Pomalidomide: Evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects

Abstract

Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.

Pomalidomide for multiple myeloma

“…The clearance pathways reported include CYP450-mediated metabolism (primarily CYP1A2 and CYP3A4 isozymes), glutarimide ring hydrolysis and excretion in its unchanged form (<10%). Hydroxylation of pomalidomide with subsequent glucuronidation is the predominant metabolic route [24]. Based on in vitro data, pomalidomide is not an inhibitor or inducer of CYPP450 isoenzymes and does not inhibit any drug transporters that were studied [23].…”

“…Its maximum plasma concentration occurs between 2 and 3 h post-dose [23,24]. • Distribution: pomalidomide has a mean volume of distribution between 62 and 138 l at steady state [23].…”

Pomalidomide for the management of relapsed and refractory multiple myeloma: a case report and review of literature

“…Накопление помалидомида в результате длительного применения реализуется повышением концентрации приблизительно на 27-31 % [19]. Помалидомид мета-болизируется в печени с помощью цитохрома P450, в основном изоэнзимами CYP1A2 и CYP3A4 и мини-мально CYP2C19 и CYP2D6 [20]. Период полувыве-дения помалидомида у здоровых мужчин составляет приблизительно 9,5 ч, у пациентов с ММ -7,5 ч [19].…”

Pomalidomide for Treatment of Relapsed and Refractory Multiple Myeloma

“…Паци-ентам, принимающим помалидомид, лучше ограничивать назначение таких препаратов фторхинолонового ряда, как ципрофлоксацин, эноксацин, поскольку они ингиби-руют активность изофермента CYP1A2 цитохрома Р450 в печени, участвующего в метаболизме препарата, и могут привести к неприемлемой токсичности. Применение других препаратов из группы фторхинолонов (норфлок-сацин, офлоксацин, левофлоксацин и моксифлоксацин) вполне безопасно [39].…”