodialysis and blood collection was kept constant within the same patient whenever possible. Pemafibrate 0.1-mg or placebo tablets (1 tablet twice daily) were administered for 12 weeks.

The following medications were prohibited or restricted during the study period: fibrates, cyclosporine, rifampicin, clopidogrel hydrochloride, clarithromycin, HIV protease inhibitors, fluconazole, anion exchange resins, strong CYP3A4 inducers, CYP2C8 inhibitors, CYP2C9 inhibitors, CYP3A4 inhibitors or inducers (moderate or greater), and OATP1B1 or OATP1B3 inhibitors.

Dyslipidemia drugs not designated as concomitant use-prohibited drugs were designated as concomitant use-restricted drugs, which prohibits the initiation of new dosing, discontinuation, or changes in dosing and dosage while maintaining the same dosage and administration. However, if needed, polyunsaturated fatty acids (ethyl icosapentate and omega-3 fatty acid ethyl ester) could be added to ensure patients’ safety in patients with severely elevated TG levels.

Sample Collection and Measurements

Plasma drug concentrations were measured at Shin Nippon Biomedical Laboratories, Ltd. (Wakayama, Japan), and all other laboratory tests were conducted at LSI Medience Corporation (Tokyo, Japan). Samples were obtained at 0, 4, 8, and 12 weeks, and patients were required to be fasted for at least 10 hours before taking the blood samples. The formulas used for eGFR in women and men were as follows: eGFR=194×serum creatinine^−1.094×age^−0.287 for men and eGFR=194×serum creatinine^−1.094×age^−0.287×0.739 for women³¹⁾.

Study Endpoints

The primary endpoint was the area under the concentration vs time curve within the dosing interval (τ) (AUC_τ) of the unchanged form of pemafibrate after 0.2 mg/day administered repeatedly for 12 weeks. Secondary endpoints were plasma pemafibrate/pemafibrate metabolite concentrations and pharmacokinetic parameters (maximum plasma concentration [C_max], time to maximum plasma concentration [t_max], estimate of the terminal elimination half-life [t_1/2], elimination rate constant [Kel], mean residence time at steady state [MRT_ss], apparent clearance at steady state [CL_ss/F], apparent volume of distribution at steady state [Vd_ss/F], and trough concentration [C_trough]). The metabolites evaluated include K-15823 (hydroxylated 4-methoxyphenyl group of pemafibrate [position 3]), K-15834 (hydroxylated benzoxazole group of pemafibrate [position 6]), K-15828 (desmethylated 4-methoxyphenyl group of pemafibrate), K-15827 (methoxyphenyl-removed form of pemafibrate), K-23467 (N-dealkylated pemafibrate), K-23469 (decarboxylated pemafibrate), and K-23605 (oxidized benzyl position of pemafibrate).

Safety was evaluated based on adverse events (AEs) and adverse drug reactions (ADRs), rhabdomyolysis-related AEs and ADRs, and changes in laboratory parameters (CK, eGFR, and creatinine). Efficacy was evaluated based on the results of lipid parameters (TG, total cholesterol [TC], LDL-C, HDL-C, non-HDL-C, free fatty acids, and remnant-like lipoprotein particle cholesterol).

Statistical Analysis

The target number of patients was eight in Group A (six in the pemafibrate group and two in the placebo group), four in Group B (three in the pemafibrate group and one in the placebo group), and eight in Group C (six in the pemafibrate group and two in the placebo group). Using the variance of AUC_τ (0.075) of pemafibrate observed in a previous study (data on file), in which pemafibrate 0.1 mg was administered twice daily for 7 days repeatedly, the number of patients was calculated to be four in each group with a 90% power when the upper limit of the 90% confidence interval (CI) for the ratio of geometric mean does not exceed 2.0. Considering possible missing data due to lack of measurement during hospitalization, discontinuation, or dropouts, the number of patients in the severe renal impairment group was set to nine for Group A+B.

Regarding the analysis sets, the pharmacokinetic analysis set included patients who received the study drug and for whom plasma drug concentration data were available at the subsequent 12-week hospitalization. The safety analysis set included patients randomly assigned to receive at least one dose of the study drug for the treatment phase. The efficacy analysis set included patients who were randomly assigned to receive at least one dose of the study drug during the treatment phase and had baseline and post-baseline measurements.

Primary endpoints were the ratio of the geometric mean values of AUC_τ of pemafibrate at 12 weeks of treatment in the severe renal impairment group (Group A+B) to the control group (Group C) and its 90% CI. The risk of fibrate-induced rhabdomyolysis was estimated to increase from the point at which plasma concentration was two-fold that of the usual dose established for TG-lowering purposes^{13, 14)}. If the upper limit of 90% CI did not exceed 2.0, it was determined that pemafibrate could be administered to patients with severe renal impairment without increasing the risk of rhabdomyolysis^{14, 21)}. Secondary endpoints were the ratios of the geometric mean values and its 90% CI of C_max, t_max, t_1/2, Kel, MRT_ss, CL_ss/F, Vd_ss/F, and C_trough of pemafibrate at 12 weeks of treatment in the severe renal impairment group (Group A+B) and the control group (Group C). The relationships between eGFR level and AUC_τ and C_max were plotted.

For the safety evaluation, AEs were coded according to the Medical Dictionary for Regulatory Activities/J (MedDRA/J) Version 23.0. The incidences of AEs and ADRs were calculated. For biochemical parameters such as CK, eGFR, and creatinine, basic statistics (mean and standard deviation) at each time point were calculated. For the efficacy evaluation, basic statistics at each time point and the percentage change from baseline values of lipid-related tests were calculated. The significance level was 5%, and all tests were two-sided. The software used for the statistical analysis was 64-bit SAS Ver. 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Patient Disposition and Baseline Characteristics

Fig.1 shows the disposition of the patients. Of the 29 patients who provided informed consent to participate in the study, seven were excluded because of screening failure, and one was excluded due to withdrawal of consent. The remaining 21 patients met the eligibility criteria and were randomly assigned to receive either pemafibrate 0.1-mg tablet or placebo tablet twice daily for 12 weeks. Enrollment was completed under circumstances different from those planned. For instance, enrollment was terminated when four patients were predicted to have reached the 12-week observation point in each group, Groups A+B and C, as this was required to analyze the primary endpoint in the pemafibrate group. In Group A, four patients received pemafibrate, and two received placebo; in Group B, four patients received pemafibrate, and one received placebo; and in Group C, eight patients received pemafibrate, and two received placebo. Five, five, and nine patients in Groups A, B, and C, respectively, completed the study.

Fig.1. Patient disposition

Group A: patients with an estimated glomerular filtration rate (eGFR) ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis.

Group B: patients undergoing hemodialysis.

Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

Table 1 summarizes the baseline characteristics of the safety analysis set. At baseline, patients had a mean age of 64.8 years, 85.7% were men, the mean body mass index was 27.2 kg/m², and the mean TG level was 219.2 mg/dL. In Groups A, B, and C, the mean eGFR was 22.7, 3.8, and 40.3 mL/min/1.73 m², respectively. The following renal-related complications were observed for the total population (safety analysis set) at baseline: chronic kidney disease (n=17), renal anemia (n=5), renal cysts (n=3), diabetic nephropathy (n=2), IgA nephropathy (n=2), nephrotic syndrome (n=1), nephrocalcinosis (n=1), renal mass (n=1), and renal atrophy (n=1). The baseline characteristics of the pharmacokinetics analysis set are shown in Supplementary Table 1.

Table 1.Patient background (safety analysis set)

	Group A			Group B
	Pemafibrate n = 4	Placebo n = 2	All N = 6	Pemafibrate n = 4	Placebo n = 1	All N = 5
Age (years)	67.5 [12.8]	64.5 [13.4]	66.5 [11.7]	58.3 [12.6]	58.0 [-]	58.2 [10.9]
Sex
Men, n (%)	4 (100.0)	1 (50.0)	5 (83.3)	3 (75.0)	0 (0.0)	3 (60.0)
Women, n (%)	0 (0.0)	1 (50.0)	1 (16.7)	1 (25.0)	1 (100.0)	2 (40.0)
Body weight (kg)	78.0 [9.9]	81.2 [30.3]	79.1 [15.6]	70.6 [15.2]	77.5 [-]	72.0 [13.5]
BMI (kg/m2)	28.6 [4.8]	29.8 [5.7]	29.0 [4.5]	25.4 [1.8]	29.8 [-]	26.3 [2.5]
eGFR (mL/min/1.73m2)	25.9 [3.5]	16.1 [12.3]	22.7 [8.0]	3.7 [0.7]	4.1 [-]	3.8 [0.7]
TG (mg/dL)	233.0 [37.4]	254.0 [18.4]	240.0 [32.0]	216.8 [84.8]	168.0 [-]	207.0 [76.6]
Concomitant statin, n (%)	2 (50.0)	2 (100.0)	4 (66.7)	2 (50.0)	0 (0.0)	2 (40.0)
Complications
Diabetes mellitus, n (%)	3 (75.0)	0 (0.0)	3 (50.0)	1 (25.0)	1 (100.0)	2 (40.0)
Hypertension, n (%)	4 (100.0)	2 (100.0)	6 (100.0)	4 (100.0)	1 (100.0)	5 (100.0)

	Group C			Group A+B+C
	Pemafibrate n = 8	Placebo n = 2	All N = 10	Pemafibrate n = 16	Placebo n = 5	All N = 21
Age (years)	66.3 [10.3]	70.5 [10.6]	67.1 [9.9]	64.6 [11.3]	65.6 [10.0]	64.8 [10.8]
Sex
Men, n (%)	8 (100.0)	2 (100.0)	10 (100.0)	15 (93.8)	3 (60.0)	18 (85.7)
Women, n (%)	0 (0.0)	0 (0.0)	0 (0.0)	1 (6.3)	2 (40.0)	3 (14.3)
Body weight (kg)	74.3 [6.4]	60.8 [14.2]	71.6 [9.3]	74.3 [9.6]	72.3 [19.8]	73.8 [12.2]
BMI (kg/m2)	27.0 [2.2]	25.5 [5.7]	26.7 [2.8]	27.0 [3.0]	28.1 [4.6]	27.2 [3.3]
eGFR (mL/min/1.73m2)	42.4 [9.6]	31.9 [1.3]	40.3 [9.6]	28.6 [17.7]	20.0 [13.4]	26.6 [16.9]
TG (mg/dL)	215.3 [52.1]	203.0 [14.1]	212.8 [46.5]	220.1 [55.2]	216.4 [38.9]	219.2 [50.9]
Concomitant statin, n (%)	4 (50.0)	1 (50.0)	5 (50.0)	8 (50.0)	3 (60.0)	11 (52.4)
Complications
Diabetes mellitus, n (%)	5 (62.5)	1 (50.0)	6 (60.0)	9 (56.3)	2 (40.0)	11 (52.4)
Hypertension, n (%)	6 (75.0)	2 (100.0)	8 (80.0)	14 (87.5)	5 (100.0)	19 (90.5)

Data in the table are mean [standard deviation] unless otherwise indicated. Group A: patients with an eGFR ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis. Group B: patients undergoing hemodialysis. Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate, TG, triglyceride

Supplementary Table 1.Patient background characteristics in the pemafibrate groups (pharmacokinetic analysis set)

	Group A n = 4	Group B n = 4	Group C n = 7	Group A+B+C n = 15
Age (years)	67.5 [12.8]	58.3 [12.6]	68.6 [8.5]	65.5 [11.0]
Sex
Men, n (%)	4 (100.0)	3 (75.0)	7 (100.0)	14 (93.3)
Women, n (%)	0 (0.0)	1 (25.0)	0 (0.0)	1 (6.7)
Body weight (kg)	78.0 [9.9]	70.6 [15.2]	74.1 [6.9]	74.2 [9.9]
BMI (kg/m2)	28.6 [4.8]	25.4 [1.8]	26.6 [2.2]	26.8 [3.0]
eGFR (mL/min/1.73m2)	25.9 [3.5]	3.7 [0.7]	42.2 [10.3]	27.6 [17.8]
TG (mg/dL)	233.0 [37.4]	216.8 [84.8]	214.9 [56.2]	220.2 [57.1]
Concomitant statin, n (%)	2 (50.0)	2 (50.0)	3 (42.9)	7 (46.7)
Complications
Diabetes mellitus, n (%)	3 (75.0)	1 (25.0)	5 (71.4)	9 (60.0)
Hypertension, n (%)	4 (100.0)	4 (100.0)	5 (71.4)	13 (86.7)

Data in the table are mean [standard deviation] unless otherwise indicated.

Group A: patients with an eGFR ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis.

Group B: patients undergoing hemodialysis.

Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; TG, triglyceride

Regarding concomitant use of statins, four patients in Group A received concomitant statins: two received pemafibrate and two, placebo. In Group B, two patients received pemafibrate and concomitant statins. Group C included five patients using statins concomitantly: four received pemafibrate and one, placebo. The statins used concomitantly were atorvastatin in eight patients, rosuvastatin in two patients, and pitavastatin in one patient. The major concomitant drugs used for treating dyslipidemia, diabetes, and hypertension other than statins were calcium channel blockers (n=14, 66.7%), angiotensin receptor blockers (n=12, 57.1%), beta-blockers (n=12, 57.1%), diuretics (n=9, 42.9%), and dipeptidyl peptidase 4 inhibitors (n=6, 28.6%).

Pharmacokinetics

Plasma concentrations of pemafibrate prior to administration at Week 4, Week 8, and Week 12 were similar between groups of renal impairment. The mean plasma concentrations of pemafibrate at Week 12 reached its highest in all renal impairment groups at 1 to 1.5 hours after administration and disappeared quickly thereafter.

Table 2 summarizes the main pharmacokinetic parameters of pemafibrate. The geometric mean of AUC_τ of pemafibrate was 7.333 ng·h/mL in Group A+B and 7.991 ng·h/mL in Group C. The geometric mean ratio of the AUC_τ of pemafibrate in Group A+B to Group C at 12 weeks, the primary endpoint, was 0.92, with a 90% CI of 0.62 to 1.36. The upper limit of the 90% CI did not exceed the predetermined criterion of 2.0. With or without using concomitant statins, there was no consistent trend in the AUC_τ and C_max of pemafibrate (Fig.2).

Table 2. AUC_τ and C_max of pemafibrate

	Control group	Severe renal impairment groups
	Group C (N = 7)	Group A+B (N = 8)	Group A (n = 4)	Group B (n = 4)
AUCτ (ng・h/mL)
Geometric mean	7.991	7.333	6.791	7.919
Ratio of geometric mean	-	0.92	0.85	0.99
[90% CI]		[0.62, 1.36]	[0.51, 1.42]	[0.60, 1.63]
Cmax (ng/mL)
Geometric mean	2.276	1.885	1.974	1.799
Ratio of geometric mean	-	0.83	0.87	0.79
[90% CI]		[0.59, 1.16]	[0.55, 1.36]	[0.50, 1.26]

Group A: patients with an estimated glomerular filtration rate (eGFR) ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis. Group B: patients undergoing hemodialysis. Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

Abbreviations: AUC_τ, area under the concentration vs time curve within the dosing interval (τ); CI, confidence interval; C_max, maximum plasma concentration

Fig.2. Effect of baseline eGFR on pemafibrate AUC_τ and C_max with and without the use of statins

Group A: patients with an eGFR ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis.

Group B: patients undergoing hemodialysis.

Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

Abbreviations: AUC_τ, area under the concentration vs time curve within the dosing interval (τ); C_max, maximum plasma concentration; eGFR, estimated glomerular filtration rate

Other pharmacokinetic parameters were similar in Group C and Group A+B (Supplementary Table 2). In Group A+B to Group C, the geometric mean ratio of t_max was 1.11 (0.82, 1.50); t_1/2, 0.85 (0.59, 1.23); Kel, 1.18 (0.82, 1.71); MRT_ss, 0.99 (0.72, 1.36); CL_ss/F, 1.09 (0.73, 1.61); and Vd_ss/F, 0.92 (0.68, 1.24). The geometric mean of trough values (C_trough) could not be calculated because the lowest concentration was below the detection limit (0.001 ng/mL). Two of the seven pemafibrate metabolites measured (K-23469 and K-23605) were higher (C_max ratio; 3.3 - 14.4) in Group B relative to Group C. In most cases, the concentration of both metabolites decreased to the lower limit of quantitation 4 weeks after discontinuing pemafibrate administration.

Supplementary Table 2.Pharmacokinetic parameters of pemafibrate

	Control group	Severe renal impairment group
	Group C (N = 7)	Group A+B (N = 8)	Group A (n = 4)	Group B (n = 4)
tmax (h)
Geometric mean	1.06	1.18	1.22	1.13
Ratio of geometric mean	-	1.11	1.16	1.07
[90% CI]		[0.82, 1.50]	[0.75, 1.78]	[0.70, 1.63]
t1/2 (h)
Geometric mean	3.61	3.08	3.23	2.94
Ratio of geometric mean	-	0.85	0.89	0.81
[90% CI]		[0.59, 1.23]	[0.54, 1.48]	[0.52, 1.28]
Kel (1/h)
Geometric mean	0.19	0.23	0.22	0.24
Ratio of geometric mean	-	1.18	1.13	1.24
[90% CI]		[0.82, 1.71]	[0.68, 1.86]	[0.79, 1.96]
MRTss (h)
Geometric mean	4.08	4.04	3.76	4.33
Ratio of geometric mean	-	0.99	0.92	1.06
[90% CI]		[0.72, 1.36]	[0.62, 1.37]	[0.70, 1.61]
CLss/F (L/h)
Geometric mean	12.52	13.62	14.70	12.62
Ratio of geometric mean	-	1.09	1.17	1.01
[90% CI]		[0.73, 1.61]	[0.70, 1.96]	[0.61, 1.66]
Vdss/F (L)
Geometric mean	65.35	60.23	68.27	53.14
Ratio of geometric mean	-	0.92	1.04	0.81
[90% CI]		[0.68, 1.24]	[0.71, 1.55]	[0.54, 1.22]
Ctrough (ng/mL)
Geometric mean	-	-	-	-
Ratio of geometric mean	-	-	-	-
[90% CI]		[-, -]	[-, -]	[-, -]

Group A: patients with an estimated glomerular filtration rate (eGFR) ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis.

Group B: patients undergoing hemodialysis.

Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

Abbreviations: CI, confidence interval; CL_ss/F, apparent clearance at steady state; C_trough, trough concentration; Kel, elimination rate constant; MRT_ss, mean residence time at steady state; t_max, time to maximum plasma concentration; t_1/2, estimate of the terminal elimination half-life; Vd_ss/F, apparent volume of distribution at steady state

Safety

The AEs are listed in Table 3. The numbers of AEs occurring in the pemafibrate group of Group A were 2/4 (50%); in Group B, 2/4 (50%); and in Group C, 3/8 (37.5%), while in the placebo groups, the numbers of AEs were 2/2 (100%) in Group A, 1/1 (100%) in Group B, and 1/2 (50%) in Group C. One case of ADR occurred in the pemafibrate group of Group C.

Table 3.Summary of adverse events

	Group A		Group B		Group C
	Pemafibrate	Placebo	Pemafibrate	Placebo	Pemafibrate	Placebo
Adverse events	2 (50.0) [2]	2 (100.0) [3]	2 (50.0) [3]	1 (100.0) [3]	3 (37.5) [5]	1 (50.0) [1]
Serious adverse events	0	0	0	0	0	0
Adverse drug reactions	0	0	0	0	1 (12.5) [1]	0
Gastrointestinal disorders
Constipation	0	0	0	0	1 (12.5) [1]	0
Nausea	0	0	0	0	1 (12.5) [1]	0
Periodontal disease	0	0	1 (25.0) [1]	0	0	0
General disorders and administration site conditions
Chest pain	0	0	0	0	1 (12.5) [1]	0
Immune system disorders
Seasonal allergy	0	0	0	1 (100.0) [1]	0	0
Infections and infestations
Furuncle	1 (25.0) [1]	0	0	0	0	0
Nasopharyngitis	0	0	0	1 (100.0) [2]	0	0
Urinary tract infection	0	1 (50.0) [1]	0	0	0	0
Injury, poisoning and procedural complications
Shunt stenosis	0	0	1 (25.0) [1]	0	0	0
Investigations
Blood creatine kinase increased	1 (25.0) [1]	0	0	0	0	0
Myoglobin urine present	0	0	0	0	1 (12.5) [1]†, ‡	0
Metabolism and nutrition disorders
Hyperuricemia	0	0	0	0	0	1 (50.0) [1]
Musculoskeletal and connective tissue disorders
Arthralgia	0	0	0	0	1 (12.5) [1]	0
Limb discomfort	0	1 (50.0) [1]†	0	0	0	0
Nervous system disorders
Facial paralysis	0	1 (50.0) [1]	0	0	0	0
Skin and subcutaneous tissue disorders
Eczema	0	0	1 (25.0) [1]	0	0	0

Data in the table are number of patients (percentage) [number of events].

Group A: patients with an estimated glomerular filtration rate (eGFR) ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis.

Group B: patients undergoing hemodialysis.

Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

^†Discontinuation of study drug administration.

^‡The adverse event was considered an adverse drug reaction.

No deaths, rhabdomyolysis, or other serious AEs were observed. Two rhabdomyolysis-related AEs were reported: one in Group A, CK elevation, and one in Group C, mildly urinary myoglobin. The latter was considered an ADR, which led to study drug discontinuation. The myoglobinuria recovered about 1 month after drug discontinuation. Detailed reports of these cases are provided in the Supplementary Materials.

There was a case of discontinuation in the Group A placebo group due to limb discomfort. Changes in CK, eGFR, and creatinine levels during the study period are shown in Table 4. No creatinine increase or eGFR decrease was observed in the patients treated with pemafibrate. One case of an AE of CK elevation was transient and self-limited in the Group A pemafibrate group (described above). No specific statistical analyses were performed for CK, eGFR, and creatinine, but no consistent trends were observed in the other groups.

Table 4.Changes in creatine kinase, eGFR, and creatinine levels during the study period

		Group A						Group B						Group C
		Pemafibrate			Placebo			Pemafibrate			Placebo			Pemafibrate			Placebo
		n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)
CK (U/L)	Week 0	4	140.0	(59.1)	2	202.0	(2.8)	4	75.8	(9.8)	1	62.0	-	8	153.5	(83.5)	2	75.0	(1.4)
	Week 4	4	148.5	(42.5)	1	282.0	-	4	110.3	(67.3)	1	58.0	-	7	127.4	(68.6)	2	50.5	(19.1)
	Week 8	4	1113.8	(1878.8)	1	143.0	-	4	110.3	(63.7)	1	55.0	-	7	125.6	(42.4)	2	56.0	(24.0)
	Week 12	4	127.0	(62.6)	1	64.0	-	4	108.0	(34.3)	1	37.0	-	7	110.7	(51.1)	2	54.5	(13.4)
eGFR (mL/min/ 1.73m2)	Week 0	4	25.9	(3.5)	2	16.1	(12.3)	4	3.7	(0.7)	1	4.1	-	8	42.4	(9.6)	2	31.9	(1.3)
	Week 4	4	23.5	(3.7)	1	21.3	-	4	3.7	(0.6)	1	4.1	-	7	42.0	(7.4)	2	27.4	(5.9)
	Week 8	4	24.5	(4.0)	1	21.7	-	4	3.5	(0.7)	1	4.0	-	7	40.6	(7.6)	2	26.3	(4.7)
	Week 12	4	23.4	(4.9)	1	22.7	-	4	4.7	(0.4)	1	5.9	-	7	41.5	(9.9)	2	26.7	(6.0)
Creatinine (mg/dL)	Week 0	4	2.1	(0.2)	2	4.3	(3.8)	4	12.3	(1.9)	1	8.9	-	8	1.4	(0.4)	2	1.7	(0.1)
	Week 4	4	2.3	(0.3)	1	1.9	-	4	12.4	(1.9)	1	8.8	-	7	1.4	(0.2)	2	2.0	(0.3)
	Week 8	4	2.2	(0.3)	1	1.8	-	4	12.9	(2.5)	1	9.1	-	7	1.4	(0.2)	2	2.1	(0.3)
	Week 12	4	2.4	(0.4)	1	1.7	-	4	9.7	(0.7)	1	6.4	-	6	1.4	(0.4)	2	2.1	(0.3)

Group A: patients with an eGFR ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis. Group B: patients undergoing hemodialysis.

Group C: patients with an eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis.

Abbreviations: CK, creatine kinase; eGFR, estimated glomerular filtration rate; SD, standard deviation

Efficacy

The lipid parameters measured in this study are summarized in Supplementary Table 3. In the pemafibrate group, TG levels decreased, LDL-C levels remained unchanged, HDL-C levels remained unchanged or increased, and TC levels remained unchanged in all groups. No statistical tests were performed because of the small number of patients.

Supplementary Table 3.Summary of lipid parameters

		Group A						Group B						Group C
		Pemafibrate			Placebo			Pemafibrate			Placebo			Pemafibrate			Placebo
		n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)
TG (mg/dL)	Week 0	4	233.0	(37.4)	2	254.0	(18.4)	4	216.8	(84.8)	1	168.0	-	8	215.3	(52.1)	2	203.0	(14.1)
	Week 12	4	149.0	(54.5)	1	237.0	-	4	174.5	(71.8)	1	118.0	-	7	162.1	(39.4)	2	173.0	(53.7)
	% change	4	-32.6	(34.4)	1	-11.2	-	4	-19.1	(22.2)	1	-29.8	-	7	-17.5	(37.0)	2	-15.5	(20.6)
TC (mg/dL)	Week 0	4	168.0	(21.0)	2	161.0	(25.5)	4	198.3	(26.7)	1	220.0	-	8	193.8	(24.9)	2	243.0	(76.4)
	Week 12	4	170.0	(13.9)	1	222.0	-	4	211.0	(24.7)	1	186.0	-	7	190.3	(17.1)	2	187.5	(12.0)
	% change	4	2.3	(14.6)	1	24.0	-	4	6.9	(8.7)	1	-15.5	-	7	-2.7	(12.6)	2	-18.0	(30.7)
LDL-C† (mg/dL)	Week 0	4	84.5	(17.4)	2	81.0	(11.3)	4	123.3	(29.2)	1	152.0	-	8	114.0	(33.1)	2	160.0	(66.5)
	Week 12	4	91.5	(18.9)	1	117.0	-	4	126.5	(16.1)	1	131.0	-	7	111.4	(24.6)	2	120.5	(13.4)
	% change	4	9.1	(14.7)	1	31.5	-	4	6.7	(26.2)	1	-13.8	-	7	-1.1	(27.9)	2	-15.7	(43.4)
HDL-C (mg/dL)	Week 0	4	45.0	(24.9)	2	31.5	(7.8)	4	36.8	(11.5)	1	34.0	-	8	48.1	(17.6)	2	42.0	(11.3)
	Week 12	4	49.3	(24.4)	1	60.0	-	4	51.5	(17.3)	1	32.0	-	7	48.9	(9.4)	2	36.0	(4.2)
	% change	4	11.3	(7.0)	1	62.2	-	4	39.6	(6.4)	1	-5.9	-	7	6.4	(20.5)	2	-12.5	(13.5)
Non-HDL-C (mg/dL)	Week 0	4	123.0	(23.2)	2	129.5	17.7	4	161.5	(21.1)	1	186.0	-	8	145.6	(28.2)	2	201.0	(65.1)
	Week 12	4	120.8	(26.2)	1	162.0	-	4	159.5	(23.0)	1	154.0	-	7	141.4	(25.4)	2	151.5	(16.3)
	% change	4	-1.0	(19.7)	1	14.1	-	4	-0.7	(11.9)	1	-17.2	-	7	-4.4	(12.7)	2	-19.1	(34.3)
RLP-C (mg/dL)	Week 0	4	11.5	(3.7)	2	12.5	0.3	4	11.8	(3.9)	1	10.4	-	8	10.4	(2.7)	2	11.5	(2.4)
	Week 12	4	6.5	(3.5)	1	11.3	-	4	7.5	(2.4)	1	6.1	-	7	6.3	(1.7)	2	7.8	(3.3)
	% change	4	-33.4	(56.0)	1	-11.0	-	4	-35.0	(20.0)	1	-41.4	-	7	-33.8	(31.7)	2	-28.0	(44.0)
FFA (mEq/L)	Week 0	4	0.4	(0.2)	2	0.5	0.2	4	0.3	(0.2)	1	0.3	-	8	0.7	(0.4)	2	0.5	(0.2)
	Week 12	4	0.5	(0.3)	1	0.5	-	4	0.5	(0.2)	1	0.2	-	7	0.6	(0.3)	2	0.5	(0.2)
	% change	4	30.6	(54.7)	1	-14.3	-	4	140.8	(203.3)	1	-8.0	-	7	-9.7	(40.8)	2	15.4	(13.5)

^†The direct method was used to measure LDL-C.

Abbreviations: FFA, free fatty acid; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; RLP-C, remnant like particles-cholesterol; SD, standard deviation; TC, total cholesterol; TG, triglyceride

Discussion

This is the first report to investigate in detail the pharmacokinetics of repeated pemafibrate administration in patients with and without statin use who had both dyslipidemia and severe renal impairment. The main findings were that the AUC_τ of pemafibrate was not affected by the degree of renal impairment. There was no notable relationship between the degree of renal impairment and incidence of AEs, and no new safety concerns were observed in this study. Altogether, pemafibrate could be administered to patients with severe renal impairment without increasing the risk of rhabdomyolysis.

These findings are consistent with those of a recent phase 3 trial, which reported that pemafibrate plasma concentrations were not elevated in patients with CKD during the study³⁰⁾. The upper limit of the 90% CI of the AUC_τ ratio, the primary endpoint, was less than 2.0, suggesting that the impact of renal impairment on pemafibrate pharmacokinetics may not be clinically relevant. As noted in the statistical analysis section, it has been suggested that fenofibrate and bezafibrate increase blood drug levels and increase the risk of rhabdomyolysis when given to patients with CKD. However, in this study, there was no consistent trend in the AUC_τ and C_max of pemafibrate regardless of the eGFR. The concentrations of two pemafibrate metabolites (K-23469 and K-23605) were elevated in Group B; however, both concentrations remained below the no-observed-adverse-effect level reported in the non-clinical studies that supported pemafibrate approval (data on file), indicating that the concern for chronic toxicity was minimal. Notably, all pemafibrate metabolites have little or no PPARα agonist activity (data on file). Taken together, this evidence suggests that pemafibrate may be safer than fibrates in patients with severe renal impairment.

No previous studies have reported the use of pemafibrate in combination with statins in patients with severe renal impairment. In this study, pemafibrate showed no consistent increases in plasma concentrations even under statin combination. While the mechanism is not fully clear, statin-fibrate combination therapy is thought to increase rhabdomyolysis³²⁾. At least, on the pemafibrate serum concentration side, combination of pemafibrate and statin is unlikely to increase the incidence of rhabdomyolysis. A recent clinical trial in healthy male volunteers showed that the statin combination had no effect on pemafibrate exposure²²⁾. In a global phase 3 randomized controlled study evaluating the effect of pemafibrate on cardiovascular events in patients with type 2 diabetes, in which ≥ 95% of patients were taking statins, pemafibrate did not increase muscle-related AEs compared with placebo (hazard ratio [95% CI] was 0.94 [0.88–1.01], P=0.08)³³⁾. Although this study did not examine aspects other than drug blood levels, it is speculated that pemafibrate can be used in combination with statin without significantly increasing the risk of muscular symptoms.

Among patients with severe or moderate CKD treated with pemafibrate, there was no relationship between the degree of renal impairment and incidence of AEs, which is also consistent with the previous phase 3 study of patients with moderate CKD treated with pemafibrate²³⁾. Furthermore, we focused specifically on rhabdomyolysis-related events. One patient in the Group C pemafibrate group had a mild ADR: positive urinary myoglobin. Because the patient had a CK level of 339 U/L at AE onset, rhabdomyolysis was ruled out. In a previous report, the CK value (mean was 43,882 U/L) at the peak of the onset of rhabdomyolysis was higher than the present case³⁴⁾. As the patient recovered within 1 month after discontinuing the medication, no major safety issues were considered.

In previous reports, fibrates are known to worsen renal function markers, but these changes were much less marked in the pemafibrate groups^{25-28, 35, 36)}. Unlike existing fibrates, which are renally excreted, pemafibrate is metabolized hepatically and its exposure did not increase. No safety concerns were raised in terms of pharmacokinetics in patients with severe renal impairment. Based on the results of this study and post-marketing ADR/AE reports, the contraindication for patients with severe renal impairment was lifted from pemafibrate package insert in Japan in 2022. However, we must continue to monitor CK, eGFR, and creatinine carefully when administering the drug to patients with renal impairment. These parameters appeared to be unchanged in this study, but this may be because of the small number of patients.

This study had several limitations. The number of cases was small: limited to one to eight cases per group. The percentage of patients with diabetes was not equally distributed among groups. The participants were all Japanese, and thus, there is a concern of lack of generalizability to other ethnicities. The participants may differ from the patients encountered in routine clinical practice. Further information on the usefulness of pemafibrate in daily clinical practice in patients with renal impairment is needed. As this study was conducted with 12-week dosing, further long-term safety evaluation is needed.

In conclusion, repeated administration of pemafibrate in patients with severe renal impairment did not increase pemafibrate exposure. The results suggest that pemafibrate may be useful as a TG-lowering treatment for patients with severe renal impairment.

Funding

This research was funded by Kowa Company, Ltd. (Tokyo, Japan).

Conflict of Interest

Ishibashi S has received personal fees from Kowa Company, Ltd. Arai H has received personal fees from Daiichi Sankyo Company, Limited, MSD K.K., Kowa Company, Ltd., Takeda Pharmaceutical Company Limited, and Otsuka Pharmaceutical Co., Ltd. Yokote K has received personal fees and grants from MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Astellas Pharma Inc., Sumitomo Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Daiichi Sankyo Company, Limited, and Taisho Pharmaceutical Co., Ltd.; personal fees from AstraZeneca K.K., Novartis Pharma K.K., Boehringer Ingelheim International GmbH., and Pfizer Japan Inc.; and grants from Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Abbott Japan LLC. Araki E has received personal fees and grants from Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., and Novo Nordisk Pharma Ltd.; personal fees from AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Kowa Company, Ltd., and Daiichi Sankyo Company, Limited; and grants from Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., and Roche Diagnostics K.K. Watanabe M, Nakanishi M, Makinose Y, Suganami H, and Kurihara Y are employees of Kowa Company, Ltd. Yamashita S has received personal fees from Kowa Company, Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Skylight Biotech, Inc., and Hayashibara Co., Ltd.

Acknowledgements

The authors thank all patients and physicians who participated in this study. The authors wish to thank Keyra Martinez Dunn, MD, of Edanz (www.edanz.com), whose fee was paid by Kowa Company, Ltd., for providing medical writing support in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp-2022).

Author Contributions

Ishibashi S: Conceptualization, Methodology, Writing-Original Draft, Writing-Review & Editing, Visualization, Supervision. Arai H: Conceptualization, Methodology, Writing-Review & Editing. Yokote K: Conceptualization, Methodology, Writing-Review & Editing. Araki E: Conceptualization, Methodology, Writing-Review & Editing. Watanabe M: Writing-Review & Editing. Nakanishi M: Methodology, Writing-Review & Editing. Makinose Y: Methodology, Writing-Review & Editing. Suganami H: Methodology, Formal analysis, Data Curation, Writing-Review & Editing, Visualization. Kurihara Y: Methodology, Writing-Review & Editing, Project administration. Yamashita S: Conceptualization, Methodology, Writing-Review & Editing.

Data Availability

Data not available.

Supplementary Text

Methods

The main inclusion criteria were as follows:

• Patients with dyslipidemia whose age at the time of obtaining consent was ≥ 20 years;

• Men or postmenopausal women;

• Fasting serum triglyceride level ≥ 150 mg/dL in the screening test;

• Patients with any of the following:

· Estimated glomerular filtration rate (eGFR) ＜30 mL/min/1.73m² at screening and not undergoing hemodialysis (Group A),

· Patients undergoing hemodialysis (Group B),

· Patients with eGFR ≥ 30 and ＜60 mL/min/1.73m² at screening and not undergoing hemodialysis (Group C)

The main exclusion criteria were as follows:

• Patients with severe hepatic disorder, cirrhosis, or biliary obstruction;

• Patients with gallstones;

• Pregnant women or those with suspected pregnancy;

• Patients receiving or requiring continuous administration of concomitant drugs prohibited during the study period;

• Kidney transplant recipients;

• Patients who were complicated with poorly controlled nephrotic syndrome;

• Patients on or previously treated with pemafibrate;

• Patients with at least one liver function test value (aspartate aminotransferase, alanine aminotransferase) exceeding 2.5 times the upper limit of the reference range in the screening test;

• Patients whose creatine kinase (CK) level at screening exceeded 5 times the upper limit of the reference range;

• Patients with poorly controlled thyroid disease;

• Patients who had an acute myocardial infarction or stroke within 3 months prior to obtaining consent;

• Patients with complications of malignant tumors under treatment;

• Patients who underwent a whole blood extraction of ≥ 200 mL within 4 weeks prior to study drug administration, a whole blood extraction of ≥ 400 mL within 16 weeks prior to study drug administration, or who gave a component blood donation (plasma or platelet components) within 2 weeks before study drug administration;

• Patients with a history of serious drug allergy (e.g., anaphylactic shock);

• Patients participating in other clinical trials or clinical studies at the time of obtaining consent or who had received a study drug other than a placebo for less than 16 weeks;

• Patients deemed inappropriate for study participation by the investigator

Results

Safety

The rhabdomyolysis-related adverse event (AE) in the pemafibrate group of Group A was an increase in CK level (3926 U/L at 8 weeks). There was a preceding exercise episode, and CK levels decreased spontaneously without a change in pemafibrate dosage or any treatment. Thus, the event was determined to be unrelated to pemafibrate.

The rhabdomyolysis-related AE in the pemafibrate group of Group C was elevated urinary myoglobin. It was mild in severity but led to a study drug discontinuation. Since it could not be ruled out that this AE was attributable to pemafibrate, this event was considered an ADR. Urinary myoglobin levels recovered at follow-up approximately 1 month after pemafibrate administration was discontinued.

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