Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol
Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistance...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116300907 |
| _version_ | 1818308928206798848 |
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| author | Anne Schlegel Cyril Buhler Flavien Devun Céline Agrario Saïk Urien François Lokiec Jian-Sheng Sun Marie Dutreix |
| author_facet | Anne Schlegel Cyril Buhler Flavien Devun Céline Agrario Saïk Urien François Lokiec Jian-Sheng Sun Marie Dutreix |
| author_sort | Anne Schlegel |
| collection | DOAJ |
| description | Increased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5′-end to facilitate its cellular uptake. We report here the preclinical pharmacokinetic and toxicology studies of subcutaneous coDbait administration in rodents and monkeys. Maximum plasma concentration occurred between 2 to 4 hours in rats and at 4 hours in monkeys. Increase in mean AUC0–24h was linear with dose reaching 0.5 mg·h/ml for the highest dose injected (32 mg) for both rats and monkeys. No sex-related differences in maximum concentration (Cmax) nor AUC0–24h were observed. We extrapolated these pharmacokinetic results to humans as the subcutaneous route has been selected for evaluation in clinical trials. Tri-weekly administration of coDbait (from 8 to 32 mg per dose) for 4 weeks was overall well tolerated in rats and monkeys as no morbidity/mortality nor changes in clinical chemistry and histopathology parameters considered to be adverse effects have been observed. |
| first_indexed | 2024-12-13T07:22:04Z |
| format | Article |
| id | doaj.art-11fc835f0c2b438bb9f57017e2f55d24 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-13T07:22:04Z |
| publishDate | 2012-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-11fc835f0c2b438bb9f57017e2f55d242022-12-21T23:55:23ZengElsevierMolecular Therapy: Nucleic Acids2162-25312012-01-011C10.1038/mtna.2012.27Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to CholesterolAnne Schlegel0Cyril Buhler1Flavien Devun2Céline Agrario3Saïk Urien4François Lokiec5Jian-Sheng Sun6Marie Dutreix7DNA Therapeutics, Evry, FranceDNA Therapeutics, Evry, FranceDNA Therapeutics, Evry, FranceDNA Therapeutics, Evry, FranceUniversité Paris Descartes, Sorbonne Paris Cité, Paris, FranceInstitut Curie, Hôpital René Huguenin, Saint-Cloud, FranceDNA Therapeutics, Evry, FranceInstitut Curie, Centre de Recherche, Centre National de Recherche Scientifique (CNRS) UMR3347, Institut National de la Santé et de Recherche Médicale (INSERM) U1021, Université Paris-Sud 11, Centre Universitaire, Orsay, FranceIncreased DNA repair activity in cancer cells is one of their primary mechanisms of resistance to current radio- and chemotherapies. The molecule coDbait is the first candidate in a new class of drugs that target the double-strand DNA break repair pathways with the aim of overcoming these resistances. coDbait is a 32-base pair (bp) double-stranded DNA molecule with a cholesterol moiety covalently attached to its 5′-end to facilitate its cellular uptake. We report here the preclinical pharmacokinetic and toxicology studies of subcutaneous coDbait administration in rodents and monkeys. Maximum plasma concentration occurred between 2 to 4 hours in rats and at 4 hours in monkeys. Increase in mean AUC0–24h was linear with dose reaching 0.5 mg·h/ml for the highest dose injected (32 mg) for both rats and monkeys. No sex-related differences in maximum concentration (Cmax) nor AUC0–24h were observed. We extrapolated these pharmacokinetic results to humans as the subcutaneous route has been selected for evaluation in clinical trials. Tri-weekly administration of coDbait (from 8 to 32 mg per dose) for 4 weeks was overall well tolerated in rats and monkeys as no morbidity/mortality nor changes in clinical chemistry and histopathology parameters considered to be adverse effects have been observed.http://www.sciencedirect.com/science/article/pii/S2162253116300907nucleic acidcholesterol-conjugatepreclinical study |
| spellingShingle | Anne Schlegel Cyril Buhler Flavien Devun Céline Agrario Saïk Urien François Lokiec Jian-Sheng Sun Marie Dutreix Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol Molecular Therapy: Nucleic Acids nucleic acid cholesterol-conjugate preclinical study |
| title | Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol |
| title_full | Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol |
| title_fullStr | Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol |
| title_full_unstemmed | Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol |
| title_short | Pharmacokinetics and Toxicity in Rats and Monkeys of coDbait: A Therapeutic Double-stranded DNA Oligonucleotide Conjugated to Cholesterol |
| title_sort | pharmacokinetics and toxicity in rats and monkeys of codbait a therapeutic double stranded dna oligonucleotide conjugated to cholesterol |
| topic | nucleic acid cholesterol-conjugate preclinical study |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116300907 |
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