Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors.

PURPOSE: Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m(2) in the 6-hour IVS, and from 250 mg/m(2) in the 3-hour IVS, were studied. RESULTS: Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m(2) for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m(2) or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients. CONCLUSION: Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m(2) infused over 6 hours on days 1, 8, and 15 every 28 days.

Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone.

INTRODUCTION: Luteinizing hormone-releasing hormone (LHRH) agonists (e.g., triptorelin) reduce ovarian estrogen production in premenopausal women with hormone-sensitive breast cancer. Aromatase inhibitors (e.g., exemestane) inhibit extraovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist. METHODS: Healthy premenopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once daily for 8 weeks, from day 1 to day 56. The primary objective was to evaluate the effect of T +/- EX on estradiol (E(2)) suppression by comparing the AUC(day 36-57 )for the 2 treatments. Secondary objectives included evaluation of estrone (E(1)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety. RESULTS: Twenty-eight (14 in each arm) were evaluable for efficacy and PK. Mean plasma estrogen levels (AUC(day 36-57)) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 vs. 54.0 pg d/ml [-62%; P < 0.05], and 38.9 vs. 198.0 pg d/ml [-80%; P < 0.01] for E(2) and E(1), respectively). Coadministration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T. Both treatments were well tolerated. CONCLUSIONS: Coadministration of T and EX resulted in greater estrogen suppression than when T was given alone. These findings could translate into improved clinical outcomes for premenopausal breast cancer patients receiving LHRH agonists.

A predictive model for exemestane pharmacokinetics/pharmacodynamics incorporating the effect of food and formulation.

AIMS: Exemestane (Aromasin) is an irreversible aromatase inactivator used for the treatment of postmenopausal women with advanced breast cancer. The objective of this study was to evaluate the effect of formulation comparing a sugar-coated tablet (SCT) with a suspension and food on the pharmacokinetics (PK) and pharmacodynamics (PD) with respect to plasma estrone sulphate (E1S) concentrations of exemestane, using a PK/PD approach. METHODS: This was an open, three-period, randomized, crossover study. Twelve healthy postmenopausal women received single oral doses of 25 mg exemestane as a SCT after fasting or food and as a suspension after fasting. Exemestane and E1S concentrations were determined before and up to 14 days after drug administration. Population analysis was performed in two steps: (i) a compartmental PK model was selected incorporating the effect of food and formulation; (ii) conditional on the PK model, a PD model was developed employing indirect response models. Model selection was performed using standard statistical tests. Validation and assessment of the predictive capability of the selected model was performed using real test data sets obtained from the literature. RESULTS: A three-compartment model with first-order elimination rate best described exemestane disposition (k12 0.454, k21 0.158, k13 0.174, k31 0.016 and k 0.738 h(-1)). Absorption was described by a mono-exponential function [ka 2.3 (SCT after fasting), 1.1 (SCT after food) and 7.6 h(-1) (suspension); lag time 0.2 h]. The PD model assumed that E1S plasma concentrations are determined by a zero-order synthesis rate (6.5 pg ml(-1) h(-1)) and a first-order elimination constant (0.032 h(-1)). Exemestane inhibited E1S synthesis with a C50 value of 22.1 pg ml(-1). The mean population estimates were used to simulate the administration of different doses of the drug (0.5, 1, 2.5, 5 and 25 mg day(-1)). The model predictions were in agreement with historical data. CONCLUSIONS: Exemestane absorption is influenced by the formulation of the drug and by food, but its disposition is independent of both. PK differences do no translate into clinically important differences in the PD. The PK/PD model developed was able to predict successfully the response to different doses and administration schedules with respect to oestrogen suppression.

The effects of degree of hepatic or renal impairment on the pharmacokinetics of exemestane in postmenopausal women.

PURPOSE: Two studies were conducted to compare the pharmacokinetics and tolerability of exemestane in postmenopausal subjects with various degrees of impairment of hepatic or renal function with those in healthy postmenopausal subjects. METHODS: All subjects were postmenopausal females. In study 1, nine subjects had normal hepatic function (Child-Pugh grade A), and nine had moderately (grade B) and eight severely (grade C) impaired hepatic function. In study 2, six subjects had normal renal function, and six moderately (creatinine clearance, CrCL, 30-60 ml/min per 1.73 m(2)) and seven severely (CrCL <29 ml/min per 1.73 m(2)) impaired renal function. Each subject took a single oral dose of 25 mg exemestane. Samples of plasma (to 168 h after dosing) and urine (to 72 h in study 1, or 96 h in study 2) were taken for pharmacokinetic analysis. Safety and tolerability were assessed by monitoring vital signs, laboratory safety tests, ECG and adverse events. RESULTS: Exposure to exemestane was increased two- to threefold in patients with hepatic impairment. Thus, the geometric mean AUC(0- infinity ) values were 41.71 (90% CI 32.2 to 54.0), 99.02 (76.5 to 128.2) and 118.59 ng.h/ml (90.2 to 156.0) in healthy subjects, and in patients with moderate and severe hepatic impairment, respectively ( P<0.01). C(max) also increased twofold. Compared with healthy subjects, patients with hepatic impairment had lower apparent oral clearance and apparent volume of distribution of exemestane. Renal impairment was also associated with two- to threefold increases in AUC(0- infinity ): 34.64 (90% CI 23.9 to 50.2), 94.10 (64.9 to 136.4) and 65.52 ng.h/ml (46.5 to 92.4) in healthy subjects, and in patients with moderate and severe hepatic impairment, respectively ( P<0.05). C(max) did not change significantly. Apparent oral clearance was directly correlated with CrCL ( r(2)=0.43). Exemestane was tolerated well, with no safety concerns. CONCLUSIONS: Oral clearance of exemestane was reduced in the presence of significant hepatic or renal disease. However, in view of the relatively large safety margin and the mild nature of the side effects of exemestane, the therapeutic implications of these changes in pharmacokinetics are considered minor and of no clinical significance.