title: A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers.
abstract: AZD5438 is a novel cyclin-dependent kinase inhibitor with preclinical pharmacodynamic (PD) activity against a range of human tumour xenografts. A first-in-man tolerability and pharmacokinetic (PK) study involving single ascending doses of AZD5438 was conducted in healthy male volunteers. Single oral doses ranging from 5 to 160 mg were studied in 23 subjects. Dose-limiting nausea and vomiting occurred at 160 mg in the absence of prophylactic anti-emetics. The maximum tolerated dose (the dose at which no dose limiting toxicities occurred) was 80 mg, and the maximum well-tolerated dose was deemed to be 60 mg, which was associated with grade1 nausea but no vomiting. Tmax occurred between 0.5-3.0 hours with a relatively short plasma half-life of 1-3 h. The coefficient of variation of exposures within a dose level ranged from 22-71% (AUC) to 16-63% (C max), and exposure increased with increasing dose across the doses studied. <1% of the parent compound was excreted in the urine, suggesting metabolism as the major clearance mechanism. The maximum well-tolerated dose and a number of doses below this level will be taken forward into a PD study using normal tissue biomarkers in humans to determine proof of AZD5438's action on the cell cycle. The pharmacokinetic profile of AZD5438 determined within this study will be used to guide the time-points for PD analysis within the planned PD study.
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK .
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Dominic
authors.initials: D
authors.lastname: Smethurst
authors.forename: Jim
authors.initials: J
authors.lastname: Growcott
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Barrass
authors.forename: John R
authors.initials: JR
authors.lastname: Foster
authors.forename: Salvatore
authors.initials: S
authors.lastname: Febbraro
authors.forename: Helen
authors.initials: H
authors.lastname: Swaisland
authors.forename: Andrew
authors.initials: A
authors.lastname: Hughes
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000633:toxicity*; D012016:Reference Values; D012449:Safety
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011743:Pyrimidines; C521840:AZD5438; D018844:Cyclin-Dependent Kinases