WO2002083063A2 - Method of improving systemic exposure of subcutaneously administered therapeutic proteins - Google Patents
Method of improving systemic exposure of subcutaneously administered therapeutic proteins Download PDFInfo
- Publication number
- WO2002083063A2 WO2002083063A2 PCT/US2001/051617 US0151617W WO02083063A2 WO 2002083063 A2 WO2002083063 A2 WO 2002083063A2 US 0151617 W US0151617 W US 0151617W WO 02083063 A2 WO02083063 A2 WO 02083063A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- therapeutic protein
- systemic exposure
- administration
- systemic
- day
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- a therapeutic delivered iv takes longer to administer when compared to sc administration, and as a result is a more costly therapy.
- sc administration is not without drawbacks. For example, there are physical limitations on the maximum dose which can be delivered at the injection site.
- the systemic exposure of, e.g., an anti-RSN monoclonal antibody administered sc is comparable to that administered iv and the bioavailability is not affected by the amount of the therapeutic protein administered (see, e.g., Davis et al., Drug Met. Disp., 23:1028-1036 (1995)).
- the extent of absorption i.e., systemic exposure
- the amount of the therapeutic protein that enters the blood stream see e.g., Davis and Bugelski, Drug Delivery, 5: 95-100 (1998).
- systemic diseases such as cancer
- the present invention relates generally to the field of therapeutic proteins, and dosing regimens that enhance systemic exposure and thus pharmacologic effectiveness of therapy.
- the present invention provides an improved method for treating diseases by increasing the systemic response to a therapeutic protein which binds to specific receptors and/or endogenous proteins present in the lymphatic system. More specifically, the present invention provides an improved method for treating diseases by increasing the systemic exposure to interleukin-18 (IL-18) which binds to specific receptors and/or endogenous proteins present in the lymphatic system.
- IL-18 interleukin-18
- Fig 1 - Figure 1 is a graph showing mean plasma IL-18 concentration versus time profiles following an intravenous dose (0.1, 1 or 10 mg/kg) to Cynomolgus monkeys.
- Fig 2(a) - Figure 2a is a graph showing mean plasma IL-18 concentrations versus time profiles following single and repeat intravenous administration (10 mg kg/day for 5 days).
- Fig 2(b) - Figure 2b is a graph showing mean plasma IL-18 concentrations versus time profiles following single and repeat intravenous administration (30 mg/kg/day for 5 days).
- Fig 2(c) - Figure 2c is a graph showing mean plasma D -18 concentrations versus time profiles following single and repeat intravenous administration (75 mg/kg/day for 5 days).
- Fig 3(a) - Figure 3a is a graph showing mean plasma IL-18 concentration versus time profiles following single and repeat subcutaneous administration (10 mg/kg/day for 4 days).
- Fig 3(b) - Figure 3b is a graph showing mean plasma IL-18 concentration versus time profiles following single and repeat intravenous administration (10 mg/kg/day for 5 days).
- Fig 4 - Figure 4 is a graph showing mean (SD) bioavailability of IL-18 following single and repeat subcutaneous administration.
- IL-18 therapeutic proteins
- systemic exposure to a therapeutic protein, such as IL-18 is increased more than expected based on the single subcutaneous dose pharmacokinetic profile and more than expected based on the single and multiple intravenous dose pharmacokinetic profile and allows for the improved treatment of systemic diseases, such as cancer, bacterial infections, viral infections, fungal infections and parasitic infections.
- a saturating subcutaneous dose (or doses) of a therapeutic protein such as IL-18
- subsequent administrations also given subcutaneously, result in at least 50% greater systemic exposure than an equivalent subcutaneous dose administered without the benefit of the saturating dose or doses.
- the systemic exposure of such therapeutic protein is increased by at least 2-fold, more preferably it is increased by at least 4-fold.
- the relative systemic exposure of a single sc dose compared to a single iv dose, i.e., the apparent absolute bioavailability is approximately 15% in Cynomolgus monkeys (compare Tables 1 and 2, day 1 AUC 0 . 2 , 10 mg/kg).
- Figure 1 shows mean plasma IL-18 concentration versus time profiles following a single intravenous dose (0.1, 1 or 10 mg/kg) to monkeys.
- Plasma concentrations declined in a bi-phasic manner after intravenous administration with a steep initial phase characterized by a half-life of ⁇ 5 min.
- the terminal disposition phase had a long half-life of -24 h but the concentrations during this phase were low.
- Due to a relatively rapid clearance from blood following iv administration iv administered IL-18 does not accumulate with multiple dosing, and when IL-18 is administered daily, the systemic exposure over 24 h (AUC 0-2 ) is approximately the same from day to day (Table 1, day 1 vs day 5 AUC 0-2 ).
- Figures 2a- 2c show mean plasma IL-18 concentraton versus time profiles following single and repeat intravenous administration (10-75 mg/kg).
- the daily systemic exposure increased in a dose proportional manner between doses of 10 and 75 mg/kg following single and repeat iv dosing, indicating linear pharmacokinetics of IL-l ⁇ " (see also Table 1).
- FIGS. 3a and 3b show the mean plasma EL- 18 concentration versus time profiles following single and repeat subcutaneous or intravenous administration (10 mg kg dose). After subcutaneous administration, the maximum plasma concentrations were observed at ⁇ 0.5 hours indicating that IL-18 is rapidly absorbed from the sc injection site.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002580868A JP2004532843A (en) | 2000-11-03 | 2001-11-01 | Method for improving systemic exposure of therapeutic protein for subcutaneous administration |
AU2001297793A AU2001297793A1 (en) | 2000-11-03 | 2001-11-01 | Method of improving systemic exposure of subcutaneously administered therapeutic proteins |
EP01273890A EP1353622A4 (en) | 2000-11-03 | 2001-11-01 | Method of improving systemic exposure of subcutaneously administered therapeutic proteins |
US10/415,738 US20040042999A1 (en) | 2001-11-01 | 2001-11-01 | Method of improving systemic exposure of subcutaneously administered therapeutic proteins |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24561800P | 2000-11-03 | 2000-11-03 | |
US60/245,618 | 2000-11-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002083063A2 true WO2002083063A2 (en) | 2002-10-24 |
WO2002083063A3 WO2002083063A3 (en) | 2003-08-28 |
Family
ID=22927410
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/051617 WO2002083063A2 (en) | 2000-11-03 | 2001-11-01 | Method of improving systemic exposure of subcutaneously administered therapeutic proteins |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1353622A4 (en) |
JP (1) | JP2004532843A (en) |
AU (1) | AU2001297793A1 (en) |
WO (1) | WO2002083063A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2059253A2 (en) * | 2006-09-14 | 2009-05-20 | The Trustees Of The University Of Pennsylvania | Modulation of regulatory t cells by human il-18 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4847325A (en) * | 1988-01-20 | 1989-07-11 | Cetus Corporation | Conjugation of polymer to colony stimulating factor-1 |
EP0712913A1 (en) * | 1994-11-17 | 1996-05-22 | Canon Kabushiki Kaisha | Ink-jet color recording process and ink set therefor |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999007851A1 (en) * | 1997-08-07 | 1999-02-18 | Toray Industries, Inc. | CANINE INTERLEUKIN 18, CANINE INTERLEUKIN 1β CONVERTASE, DNA SEQUENCES ENCODING THE SAME, PROCESS FOR PRODUCING INTERLE UKIN 18, AND REMEDIES FOR CANINE IMMUNOLOGICAL DISEASES |
-
2001
- 2001-11-01 EP EP01273890A patent/EP1353622A4/en not_active Withdrawn
- 2001-11-01 JP JP2002580868A patent/JP2004532843A/en active Pending
- 2001-11-01 WO PCT/US2001/051617 patent/WO2002083063A2/en active Application Filing
- 2001-11-01 AU AU2001297793A patent/AU2001297793A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4847325A (en) * | 1988-01-20 | 1989-07-11 | Cetus Corporation | Conjugation of polymer to colony stimulating factor-1 |
EP0712913A1 (en) * | 1994-11-17 | 1996-05-22 | Canon Kabushiki Kaisha | Ink-jet color recording process and ink set therefor |
Non-Patent Citations (5)
Title |
---|
DATABASE MEDLINE [Online] January 1997 MICALLEF: 'IN VIVO ANTITUMOR EFFECTS OF MURINE INTERFERON-GAMMA-INDUCING FA TOR/INTERLEUKIN-18 IN MICE BEARING SYGENEIC METH A SARCOMA MALIGNANT ASCITES', XP002964696 Database accession no. 97220033 & CANCER IMMUNOLOGY IMMUNOTHERAPY vol. 43, no. 6, 01 January 1997, pages 361 - 367 * |
DATABASE MEDLINE [Online] TANAKA-KATAOKA: 'IN VIVO ANTIVIRAL EFFECT OF INTERLEUKIN 18 IN A MOUSE OF VACCINIA VIRUS INFECTION', XP002964671 Database accession no. 99365045 & CYTOKINE vol. 11, no. 8, August 1999, pages 593 - 599 * |
MASTROENI: 'INTERLEUKIN 18 CONTRIBUTES TO HOST RESISTANCE AND GAMMA INTERFERON PRODUCTION IN MICE INFECTED WITH VIRULENT SALMONELLA TYPHIMURIUM' INFECTION AND IMMUNITY vol. 67, no. 2, February 1999, pages 478 - 483, XP002964670 * |
OHKUSU: 'POTENTIALITY OF INTERLEUKIN-18 AS A USEFUL REAGENT FOR TREATMENT AND PREVENTION OF LEISHMANIA MAJOR INFECTION' INFECTION AND IMMUNITY vol. 68, no. 5, May 2000, pages 2449 - 2456, XP002964672 * |
See also references of EP1353622A2 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2059253A2 (en) * | 2006-09-14 | 2009-05-20 | The Trustees Of The University Of Pennsylvania | Modulation of regulatory t cells by human il-18 |
EP2059253A4 (en) * | 2006-09-14 | 2011-09-14 | Univ Pennsylvania | Modulation of regulatory t cells by human il-18 |
US8679471B2 (en) | 2006-09-14 | 2014-03-25 | The Trustees Of The Univesity Of Pennsylvania | Modulation of regulatory T cells by human IL-18 |
Also Published As
Publication number | Publication date |
---|---|
EP1353622A2 (en) | 2003-10-22 |
WO2002083063A3 (en) | 2003-08-28 |
AU2001297793A1 (en) | 2002-10-28 |
EP1353622A4 (en) | 2005-06-22 |
JP2004532843A (en) | 2004-10-28 |
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