Pemafibrate

Pemafibrate activates PPARα by binding to this receptor and regulates the target gene expression, leading to decreased plasma triglyceride (TG) concentration, decreased triglyceride-rich lipoprotein, decreased apolipoprotein (Apo) C-3, and increased HDL-cholesterol.

(1) The activation of PPARα by pemafibrate was more potent than the activation of PPARγ or PPARδ, indicating the selectivity of pemafibrate to PPARα (in vitro).

(2) Pemafibrate inhibited TG synthesis in the liver (rats).

(3) Pemafibrate significantly reduced TG secretory rate (rats).

(4) Pemafibrate increased LPL activity (rats).

(5) Pemafibrate significantly reduced plasma concentrations of ApoC-3 and Angiopoietin-like Protein 3, which negatively regulate LPL activity; moreover, pemafibrate inhibited the gene expression (Apoc3, Angptl3) in the liver. In addition, pemafibrate upregulated the expression of genes (Aco, Cpt1a) involved in β-oxidation of free fatty acids that inhibits LPL activity (rats).

(6) Pemafibrate facilitated plasma TG clearance (rats).

(7) Pemafibrate increased plasma concentration of fibroblast growth factor 21 (FGF21), a protein that reduces TG concentration and increases HDLcholesterol concentration (rats).

Pharmacological action

(1) Effect of reducing plasma lipid

When pemafibrate was orally administered to rats with high fructose-induced hypertriglyceridemia, plasma TG concentration was decreased in a dosedependent manner.

(2) Effect of increasing HDL-cholesterol

When pemafibrate was orally administered to human ApoA-1 transgenic mice, plasma concentration of HDL-cholesterol and concentration of human ApoA-1 were increased.

(3) Anti-arteriosclerotic effect

When pemafibrate was orally administered to LDL-receptor deficient mice under high fat/high cholesterol diet, the area of lipid deposition area in the aortic sinus was decreased.

Plasma pemafibrate concentration

(1) Single dose administration

When a single dose of pemafibrate 0.1 mg was orally administered under fasted conditions to healthy Japanese adult males (16 subjects), the plasma concentration versus time and pharmacokinetic parameters are as presented in the following figure.

Figure. The plasma concentration versus time after a single oral dose in fasted healthy adult males:

Mean + SD (n=16)

Pharmacokinetic parameters after a single oral dose in fasted healthy adult males:

C_max, AUC_0-inf, t_1/2: Mean ± SD
t_max: Median (Minimum, Maximum)
n=16

(2) Repeated dose administration

When pemafibrate 0.2 mg/day or 0.4 mg/day was orally administered twice daily after breakfast and dinner for 7 days to healthy Japanese adult males (8 subjects), the pharmacokinetic parameters on Day 1 and Day 7 are as presented in the following table. The plasma concentration reached a steady state on Day 2. The accumulation ratio based on AUC_0-τ (repeated dosing/initial dosing, Mean ± SD) were 1.0997±0.0688 and 1.1169±0.1814, respectively.

Pharmacokinetic parameters after repeated oral doses in healthy adult males:

C_max, AUC_0-τ, t_1/2: Mean ± SD, -: Not calculated
t_max: Median (Minimum, Maximum)
n=8

(3) Food effect

When a single dose of pemafibrate 0.1 mg was orally administered to healthy Japanese adult males (16 subjects), the ratio [90% CI] of geometric means of fasted state to fed state for C_max and AUC_0-t were 0.873 [0.803, 0.950] and 0.911 [0.863, 0.961].

Absorption

The absolute bioavailability of pemafibrate was 61.5% (Data for non-Japanese subjects).

Plasma protein binding ratio

The human plasma protein binding ratio of pemafibrate was ≥99%.

Metabolism

(1) When a single dose of ¹⁴C-pemafibrate was orally administered to healthy adult subjects, the main metabolites in plasma were an oxidized form at the benzyl position, and a mixture of glucuronide conjugate of dicarboxylated form and N-dealkylated form (Data for non-Japanese subjects).

(2) pemafibrate is a substrate of CYP2C8, CYP2C9, CYP3A4, CYP3A7, UGT1A1, UGT1A3, and UGT1A8 (in vitro).

Excretion

(1) When a single dose of ¹⁴C-pemafibrate was administered to healthy adult subjects, excretion of radioactivity in urine and feces up to 216 hours after administration was 14.53% and 73.29%, respectively (Data for non-Japanese subjects). pemafibrate is excreted mainly in the feces.

(2) pemafibrate is a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, OCT2, and NTCP (in vitro).

Drug interactions

(1) Co-administration with cyclosporin, rifampicin, clopidogrel, clarithromycin, fluconazole, digoxin, or warfarin

When pemafibrate was co-administered with each drug in healthy adult subjects (non-Japanese), the effect on the pharmacokinetic parameters was as presented in the following table.

Effect of co-administration of pemafibrate and each drug on pharmacokinetic parameters (data for non-Japanese subjects):

^a Geometric mean ratios [90% CI] of pemafibrate monotherapy after repeated administration of rifampicin to pemafibrate monotherapy before repeated administration of rifampicin for C_max and AUC_0-inf.
^b AUC_0-τ
^c On Day 3 through Day 9, the dosage was adjusted to achieve an international normalized ratio of prothrombin time (PT-INR) of 1.2 to 2.2. On Day 10 and thereafter, the maintenance dose that achieved PT-INR of 1.2 to 2.2 was administered.
^* Least square mean ratios [90% CI] of repeated co-administration of warfarin with pemafibrate to repeated warfarin monotherapy for PT-INR and PT were 1.0196 [0.9878, 1.0514] (n=19) and 1.0191 [0.9869, 1.0512] (n=19).
Note: The approved dosage and administration of pemafibrate is an oral dose of 0.1 mg twice daily, and the maximum dosage is an oral dose of 0.2 mg twice daily.

(2) Co-administration with HMG-CoA reductase inhibitors

When pemafibrate and HMG-CoA reductase inhibitors were co-administered to healthy adult males (Japanese and non-Japanese), the effect of coadministration on the pharmacokinetic parameters was as presented in the following table.

Effect of co-administration of pemafibrate and each drug on pharmacokinetic parameters (data for Japanese and non-Japanese subjects):

Special populations

Pharmacokinetics in Patients with Fatty Liver and Patients with Hepatic Cirrhosis

When a single dose of pemafibrate 0.2 mg was orally administered to Japanese patients with fatty liver and patients with hepatic cirrhosis, the ratios of pharmacokinetic parameters (patients with fatty liver or with hepatic cirrhosis to subjects with normal hepatic function) were as presented in the following table. Compared with subjects with normal hepatic function, the exposure was higher in patients with fatty liver and patients with hepatic cirrhosis.

Ratios [90% CI] of geometric means of patients with fatty liver or hepatic cirrhosis to subjects with normal hepatic function (n=8) for C_max and AUC_0-t:

Pharmacokinetics in Patients with Renal Impairment

When a single dose of pemafibrate 0.2 mg was orally administered to Japanese patients with renal impairment (mild, moderate, severe, or end-stage renal failure), the ratios of pharmacokinetic parameters (patients with renal impairment to subjects with normal renal function) were as presented in the following table. Compared with subjects with normal renal function, the exposure was higher in patients with renal impairment; however, the exposure did not increase as the renal function reduced.

Ratios [90% CI] of geometric means of patients with renal impairment to subjects with normal renal function (n=8) for C_max and AUC_0-t:

Pemafibrate was orally administered at a dose of 0.1 mg twice daily in morning and evening for 12 weeks to patients with dyslipidemia accompanied by high TG value and renal impairment (severe renal impairment with eGFR <30 mL/min/1.73 m² or on dialysis and mild-to-moderate renal impairment with eGFR ≥30 and <60 mL/min/1.73 m²). The ratio and 90% CI of geometric means of AUC_0-τ in patients with severe renal impairment compared to those with mild-to-moderate renal impairment (control group) at Week 12 were as presented in the following table. The level of exposure did not increase in patients with severe renal impairment.

Ratio [90% CI] of geometric means of AUC_0-τ in patients with severe renal impairment (n=8) compared to those with mild-tomoderate renal impairment (n=7):

Pharmacokinetic parameters were presented in the following table.

Pharmacokinetic parameters after repeated oral administration in patients with dyslipidemia accompanied by high TG value and renal impairment:

Mean ± SD

In a carcinogenicity study in mice (≥0.075 mg/kg/day), an increase in the incidence of hepatocellular carcinomas and hepatocellular adenomas was observed. In a carcinogenicity study in rats (≥0.3 mg/kg/day in male rats and ≥1 mg/kg/day in female rats), an increase in the incidence of hepatocellular carcinomas, hepatocellular adenomas, pancreatic acinar cell carcinomas, pancreatic acinar cell adenomas, testicular Leydig cell adenomas, and thyroidal follicular epithelial cell adenomas was observed. All of these findings are considered to be specific to rodents.