Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

Centro Integral Oncológico Clara Campal Madrid Spain

Chang Gung Memorial Hospital Kaohsiung Branch Kaohsiung Taiwan

Chang Gung Memorial Hospital Linkou Branch Taoyuan Taiwan

Hospital General de Elche Elche Spain

JNSZ Megyei Hetényi Géza Kórház Rendelöintézet Szolnok Hungary

Korea University Guro Hospital Seoul South Korea

Mayo Clinic Rochester Minnesota USA

Merrimack Pharmaceuticals Inc Cambridge Massachusetts USA

National Institute of Oncology Budapest Hungary

Onkologicka Klinika Lekarska Fakulta Univerzity Palackeho a Fakultni Nemocnice Olomouc Czech Republic

Samsung Medical Center Sungkyunkwan University School of Medicine Seoul South Korea

Westmead Hospital Westmead Australia

Zobrazit více v PubMed

Gabizon, A. & Martin, F. Polyethylene glycol‐coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs 54(suppl.4), 15–21 (1997). PubMed

Greish, K. Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting. Methods Mol. Biol. 624, 25–37 (2010). PubMed

Wang‐Gillam, A. et al Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine‐based therapy (NAPOLI‐1): a global, randomised, open‐label, phase 3 trial. Lancet 387, 545–547 (2016). PubMed

Xie, R. , Mathijssen, R.H. , Sparreboom, A. , Verweij, J. & Karlsson, M.O. Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin. Pharmacol. Ther. 72, 265–275 (2002). PubMed

Gupta, E. et al Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res. 54, 3723–3725 (1994). PubMed

Fujita, K. & Sparreboom, A. Pharmacogenetics of irinotecan disposition and toxicity: a review. Curr. Clin. Pharmacol. 5, 209–217 (2010). PubMed

Roy, A.C. et al A randomized phase II study of PEP02 (MM‐398), irinotecan or docetaxel as a second‐line therapy in patients with locally advanced or metastatic gastric or gastro‐oesophageal junction adenocarcinoma. Ann. Oncol. 24, 1567–1573 (2013). PubMed

Ramanathan, R.K.K. et al Lesion characterization with ferumoxytol MRI in patients with advanced solid tumors and correlation with treatment response to MM398, nanoliposomal irinotecan (nalIRI). 26th EORTC‐NCI‐AACR Symposium on Molecular Targets and Cancer Therapeutics Symposium. Barcelona, Spain; 2014. Abstract 261.

Chabot, G.G. Clinical pharmacokinetics of irinotecan. Clin. Pharmacokinet. 33, 245–259 (1997). PubMed

Chang, T.C. et al Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients. Cancer Chemother. Pharmacol. 75, 579–586 (2015). PubMed PMC

Tsai, C.S. , Park, J.W. & Chen, L.T. Nanovector‐based therapies in advanced pancreatic cancer. J. Gastrointest. Oncol. 2, 185–194 (2011). PubMed PMC

Chan, L.‐T. et al Phase I study of biweekly liposome irinotecan (PEP02, MM‐398) in metastatic colorectal cancer after first line oxaliplatin‐based chemotherapy. J. Clin. Oncol. 30 (2012).

Gastonguay, M.R. et al Missing data in model‐based pharmacometric applications: points to consider. J. Clin. Pharmacol. 50, 63S–674S (2010). PubMed

United States Pharmacopeia and National Formulary (USP 39‐NF 34) . Irinotecan HCl. Rockville, MD: United States Parmacopeia Convention; 2010.

Bergstrand, M. & Karlsson, M.O. Handling data below the limit of quantification in mixed effect models. AAPS J. 11, 371–380 (2009). PubMed PMC

Wang, Y. Derivation of various NONMEM estimation methods. J. Pharmacokinet. Pharmacodyn. 34, 575–593 (2007). PubMed

Kalra, A.V. et al Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. Cancer Res. 74, 7003–7013 (2014). PubMed

Raykar, V.S. et al On Ranking in Survival Analysis: Bounds on the Concordance Index (Cambridge, MA, MIT Press; 2008).

Camptosar (package insert). New York, NY: Pfizer Injectables; 2014.

Onivyde (package insert). Cambridge, MA: Merrimack Pharmaceuticals; 2015.

Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer. 6, 789–802 (2006). PubMed

Slatter, J.G. et al Pharmacokinetics, metabolism, and excretion of irinotecan (CPT‐11) following I.V. infusion of [(14)C]CPT‐11 in cancer patients. Drug Metab. Dispos. 28, 423–433 (2000). PubMed

Wallace, B.D. et al Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–835 (2010). PubMed PMC

La‐Beck, N.M. et al Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother. Pharmacol. 69, 43–50 (2012). PubMed

Hoskins, J.M. , Goldberg, R.M. , Qu, P. , Ibrahim, J.G. & McLeod, H.L. UGT1A1*28 genotype and irinotecan‐induced neutropenia: dose matters. J. Natl. Cancer Inst. 99, 1290–1295 (2007). PubMed

Iyer, L. et al UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J. 2, 43–47 (2002). PubMed

Stewart, C.F. et al UGT1A1 promoter genotype correlates with SN‐38 pharmacokinetics, but not severe toxicity in patients receiving low‐dose irinotecan. J. Clin. Oncol. 25, 2594–2600 (2007). PubMed