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.

Cyclin-dependent kinase inhibitors as potential targeted anticancer agents

“…Cyclin dependent kinases (CDKs) promote progression through the cell cycle. CDKs are positively regulated by cyclins and negatively by CDK inhibitors (p 15,16,18,19,21,27,57 ). Other kinases such as Aurora, Mps1 and Bub are also critical in chromosome segregation probably due to redundancy of CDKs in the cell and cyclin E may partner with another CDK target when CDK2 is not available [2,14].…”

Development of Cell-Cycle Inhibitors for Cancer Therapy

“…In a phase i study in healthy volunteers, the drug was found to have a relatively short half-life of 1-3 hours 57,58 . Nevertheless, pd effects were demonstrated; the drug led to statistically significant reductions in the ratio phospho-pRb /total pRb detected at 1.5 hours post-dose, but the effect disappeared at 6 hours post-dose.…”

AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

“…Phase I clinical studies revealed a welltolerated agent at up to 80 mg administered as single oral doses. The dose-limiting adverse events were nausea and vomiting (49). A further, previously reported phase I clinical study, in which the pharmacodynamic activity of AZD5438 was evaluated (23), showed that the ratio of phospho-pRb/ total pRb was significantly reduced 1.5 hours after 40 and 80 mg AZD5438 compared with placebo.…”

“…5 This model was adapted and combined with early human pharmacokinetic data (see ref. 49) to predict pRb response in buccal samples from healthy volunteers in the pharmacodynamic study described above (23). The closeness of the prediction from the model to the observed data suggested similarities in biomarker response to pRb between human xenograft cells implanted in nude mice and human buccal cells in healthy volunteers.…”