Iobenguane ¹³¹I Other names: Iobenguane I-131

Iobenguane is similar in structure to the neurotransmitter norepinephrine (NE) and is subject to the same uptake and accumulation pathways as NE. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues, such as the heart, lungs, adrenal medulla, salivary glands, liver, and spleen as well as tumors of neural crest origin. Pheochromocytoma and paraganglioma (PPGL) are tumors of neural crest origin that express high levels of the NE transporter on their cell surfaces. Following intravenous administration, iobenguane ¹³¹I is taken up and accumulates within pheochromocytoma and paraganglioma cells, and radiation resulting from radioactive decay of ¹³¹I causes cell death and tumor necrosis.

The effect of iobenguane ¹³¹I on the QTc interval was evaluated in 74 patients with unresectable pheochromocytoma or paraganglioma. At the recommended therapeutic dosage, no large mean increases from baseline in the QTc interval (i.e., >20 ms) were detected.

The pharmacokinetics (PK) of iobenguane ¹³¹I following a dosimetric dose were characterized in patients with malignant PPGL and other malignancies. The mean blood area under curve (AUC) of iobenguane ¹³¹I at the recommended dosimetric dose is 1 µCi*h/mL (CV 33%). The mean maximum concentration (C_max) for iobenguane ¹³¹I is 0.06 µCi/mL (CV 36%), which generally occurred at the end of the iobenguane ¹³¹I infusion.

Distribution

The volume of distribution (mean ± SD) of iobenguane ¹³¹I is 2893 ± 592 mL/kg. The blood levels of radioactivity declined with a distribution half-life (mean ± SD) of 0.37 ± 0.22 hours. The non-radioactive form of iobenguane ¹³¹I is 61% to 63% bound to human plasma proteins.

Elimination

The mean clearance is 62 ± 24 mL/hr/kg for iobenguane ¹³¹I and the mean terminal blood half-life is 35 ± 14 hours.

Metabolism

iobenguane ¹³¹I does not undergo hepatic metabolism.

Excretion

iobenguane ¹³¹I is primarily eliminated renally with cumulative excretion of 50 ± 10% within 24 hours and 80 ± 10% within 120 hours following iobenguane ¹³¹I administration. Unchanged ¹³¹I accounted for an average of 94% and 93% radioactivity excreted in urine collected at 0-6 and 6-24 hours post-dose, respectively. Minor metabolites detected in some patients included free ¹³¹I, quantifiable in 55% of 11 patients in Study IB11, as well as meta-iodohippuric acid (MIHA) and meta-iodobenzyl bisguanidine (MMIBG) quantifiable in one patient each.

Specific Populations

Eight of 42 patients (19%) with mild or moderate renal impairment (CLcr ≥30-89 mL/min by Cockcroft-Gault) required therapeutic dose reductions based on radiation dose estimates to critical organs exceeding Emami limits (absorbed renal dose exceeding 23 Gy). The pharmacokinetics of iobenguane ¹³¹I has not been studied in patients with severe renal impairment (CLcr <30 mL/min) or end-stage renal disease.

Drug Interaction Studies

In Vitro Studies

The non-radioactive form of iobenguane does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A. It does not induce CYP1A, 2B6, 2C9, 2C19, or 3A. It is not a substrate or inhibitor of P-glycoprotein.