Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor
Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of variou...
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Published in | Clinical cancer research Vol. 10; no. 3; pp. 909 - 915 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
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Philadelphia, PA
American Association for Cancer Research
01.02.2004
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Abstract | Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these
MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate
the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics.
Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until
tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy.
Results: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest
and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2–3 arthralgias
and myalgias were noted 2–3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency
and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K i for MMPs 2 and 9 were achieved at all of the dose levels.
Conclusions: Doses of 5–10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration
of at least 3 months and achieves trough plasma concentrations 10–100-fold greater than the K i ( in vitro inhibition constant) for the targeted MMPs (2 and 9). |
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AbstractList | Abstract
Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics.
Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy.
Results: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2–3 arthralgias and myalgias were noted 2–3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the Ki for MMPs 2 and 9 were achieved at all of the dose levels.
Conclusions: Doses of 5–10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10–100-fold greater than the Ki (in vitro inhibition constant) for the targeted MMPs (2 and 9). Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics. Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy. Results: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2–3 arthralgias and myalgias were noted 2–3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K i for MMPs 2 and 9 were achieved at all of the dose levels. Conclusions: Doses of 5–10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10–100-fold greater than the K i ( in vitro inhibition constant) for the targeted MMPs (2 and 9). Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics. Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy. The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2-3 arthralgias and myalgias were noted 2-3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K(i) for MMPs 2 and 9 were achieved at all of the dose levels. Doses of 5-10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10-100-fold greater than the K(i) (in vitro inhibition constant) for the targeted MMPs (2 and 9). |
Author | Geoff Yeun Jill Stuart-Smith Kim Binger Neil Clendeninn George Wilding Linda Paradiso Mary Dixon Kenneth R. Hande Mary Collier Donna Alberti |
Author_xml | – sequence: 1 givenname: Kenneth R surname: HANDE fullname: HANDE, Kenneth R organization: Vanderbilt University School of Medicine, Nashville, Tennessee, United States – sequence: 2 givenname: Mary surname: COLLIER fullname: COLLIER, Mary organization: Agouron Pharmaceuticals, A Pfizer Company, La Jolla, California, United States – sequence: 3 givenname: Linda surname: PARADISO fullname: PARADISO, Linda organization: Agouron Pharmaceuticals, A Pfizer Company, La Jolla, California, United States – sequence: 4 givenname: Jill surname: STUART-SMITH fullname: STUART-SMITH, Jill organization: Agouron Pharmaceuticals, A Pfizer Company, La Jolla, California, United States – sequence: 5 givenname: Mary surname: DIXON fullname: DIXON, Mary organization: Agouron Pharmaceuticals, A Pfizer Company, La Jolla, California, United States – sequence: 6 givenname: Neil surname: CLENDENINN fullname: CLENDENINN, Neil organization: Agouron Pharmaceuticals, A Pfizer Company, La Jolla, California, United States – sequence: 7 givenname: Geoff surname: YEUN fullname: YEUN, Geoff organization: Agouron Pharmaceuticals, A Pfizer Company, La Jolla, California, United States – sequence: 8 givenname: Donna surname: ALBERTI fullname: ALBERTI, Donna organization: University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, United States – sequence: 9 givenname: Kim surname: BINGER fullname: BINGER, Kim organization: University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, United States – sequence: 10 givenname: George surname: WILDING fullname: WILDING, George organization: University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, United States |
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Cites_doi | 10.1093/jnci/89.17.1260 10.1634/theoncologist.3-4-271 10.1093/jnci/93.3.178 10.1111/j.1749-6632.1999.tb07689.x 10.1038/348699a0 10.1016/B978-012545090-4/50013-6 10.1073/pnas.94.4.1402 10.1200/JCO.2000.18.5.1135 10.1634/theoncologist.4-6-509 10.1517/14728214.2.1.205 10.1053/sonc.2002.31528 10.1016/S0092-8674(00)81235-0 10.1038/370061a0 10.1074/jbc.270.10.5331 10.1023/A:1005722729132 10.1146/annurev.cb.09.110193.002545 10.1159/000468614 10.1038/nrc745 |
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Keywords | Peptidases Enzyme Phase I trial Enzyme inhibitor Hydrolases Metalloendopeptidases Pharmacokinetics Prinomastat |
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Snippet | Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these
MMPs has been postulated to... Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block... Abstract Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been... |
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SubjectTerms | Adult Aged Aged, 80 and over Alkaline Phosphatase - metabolism Antineoplastic agents Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Area Under Curve Biological and medical sciences Disease Progression Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - therapeutic use Female Humans Kinetics Male Matrix Metalloproteinase Inhibitors Maximum Tolerated Dose Medical sciences Middle Aged Organic Chemicals - pharmacokinetics Organic Chemicals - pharmacology Organic Chemicals - therapeutic use Pharmacology. Drug treatments Time Factors Tumors |
Title | Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor |
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