Table 1.
Pharmacological properties of liposomal irinotecan
| Pharmacodynamic properties |
| Intravenous pegylated liposomal (sustained-release) formulation of the selective Top1 inhibitor, IRI [8] |
| IRI (a prodrug) is converted into its 100- to 1000-fold more active metabolite, SN-38, by non-specific carboxylesterases. IRI and SN-38 bind reversibly to the Top1-DNA cleavage complex (preventing the complex from re-ligating single-strand breaks it has induced to relieve torsional strain during DNA replication, transcription and repair processes); this leads to exposure-time dependent DNA damage and cell death [8, 17, 18, 52] |
| IRI and SN-38 undergo a reversible, pH-dependent hydrolysis between active lactone and inactive carboxylate forms; the inactive form predominates at physiological pH [8, 52] |
| nal-IRI prolongs systemic circulation of IRI (while also preserving the drug in its active lactone form within the liposome interior, protecting it from hydrolysis to the inactive form, as well as premature conversion to SN-38) and improves its distribution versus conventional IRI, with preferential targeting into tumour tissue thought to reflect EPR effect [8, 53] |
| nal-IRI showed ↑ antitumour activity versus conventional IRI (attributed to prolonging SN-38 exposure within tumours) and ↓ drug-related systemic toxicity in in vitro and in vivo studies [8]. Demonstrated moderate antitumour activity in pts with GEM-pretreated mPDAC [54] |
| PK properties |
| PKs of IRI and SN-38 released from nal-IRI described by 2-compartment model with first-order elimination [55] |
| tIRI Cmax and AUC increased with dose, while tSN-38 Cmax and AUC increased proportionally and less-than-proportionally with dose, respectively, over nal-IRI dose range 50–155 mg/m2 in pts with cancer [18] |
| 95% of IRI remains encapsulated within liposomes during circulation [17, 18] |
| Vd of tIRI of 2.6 L/m2 (vs. 138 L/m2 for conventional IRI), suggesting nal-IRI largely confined to vascular fluid [17] |
| Minimal PPB (< 0.44% of tIRI) versus moderate PPB for conventional IRI (30–68%) and high PPB for SN-38 (≈ 95%) [17] |
| Metabolism of IRI released from nal-IRI similar to that of conventional IRI. IRI is extensively metabolised by multiple enzyme systems, including carboxylesterase and UDP-glucuronosyltransferase 1A1 (UGT1A1); UGT1A1 also mediates conversion of SN-38 to inactive SN-38 glucuronide (SN-38G) [8, 17, 18, 52] |
| nal-IRI PKs apparently not impacted by UGT status [55, 56], although dosage adjustments may be warranted in pts who are homozygous for the UGT1A1*28 allele (associated with ↓ UGT1A1 enzymatic activity) [17, 18] (Sect. 4). tSN-38 Css,avg was 1.06 and 0.95 ng/mL in pts homozygous and non-homozygous for the UGT1A1*28 allele, respectivelya [17, 18] |
| Disposition of nal-IRI (and conventional IRI) not fully elucidated in humans. Urinary excretion of conventional IRI is 11–20% IRI, 3% SN-38G and < 1% SN-38. Cumulative biliary and urinary excretion of IRI, SN-38 and SN-38G in range 25–50% over 48 h period following administration of conventional IRI [17, 18] |
| CL of tIRI of 0.087 L/h/m2 (vs 13.0 L/h/m2 for conventional IRI) [17] |
| t1/2 effective of tIRI and tSN-38 of 20.8 and 40.9 h (vs. 6.07 and 11.7 h for conventional IRI) [17] |
| Special pt populations |
| No dosage adjustments needed on basis of age (i.e. in elderly pts) or sex [17, 18] |
| No dosage adjustments needed in pts with mild to moderate renal impairment (CLCR 30–89 mL/min) [17, 18]. However, insufficient data in pts with severe renal impairment (CLCR < 30 mL/min) [17, 18]; nal-IRI not recommended in these pts [17] |
| tSN-38 Css,avg ↑ 37% in pts with BL bilirubin concentration of 1–2 mg/dL versus those with BL bilirubin concentration of < 1 mg/dL; however, elevated ALT or AST had no effect on tSN-38 concentrations. No data in pts with bilirubin concentrations > 2 mg/dL [17, 18] |
| tIRI Css,avg ↓ 56% and tSN-38 Css,avg ↑ 8% in Asian (East Asian) versus Caucasian (White) pts [17, 18] |
| Potential drug interactions |
| Potential for clinically relevant drug-drug interactions when co-administered with strong CYP3A4 inducers or inhibitors, or with strong UGT1A1 inhibitors; co-administration of nal-IRI with these agents should be avoided, if possible [17, 18] |
| Co-administration with 5-fluorouracil/leucovorin did not alter PKs of tIRI or tSN-38 [17, 18] |
AUC area under the plasma concentration–time curve, BL baseline, CL clearance, CLCR creatinine CL, Cmax maximum plasma concentration, Css,avg average steady-state concentration, EPR enhanced permeability and retention, GEM gemcitabine, IRI irinotecan, mPDAC metastatic pancreatic ductal adenocarcinoma, nal-IRI liposomal IRI, PK(s) pharmacokinetic(s), PPB plasma protein binding, pt(s) patient(s), RI renal impairment, Top1 topoisomerase 1, tIRI total IRI, tSN-38 total SN-38, t1/2 effective effective plasma half-life, UDP uridine 5′-diphospho-glucuronosyltransferase, UGT UDP-glucuronosyltransferase Vd volume of distribution, ↑ increased, ↓ decreased
aIn a population PK analysis that adjusted for the lower nal-IRI dose administered to pts homozygous for the UGT1A1*28 allele [17, 18]