Arimoclomol

The mechanism(s) by which arimoclomol exerts its clinical effects in patients with NPC is unknown.

The effect of arimoclomol (744 mg/day for 28 days) on serum creatinine was assessed in 16 healthy male subjects. A reversible increase in mean serum creatinine of 19% was observed after 21 days of treatment. No effect on glomerular function (GFR, ¹²⁵I-iothalamate clearance) or renal hemodynamics (effective renal plasma flow (ERPF); ¹³¹I-hippuran clearance) was observed.

Cardiac Electrophysiology

The effect of arimoclomol 124 mg and 372 mg (3 times the maximum recommended dosage) administered three times a day (372 mg/day and 1116 mg/day) on ECG was evaluated in a randomized, partially double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), multipledose, 4-way crossover trial in 34 healthy male subjects. In this trial, arimoclomol did not prolong the QTc interval to a clinically relevant extent.

Arimoclomol exhibited linear and dose proportional pharmacokinetics following oral administration of doses ranging from 62 to 372 mg (three times the maximum recommended dosage) three times a day in healthy subjects. The plasma C_max and AUC_0-8hr of arimoclomol at the 248 mg dose (two times the maximum recommended dosage) are summarized in the following table.

Geometric mean (CV%) Pharmacokinetic Parameters of Arimoclomol Following Oral Administration in Healthy Subjects:

Absorption

The absolute bioavailability of arimoclomol following oral administration has not been determined. The median time to reach maximum plasma arimoclomol concentration (t_max) was approximately 0.5 hours.

Effect of Food

No clinically significant difference in arimoclomol pharmacokinetics were observed following administration of a high-fat meal (1000 calories, 60% fat) to healthy subjects.

Distribution

The mean apparent volume of distribution (V_Z/F) of arimoclomol at steady state in healthy adult subjects is 211 L. A dose-dependent increase in arimoclomol cerebral spinal fluid concentrations was seen at steady state. Plasma protein binding of arimoclomol is approximately 10%.

Elimination

The elimination half-life of arimoclomol is approximately 4 hours. The mean apparent clearance of arimoclomol (CL/F) at steady state is 34 L/hr in healthy adult subjects.

Metabolism

Arimoclomol is predominantly metabolized through glutathionation, O-glucuronidation and NO-oxime cleavage.

Excretion

Following a single dose of radiolabeled arimoclomol 100 mg to healthy male subjects under fasted conditions, approximately 12% of the dose was recovered in feces and 77.5% in urine (42% unchanged).

Drug Interaction Studies

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Arimoclomol is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5.

Transporter Systems

Arimoclomol is an inhibitor of OCT2 and may cause relevant changes in exposure of OCT2 substrates including the endogenous substrate creatinine. Arimoclomol is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 and MATE2-K transporters. Arimoclomol is a substrate of MATE1 and MATE2-K transporters; MATE1 and MATE2-K inhibitors are not expected to have a clinically relevant effect on arimoclomol exposure.

Specific Populations

Pediatric Patients

In pediatric NPC patients who received the recommended dosing regimens, the estimated steady state mean ± SD serum C_trough and C_max arimoclomol concentrations are 206 ± 60 and 523 ± 194 ng/mL, respectively.

Patients with Renal Impairment

In a renal impairment study, subjects with moderate to severe renal impairment (estimated glomerular filtration rate [eGFR] 15-49 mL/minute) had an approximately 2-fold increase in total exposure to arimoclomol (AUC_inf) compared to subjects with normal renal function (eGFR ≥90 mL/minute). There was no clinically meaningful difference in exposure to arimoclomol in subjects with an eGFR of ≥50 mL/minute. Arimoclomol was not evaluated in patients with eGFR <15 mL/minute.

Patients with Hepatic Impairment

No clinically relevant differences in arimoclomol pharmacokinetics were observed in patients with mild to moderate hepatic impairment (Child-Pugh Score A or B) compared to subjects with normal hepatic function. Arimoclomol has not been studied in patients with severe hepatic impairment (Child-Pugh Criteria C).