Pomarza Mechanism of Action

Pharmacotherapeutic group: Immunomodulating agent. ATC code: L04AX06.
Pharmacology: Pharmacodynamics: Mechanism of action: Pomalidomide has direct anti-myeloma tumoricidal activity, immunomodulatory activities and inhibits stromal cell support for multiple myeloma tumour cell growth. Specifically, pomalidomide inhibits proliferation and induces apoptosis of haematopoietic tumour cells. Additionally, pomalidomide inhibits the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergises with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumour cell apoptosis.
Pomalidomide enhances T cell- and natural killer (NK) cell-mediated immunity and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial cells.
Pomalidomide binds directly to the protein cereblon (CRBN), which is part of an E3 ligase complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins-1 (Roc1), and can inhibit the auto-ubiquitination of CRBN within the complex. E3 ubiquitin ligases are responsible for the poly-ubiquitination of a variety of substrate proteins, and may partially explain the pleiotropic cellular effects observed with pomalidomide treatment.
In the presence of pomalidomide, substrate proteins Aiolos and Ikaros are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Pomalidomide therapy led to reduction in the levels of Ikaros in patients with relapsed lenalidomide-refractory multiple myeloma.
Pharmacokinetics: Absorption: Pomalidomide is absorbed with a maximum plasma concentration (Cmax) occurring between 2 and 3 hours and is at least 73% absorbed following administration of single oral dose. The systemic exposure (AUC) of pomalidomide increases in an approximately linear and dose proportional manner. Following multiple doses, pomalidomide has an accumulation ratio of 27 to 31% on AUC.
Coadministration with a high-fat and high-calorie meal slows the rate of absorption, decreasing mean plasma Cmax by approximately 27%, but has minimal effect on the overall extent of absorption with an 8% decrease in mean AUC. Therefore, pomalidomide can be administered without regard to food intake.
Distribution: Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steady state. Pomalidomide is distributed in semen of healthy patients at a concentration of approximately 67% of plasma level at 4 hours post-dose (approximately Tmax) after 4 days of once daily dosing at 2 mg. Binding of pomalidomide enantiomers to proteins in human plasma ranges from 12% to 44% and is not concentration dependent.
Biotransformation: Pomalidomide is the major circulating component (approximately 70% of plasma radioactivity) in vivo in healthy subjects who received a single oral dose of [14C]-pomalidomide (2 mg). No metabolites were present at >10% relative to parent or total radioactivity in plasma.
The predominant metabolic pathways of excreted radioactivity are hydroxylation with subsequent glucuronidation, or hydrolysis. CYP1A2 and CYP3A4 were identified as the primary enzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minor contributions from CYP2C19 and CYP2D6. Pomalidomide is also a substrate of P-glycoprotein in vitro. Co-administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant effect on exposure to pomalidomide. Co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole, increased mean exposure to pomalidomide compared to pomalidomide plus ketoconazole. Co-administration of fluvoxamine alone with pomalidomide increased mean exposure to pomalidomide compared to pomalidomide alone. If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered with pomalidomide, reduce the dose of pomalidomide to 50%. Administration of pomalidomide in smokers, with smoking tobacco known to induce the CYP1A2 isoform, had no clinically relevant effect on exposure to pomalidomide compared to that exposure to pomalidomide observed in non-smokers.
Based on data, pomalidomide is not an inhibitor or inducer of cytochrome P-450 isoenzymes, and does not inhibit any drug transporters that were evaluated. Clinically relevant drug-drug interactions are not anticipated when pomalidomide is coadministered with substrates of these pathways.
Elimination: Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthy patients and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a mean total body clearance (CL/F) of approximately 7-10 L/hr.
Following a single oral administration of [14C]-pomalidomide (2 mg) to healthy patients, approximately 73% and 15% of the radioactive dose was eliminated in urine and faeces, respectively, with approximately 2% and 8% of the dosed radiocarbon eliminated as pomalidomide in urine and faeces.
Pomalidomide is extensively metabolised prior to excretion, with the resulting metabolites eliminated primarily in the urine. The 3 predominant metabolites in urine (formed via hydrolysis or hydroxylation with subsequent glucuronidation) account for approximately 23%, 17%, and 12%, respectively, of the dose in the urine.
CYP dependent metabolites account for approximately 43% of the total excreted radioactivity, while non-CYP dependent hydrolytic metabolites account for 25%, and excretion of unchanged pomalidomide accounted for 10% (2% in urine and 8% in faeces).
Population Pharmacokinetics (PK): Based on population PK analysis, healthy patients and MM patients had comparable apparent clearance (CL/F) and apparent central volume of distribution (V2/F). In peripheral tissues, pomalidomide was preferentially taken up by tumors with apparent peripheral distribution clearance (Q/F) and apparent peripheral volume of distribution (V3/F) 3.7-fold and 8-fold higher, respectively, than that of healthy patients.
Paediatric population: Following a single oral dose of pomalidomide in children and young adults with recurrent or progressive primary brain tumour, the median Tmax was 2 to 4 hours post-dose. AUC0-24 and AUC0-inf followed similar trends, with total exposure in the range of approximately 700 to 800 h·ng/mL at the lower 2 doses, and approximately 1200 h·ng/mL at the high dose. Estimates of half-life were in the range of approximately 5 to 7 hours. There were no clear trends attributable to stratification by age and steroid use at the MTD.
Overall, data suggest that AUC increased nearly proportional to the increase in pomalidomide dose, while the increase in Cmax was generally less than proportional.
The pharmacokinetics of pomalidomide following oral administration dose levels of 1.9 mg/m²/day to 3.4 mg/m²/day were determined in patients with ages from 4 to 20 years with recurrent or progressive paediatric brain tumours. Pomalidomide concentration-time profiles were adequately described with a one compartment PK model with first-order absorption and elimination. Pomalidomide exhibited linear and time-invariant PK with moderate variability. The typical values of CL/F, Vc/F, Ka, lag time of pomalidomide were 3.94 L/h, 43.0 L, 1.45 h-1 and 0.454 h respectively. The terminal elimination half-life of pomalidomide was 7.33 hours. Except for body surface area (BSA), none of the tested covariates including age and sex had effect on pomalidomide PK. Although BSA was identified as a statistically significant covariate of pomalidomide CL/F and Vc/F, the impact of BSA on exposure parameters was not deemed clinically relevant.
In general, there is no significant difference of pomalidomide PK between children and adult patients.
Elderly: Based on population pharmacokinetic analyses in healthy patients and multiple myeloma patients, no significant influence of age (19-83 years) on oral clearance of pomalidomide was observed. In clinical studies, no dosage adjustment was required in elderly (>65 years) patients exposed to pomalidomide. See Dosage & Administration.
Renal impairment: Population pharmacokinetic analyses showed that the pomalidomide pharmacokinetic parameters were not remarkably affected in renally impaired patients (defined by creatinine clearance or estimated glomerular filtration rate [eGFR]) compared to patients with normal renal function (CrCl ≥60 mL/minute). Mean normalized AUC exposure to pomalidomide was 98.2% in moderate renal impairment patients (eGFR ≥30 to ≤45 mL/minute/1.73 m²) compared to patients with normal renal function. Mean normalized AUC exposure to pomalidomide was 100.2% in severe renal impairment patients not requiring dialysis (CrCl <30 or eGFR <30 mL/minute/1.73 m²) compared to patients with normal renal function. Mean normalized AUC exposure to pomalidomide increased by 35.8% in severe renal impairment patients requiring dialysis (CrCl <30 mL/minute requiring dialysis) compared to patients with normal renal function. The mean changes in exposure to pomalidomide in each of these renal impairment groups are not of a magnitude that require dosage adjustments.
Hepatic impairment: The pharmacokinetic parameters were modestly changed in hepatically impaired patients (defined by Child-Pugh criteria) compared to healthy patients. Mean exposure to pomalidomide increased by 51% in mildly hepatically impaired patients compared to healthy patients. Mean exposure to pomalidomide increased by 58% in moderately hepatically impaired patients compared to healthy patients. Mean exposure to pomalidomide increased by 72% in severely hepatically impaired patients compared to healthy patients. The mean increases in exposure to pomalidomide in each of these impairment groups are not of a magnitude for which adjustments in schedule or dose are required (see Dosage & Administration).