title: Exposure-response relationship of the synthetic epothilone sagopilone in a peripheral neurotoxicity rat model.
abstract: Since peripheral sensory neuropathy is the major, clinically relevant side effect of sagopilone we investigated the general and peripheral neurotoxicity of sagopilone administered intravenously with different doses (1.2 and 2.4 mg/kg) and schedules in 48 Wistar rats and we performed in parallel a pharmacokinetic/pharmacodynamic (PK/PD) study. A trend toward a different peripheral neurotoxicity could be assessed after 2 weeks of treatment (bolus > 30-min infusion > 3-h infusion) with both doses of sagopilone. Although sagopilone concentrations in peripheral nerve tissue above 100 ng/g were associated with a reduction in nerve conduction velocity (NCV), a clear dose-dependence of this reduction on the level of systemic exposure to sagopilone was not observed. The PK/PD evaluation revealed no consistent effect of the infusion duration on serum PK parameters or the PD read-out NCV. Sagopilone concentrations in brain, sciatic nerve, liver, and kidney were higher after bolus compared to infusion, but there were no influence of infusion duration on these concentrations. No correlation between sagopilone concentrations in any organ/tissue with NCV changes was detected. This study evidences that the PD of sagopilone is not the main determinant of the onset and severity of sagopilone-induced peripheral neurotoxicity in the investigated clinically-relevant dose range, thus indicating that further investigation might identify neuronal-specific mechanisms of action able to drive a focused strategy to prevent peripheral neurotoxicity without reducing the anticancer effectiveness of the epothilones.
authors.affiliation: Department of Neuroscience and Biomedical Technologies-DNTB, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, MB, Italy. alessia.chiorazzi@unimib.it
authors.forename: Alessia
authors.initials: A
authors.lastname: Chiorazzi
authors.forename: Joachim
authors.initials: J
authors.lastname: Höchel
authors.forename: Detlef
authors.initials: D
authors.lastname: Stöckigt
authors.forename: Annalisa
authors.initials: A
authors.lastname: Canta
authors.forename: Valentina Alda
authors.initials: VA
authors.lastname: Carozzi
authors.forename: Cristina
authors.initials: C
authors.lastname: Meregalli
authors.forename: Federica
authors.initials: F
authors.lastname: Avezza
authors.forename: Luca
authors.initials: L
authors.lastname: Crippa
authors.forename: Barbara
authors.initials: B
authors.lastname: Sala
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ceresa
authors.forename: Norberto
authors.initials: N
authors.lastname: Oggioni
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
mesh_terms: D000818:Animals; D019540:Area Under Curve; D052160:Benzothiazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D003627:Data Interpretation, Statistical; D034261:Epothilones / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D007262:Infusions, Intravenous; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000473:pathology
chemical_list: D052160:Benzothiazoles; D034261:Epothilones; C530494:sagopilone