Integrative population pharmacokinetic and pharmacodynamic dose finding approach of the new camptothecin compound namitecan (ST1968). (3rd June 2015)

• Record Type: Journal Article
• Authors: Joerger, M.; Hess, D.; Delmonte, A.; Gallerani, E.; Fasolo, A.; Gianni, L.; Cresta, S.; Barbieri, P.; Pace, S.; Sessa, C.
• Is Part Of: British journal of clinical pharmacology. Volume 80:Number 1(2015:Jul.)
• Page Start: 128
• Page End: 138
• Publication Date: 2015-06-03
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12583
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12583-sec-0001" sec-type="section"> <title>Aims</title> <p>Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development.</p> </sec> <sec id="bcp12583-sec-0002" sec-type="section"> <title>Methods</title> <p>Plasma concentration–time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1, 8) (<italic>n</italic> = 34), once every 3 weeks (D1) (<italic>n</italic> = 29) and on 3 consecutive days (D1–3) (<italic>n</italic> = 27). A linear three compartment PK model was coupled to a semiphysiological PD‐model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations.</p> </sec> <sec id="bcp12583-sec-0003" sec-type="section"> <title>Results</title> <p>Clearance was estimated to be 0.15 l h<sup>–1</sup>, with a long terminal half‐life of 48 h. Body surface area was not associated with clearance, supporting flat‐dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration–time curve (AUC) and the percentage drop of neutrophils (<italic>r</italic><sup>2</sup> = 0.51, <italic>P</italic> < 10<sup>−4</sup>) or thrombocytes (<italic>r</italic><sup>2</sup> = 0.49, <italic>P</italic> < 10<sup>−4</sup>). With a target for haematological dose‐limiting toxicity of <20%, the recommended dose was defined as 12.5 mg for the D1, 8 regimen, 23 mg for the once every 3 week regimen and 7 mg for the D1–3 regimen.</p> </sec> <sec id="bcp12583-sec-0004" sec-type="section"> <title>Conclusion</title> <p>This is the first integrated population PK–PD analysis of the new hydrophilic topoisomerase I inhibitor namitecan, that is currently undergoing early clinical development. A distinct relationship was found between drug exposure and haematological toxicity, supporting flat‐dosing once every 3 weeks as the most adequate dosing regimen.</p> </sec> </abstract>