Top

Cancer Chemotherapy and Pharmacology

Published in:

01-10-2019 | Pharmacokinetics | Original Article

Species-specific optimization of PEG~SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft

Authors: Shaun D. Fontaine, Byron Hann, Ralph Reid, Gary W. Ashley, Daniel. V. Santi

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2019

Abstract

Purpose

Optimal efficacy of a macromolecular prodrug requires balancing the rate of drug release with the rate of prodrug elimination. Since circulating macromolecules have different elimination rates in different species, a prodrug optimal for one species will likely not be for another. The objectives of this work were (a) to develop an approach to optimize pharmacokinetics of a PEG~SN-38 prodrug in a particular species, (b) to use the approach to predict the pharmacokinetics of various prodrugs of SN-38 in the mouse and human, and (c) to develop a PEG~SN-38 conjugate that is optimized for mouse tumor models.

Methods

We developed models that describe the pharmacokinetics of a drug released from a prodrug by the relationship between the rates of drug release and elimination of the prodrug. We tested the model by varying the release rate of SN-38 from PEG~SN-38 conjugates in the setting of a constant prodrug elimination rate in the mouse. Finally, we tested the antitumor efficacy of a PEG~SN-38 optimized for the mouse.

Results

Optimization of a PEG~SN-38 prodrug was achieved by adjusting the rate of SN-38 release such that the ratio of t_1/2,β of released SN-38 to the t_1/2 of prodrug elimination was 0.2–0.8. Using this approach, we could rationalize the efficacy of previous PEGylated SN-38 prodrugs in the mouse and human. Finally, a mouse-optimized PEG~SN-38 showed remarkable antitumor activity in BRCA1-deficient MX-1 xenografts; a single dose gave tumor regression, suppression, and shrinkage of massive tumors.

Conclusions

The efficacy of a macromolecular prodrug can be optimized for a given species by balancing the rate of drug release from the carrier with the rate of prodrug elimination.

Available only for authorised users

Doses of PEG~SN-38 refer to the amount of conjugated SN-38 delivered.

Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7(8):2182–2194PubMed

Slatter JG, Schaaf LJ, Sams JP, Feenstra KL, Johnson MG, Bombardt PA, Cathcart KS, Verburg MT, Pearson LK, Compton LD, Miller LL, Baker DS, Pesheck CV, Lord RS 3rd (2000) Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I.V. infusion of [(14)C]CPT-11 in cancer patients. Drug Metab Dispos 28(4):423–433PubMed

Santi DV, Schneider EL, Ashley GW (2014) Macromolecular prodrug that provides the irinotecan (CPT-11) active-metabolite SN-38 with ultralong half-life, low C(max), and low glucuronide formation. J Med Chem 57(6):2303–2314. https://doi.org/10.1021/jm401644v CrossRefPubMed

Maeda H, Tsukigawa K, Fang J (2016) A retrospective 30 years after discovery of the enhanced permeability and retention effect of solid tumors: next-generation chemotherapeutics and photodynamic therapy-problems, solutions, and prospects. Microcirculation 23(3):173–182. https://doi.org/10.1111/micc.12228 CrossRefPubMed

Zander SA, Sol W, Greenberger L, Zhang Y, van Tellingen O, Jonkers J, Borst P, Rottenberg S (2012) EZN-2208 (PEG-SN38) overcomes ABCG2-mediated topotecan resistance in BRCA1-deficient mouse mammary tumors. PLoS One 7(9):e45248. https://doi.org/10.1371/journal.pone.0045248 CrossRefPubMedPubMedCentral

Sapra P, Kraft P, Mehlig M, Malaby J, Zhao H, Greenberger LM, Horak ID (2009) Marked therapeutic efficacy of a novel polyethylene glycol-SN38 conjugate, EZN-2208, in xenograft models of B-cell non-Hodgkin’s lymphoma. Haematologica 94(10):1456–1459. https://doi.org/10.3324/haematol.2009.008276 CrossRefPubMedPubMedCentral

Garrett CR, Bekaii-Saab TS, Ryan T, Fisher GA, Clive S, Kavan P, Shacham-Shmueli E, Buchbinder A, Goldberg RM (2013) Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Cancer 119(24):4223–4230. https://doi.org/10.1002/cncr.28358 CrossRefPubMed

Matsumura Y (2011) Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect. Adv Drug Deliv Rev 63(3):184–192. https://doi.org/10.1016/j.addr.2010.05.008 CrossRefPubMed

Ri M, Suzuki K, Iida S, Hatake K, Chou T, Taniwaki M, Watanabe N, Tsukamoto T (2017) A phase I/II study for dose-finding, and to investigate the safety, pharmacokinetics and preliminary efficacy of NK012, an SN-38-incorporating macromolecular polymeric micelle, in patients with multiple myeloma. Intern Med. https://doi.org/10.2169/internalmedicine.9567-17 CrossRefPubMedPubMedCentral

10.

Hoch U, Staschen CM, Johnson RK, Eldon MA (2014) Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models. Cancer Chemother Pharmacol 74(6):1125–1137. https://doi.org/10.1007/s00280-014-2577-7 CrossRefPubMedPubMedCentral

11.

Jameson GS, Hamm JT, Weiss GJ, Alemany C, Anthony S, Basche M, Ramanathan RK, Borad MJ, Tibes R, Cohn A, Hinshaw I, Jotte R, Rosen LS, Hoch U, Eldon MA, Medve R, Schroeder K, White E, Von Hoff DD (2013) A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors. Clin Cancer Res 19(1):268–278. https://doi.org/10.1158/1078-0432.CCR-12-1201 CrossRefPubMed

12.

Santi DV, Schneider EL, Reid R, Robinson L, Ashley GW (2012) Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates. Proc Natl Acad Sci USA 109(16):6211–6216. https://doi.org/10.1073/pnas.1117147109 CrossRefPubMed

13.

Henise J, Hearn BR, Ashley GW, Santi DV (2015) Biodegradable tetra-PEG hydrogels as carriers for a releasable drug delivery system. Bioconjug Chem 26(2):270–278. https://doi.org/10.1021/bc5005476 CrossRefPubMed

14.

Schneider EL, Robinson L, Reid R, Ashley GW, Santi DV (2013) beta-eliminative releasable linkers adapted for bioconjugation of macromolecules to phenols. Bioconjug Chem 24(12):1990–1997. https://doi.org/10.1021/bc4002882 CrossRefPubMed

15.

Houghton PJ, Morton CL, Tucker C, Payne D, Favours E, Cole C, Gorlick R, Kolb EA, Zhang W, Lock R, Carol H, Tajbakhsh M, Reynolds CP, Maris JM, Courtright J, Keir ST, Friedman HS, Stopford C, Zeidner J, Wu J, Liu T, Billups CA, Khan J, Ansher S, Zhang J, Smith MA (2007) The pediatric preclinical testing program: description of models and early testing results. Pediatr Blood Cancer 49(7):928–940. https://doi.org/10.1002/pbc.21078 CrossRefPubMed

16.

Sapra P, Zhao H, Mehlig M, Malaby J, Kraft P, Longley C, Greenberger LM, Horak ID (2008) Novel delivery of SN38 markedly inhibits tumor growth in xenografts, including a camptothecin-11-refractory model. Clin Cancer Res 14(6):1888–1896. https://doi.org/10.1158/1078-0432.CCR-07-4456 CrossRefPubMed

17.

Kurzrock R, Goel S, Wheler J, Hong D, Fu S, Rezai K, Morgan-Linnell SK, Urien S, Mani S, Chaudhary I, Ghalib MH, Buchbinder A, Lokiec F, Mulcahy M (2012) Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies. Cancer 118(24):6144–6151. https://doi.org/10.1002/cncr.27647 CrossRefPubMed

18.

Koizumi F, Kitagawa M, Negishi T, Onda T, Matsumoto S, Hamaguchi T, Matsumura Y (2006) Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors. Cancer Res 66(20):10048–10056. https://doi.org/10.1158/0008-5472.CAN-06-1605 CrossRefPubMed

19.

Patnaik A, Papadopoulos KP, Tolcher AW, Beeram M, Urien S, Schaaf LJ, Tahiri S, Bekaii-Saab T, Lokiec FM, Rezai K, Buchbinder A (2013) Phase I dose-escalation study of EZN-2208 (PEG-SN38), a novel conjugate of poly(ethylene) glycol and SN38, administered weekly in patients with advanced cancer. Cancer Chemother Pharmacol 71(6):1499–1506. https://doi.org/10.1007/s00280-013-2149-2 CrossRefPubMed

20.

Masi G, Falcone A, Di Paolo A, Allegrini G, Danesi R, Barbara C, Cupini S, Del Tacca M (2004) A phase I and pharmacokinetic study of irinotecan given as a 7-day continuous infusion in metastatic colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed. Clin Cancer Res 10(5):1657–1663CrossRef

21.

Rothenberg ML, Kuhn JG, Burris HA 3rd, Nelson J, Eckardt JR, Tristan-Morales M, Hilsenbeck SG, Weiss GR, Smith LS, Rodriguez GI et al (1993) Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11(11):2194–2204. https://doi.org/10.1200/JCO.1993.11.11.2194 CrossRefPubMed

22.

Rothenberg ML, Kuhn JG, Schaaf LJ, Rodriguez GI, Eckhardt SG, Villalona-Calero MA, Rinaldi DA, Hammond LA, Hodges S, Sharma A, Elfring GL, Petit RG, Locker PK, Miller LL, von Hoff DD (2001) Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks. Ann Oncol 12(11):1631–1641CrossRef

23.

Rouits E, Guichard S, Canal P, Chatelut E (2002) Non-linear pharmacokinetics of irinotecan in mice. Anticancer Drugs 13(6):631–635CrossRef

24.

Stewart CF, Zamboni WC, Crom WR, Houghton PJ (1997) Disposition of irinotecan and SN-38 following oral and intravenous irinotecan dosing in mice. Cancer Chemother Pharmacol 40(3):259–265. https://doi.org/10.1007/s002800050656 CrossRefPubMed

25.

Xie R, Mathijssen RH, Sparreboom A, Verweij J, Karlsson MO (2002) Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin Pharmacol Ther 72(3):265–275. https://doi.org/10.1067/mcp.2002.126741 CrossRefPubMed

26.

Zhao H, Rubio B, Sapra P, Wu D, Reddy P, Sai P, Martinez A, Gao Y, Lozanguiez Y, Longley C, Greenberger LM, Horak ID (2008) Novel prodrugs of SN38 using multiarm poly(ethylene glycol) linkers. Bioconjug Chem 19(4):849–859. https://doi.org/10.1021/bc700333s CrossRefPubMed

27.

Houghton PJ, Cheshire PJ, Hallman JD 2nd, Lutz L, Friedman HS, Danks MK, Houghton JA (1995) Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36(5):393–403. https://doi.org/10.1007/BF00686188 CrossRefPubMed

28.

Guichard S, Montazeri A, Chatelut E, Hennebelle I, Bugat R, Canal P (2001) Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: pharmacokinetic and pharmacodynamic evaluation. Clin Cancer Res 7(10):3222–3228PubMed

29.

Morton CL, Wierdl M, Oliver L, Ma MK, Danks MK, Stewart CF, Eiseman JL, Potter PM (2000) Activation of CPT-11 in mice: identification and analysis of a highly effective plasma esterase. Cancer Res 60(15):4206–4210PubMed

30.

Morton CL, Iacono L, Hyatt JL, Taylor KR, Cheshire PJ, Houghton PJ, Danks MK, Stewart CF, Potter PM (2005) Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice. Cancer Chemother Pharmacol 56(6):629–636. https://doi.org/10.1007/s00280-005-1027-y CrossRefPubMed

31.

Chabot GG (1997) Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet 33(4):245–259. https://doi.org/10.2165/00003088-199733040-00001 CrossRefPubMed

32.

Ocean AJ, Starodub AN, Bardia A, Vahdat LT, Isakoff SJ, Guarino M, Messersmith WA, Picozzi VJ, Mayer IA, Wegener WA, Maliakal P, Govindan SV, Sharkey RM, Goldenberg DM (2017) Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: safety and pharmacokinetics. Cancer 123(19):3843–3854. https://doi.org/10.1002/cncr.30789 CrossRefPubMed

33.

Boerner JL, Nechiporchik N, Mueller KL, Polin L, Heilbrun L, Boerner SA, Zoratti GL, Stark K, LoRusso PM, Burger A (2015) Protein expression of DNA damage repair proteins dictates response to topoisomerase and PARP inhibitors in triple-negative breast cancer. PLoS One 10(3):e0119614. https://doi.org/10.1371/journal.pone.0119614 CrossRefPubMedPubMedCentral

34.

Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, Wang B, Lord CJ, Post LE, Ashworth A (2013) BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res 19(18):5003–5015. https://doi.org/10.1158/1078-0432.CCR-13-1391 CrossRefPubMedPubMedCentral

Title: Species-specific optimization of PEG~SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft
Authors: Shaun D. Fontaine
Byron Hann
Ralph Reid
Gary W. Ashley
Daniel. V. Santi
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keyword: Pharmacokinetics
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03903-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 4/2019

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors

A pilot study of first-line olaratumab, doxorubicin and ifosfamide in patients with metastatic soft tissue sarcoma

Population pharmacokinetics of fedratinib in patients with myelofibrosis, polycythemia vera, and essential thrombocythemia

Pharmacokinetics and safety of erlotinib and its metabolite OSI-420 in infants and children with primary brain tumors

Nanoparticle albumin-bound paclitaxel: a big nano for the treatment of gastric cancer

Population pharmacokinetics of trabectedin in adolescent patients with cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer