Phase I study assessing the safety and tolerability of barasertib (AZD1152) with low-dose cytosine arabinoside in elderly patients with AML.

INTRODUCTION: Barasertib is the pro-drug of barasertib-hydroxy-quinazoline pyrazole anilide, a selective Aurora B kinase inhibitor that has demonstrated preliminary anti-AML activity in the clinical setting. PATIENTS AND METHODS: This Phase I dose-escalation study evaluated the safety and tolerability of barasertib, combined with LDAC, in patients aged 60 years or older with de novo or secondary AML. Barasertib (7-day continuous intravenous infusion) plus LDAC 20 mg (subcutaneous injection twice daily for 10 days) was administered in 28-day cycles. The MTD was defined as the highest dose at which ≤ 1 patient within a cohort of 6 experienced a dose-limiting toxicity (DLT) (clinically significant adverse event [AE] or laboratory abnormality considered related to barasertib). The MTD cohort was expanded to 12 patients. RESULTS: Twenty-two patients (median age, 71 years) received ≥ 1 treatment cycle (n = 6, 800 mg; n = 13, 1000 mg; n = 3, 1200 mg). DLTs were reported in 2 patients (both, National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 stomatitis/mucositis; 1200 mg cohort). The most common AEs were infection (73%), febrile neutropenia (59%), nausea (50%), and diarrhea (46%). Barasertib plus LDAC resulted in an overall response rate (International Working Group criteria) of 45% (n = 10/22; according to investigator opinion). CONCLUSION: The MTD of 1000 mg barasertib in combination with LDAC in older patients with AML was associated with acceptable tolerability and preliminary anti-AML activity.

Disposition and metabolism of the specific endothelin A receptor antagonist zibotentan (ZD4054) in healthy volunteers.

Zibotentan (ZD4054) is a specific endothelin A (ET(A)) receptor antagonist that is in clinical development for the treatment of castration-resistant prostate cancer (CRPC) and has shown a promising signal for improvement in overall survival compared with placebo in a Phase II study of patients with metastatic CRPC. In this study, the pharmacokinetics, disposition and metabolism of zibotentan were evaluated following administration of a single oral dose of [(14)C]-zibotentan 15 mg to six healthy subjects. Zibotentan was rapidly absorbed, with the maximum zibotentan plasma concentration being observed 1 hour after administration. Excretion was rapid with the majority of the dose being excreted in the urine (71-94%). Total recovery of radioactivity over the 5 days of the study was high (mean 93%), with 78% of the dose being recovered within 24 hours. Concentrations of radioactivity in the plasma were similar up to 12 hours post dose, and diverged thereafter, indicating the presence of circulating metabolites. The main circulating component was zibotentan with a number of metabolites being identified in excreta. Zibotentan was well absorbed and was cleared via metabolism and urinary excretion with zibotentan-related material predominantly excreted via the urine.

An open-label, randomized, single-center, two-period, phase I, crossover study of the effect of zibotentan (ZD4054) on the pharmacokinetics of midazolam in healthy male volunteers.

BACKGROUND: Zibotentan (ZD4054) is an oral, specific endothelin A receptor antagonist presently under investigation for the treatment of hormone-resistant prostate cancer. Preclinical in vitro studies suggest that zibotentan has the potential to act as a time-dependent inhibitor of the cytochrome P450 isozyme 3A4 (CYP3A4) metabolic pathway. In clinical practice, it is likely that zibotentan will be coadministered with drugs metabolized by this pathway; the potential exists, therefore, that zibotentan-induced drug interactions could occur. OBJECTIVES: The primary objective of this study was to evaluate the effect of zibotentan on the pharmaco-kinetics of a clinically relevant dose of midazolam in healthy volunteers. Secondary objectives were to evaluate exposure to zibotentan, ensure the safety of the healthy volunteers dosed, and investigate the effect of zibotentan on the pharmacokinetics of the midazolam metabolites 1-hydroxy midazolam and 4-hydroxy midazolam. The potency of zibotentan as a CYP3A4 inhibitor was also assessed. METHODS: This was an open-label, randomized, singlecenter, 2-period, Phase I, crossover study. Volunteers were randomized in a 1:1 ratio to 1 of 2 cohorts. In cohort 1, volunteers received a single dose of midazolam 7.5 mg on day 1 (treatment A) of a 2-day study period. After a minimum 7-day washout period, volunteers received zibotentan 10 mg once daily on days 1 through 7, plus a single dose of midazolam 7.5 mg on day 6 (treatment B) of a 7-day study period. In cohort 2, volunteers received treatment B followed by treatment A, with a minimum 7-day washout period between treatments. AUC(0-infinity) and C(max) data were expressed as geometric least squares mean ratios and 90% CIs for midazolam + zibotentan:midazolam. A moderate interaction between midazolam and zibotentan was predefined to have occurred if the upper 90% CI of the ratio was >1.5. Adverse events (AEs) were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3. AE data were assessed based on information provided by the volunteer, through open-ended and nonleading verbal questions to the volunteer at each visit, and through observation by the investigational team, other care providers, or relatives. RESULTS: Six volunteers (all white) were included in each cohort (cohort 1, mean [SD] age, 48 [7] years; mean weight, 74 [6] kg; cohort 2, mean age, 51 [11] years; mean weight, 75 [13] kg). Steady-state levels of zibotentan, achieved over 7 days, increased the midazolam AUC(0-infinity) by 1.2-fold compared with midazolam alone. The upper limits of the 90% CIs for the AUC(0-infinity) and C(max) ratios were below the predefined level of 1.5 (1.37 and 1.32, respectively). Zibotentan had no apparent effect on the pharmacokinetics of 1-hydroxy midazolam and 4-hydroxy midazolam. Fatigue was reported in 11 volunteers (92%) receiving midazolam monotherapy and 10 (83%) receiving midazolam combined with zibotentan. Headache was reported in all 12 volunteers after zibotentan monotherapy. CONCLUSIONS: In this population of healthy male volunteers, once-daily zibotentan 10 mg increased the AUC(0-infinity) of midazolam 1.2-fold; however, the treatment ratio was below the predefined limit for clinical significance. Zibotentan was well tolerated when given alone or in combination with midazolam. The results indicate that once-daily zibotentan 10 mg acted as a weak inhibitor of the CYP3A4 pathway. ClinicalTrials. gov identifier: NCT00709553.

The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.

AIMS: Voriconazole is a new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers. METHODS: Two single-blind, placebo-controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg-1) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3-11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg-1 twice on day 1, then at 3 mg kg-1 twice daily on days 2-9, and once at 3 mg kg-1 on day 10. RESULTS: In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration (Cmin) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens (Cmin > 0.8 micro g ml-1). The use of a loading dose in Study B resulted in a shorter time to steady-state Cmin values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration (Cmax) 3621 and 3063 ng ml-1; areas under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) 16 535 and 13 245 ng.h ml-1, and terminal elimination phase half-lives (t1/2) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUCtau accumulation ratio 2.53-3.17, Study A) at a level that was not predictable from single-dose data. The mean concentration-time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug-related visual disturbance were reported in three subjects (Study B). CONCLUSIONS: Administration of a loading dose of 6 mg kg-1 i.v. voriconazole on the first day of treatment followed by 3 mg kg-1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.

Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety.

AIMS: Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. METHODS: Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg-1 twice daily, 4 mg kg-1 once daily, 2 mg kg-1 three times daily, or 3 mg kg-1 twice daily. Eleven subjects received 1.5 mg kg-1 three times daily, and 21 subjects were administered placebo. RESULTS: Voriconazole exhibited nonlinear (dose- and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing kel values on multiple dosing, with a consequent increase in the terminal phase t1/2. There was also notable intersubject variability in Cmax and AUCtau. The absorption of voriconazole was rapid (mean tmax= 0.9-1.7 h) after single and multiple dosing and the decline in plasma concentration-time curves after tmax was generally biphasic. By day 12, the Cmax, AUCtau, tmax, and t1/2 values for the 3 mg kg-1 twice-daily group were 2356 ng ml-1, 11 170 ng.h ml-1, 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for Cmax and AUCtau, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg-1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of Cmin values together with statistical analyses of Cmax and AUCtau values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens (Cmin > 0.8 micro g ml-1). Voriconazole was well tolerated: most treatment-related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. CONCLUSIONS: The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg-1 twice daily.

Metabolism and disposition of the antihypertensive agent moxonidine in humans.

The metabolism and pharmacokinetics of moxonidine, a potent central-acting antihypertensive agent, were studied in four healthy subjects after a single oral administration of approximately 1 mg (approximately 60 muCi) of [(14)C(3)]moxonidine. Moxonidine was rapidly absorbed, with peak plasma concentration achieved between 0.5 to 2 h postdose. The maximal plasma concentration and the area under the curve of unchanged moxonidine are lower than those determined for radioactivity, indicating presence of circulating metabolite(s). The total recovery of radiocarbon over 120 h ranged from 99.6 to 105.2%, with 92.3 to 103.3% of the radioactivity excreted in the urine and only 1.9 to 7.3% of the dose excreted in the feces. Thus, renal elimination represented the principal route of excretion of radioactivity. Metabolites of moxonidine were identified in urine and plasma samples by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry. Oxidation of moxonidine on the methyl group or on the imidazoline ring resulted in the formation of hydroxymethyl moxonidine, hydroxy moxonidine, dihydroxy moxonidine, and dehydrogenated moxonidine. Metabolite profiling results indicated that parent moxonidine was the most abundant component in the urine. The dehydrogenated moxonidine was the major urinary metabolite as well as the major circulating metabolite. Moxonidine also underwent phase II metabolism, generating a cysteine conjugate. In summary, moxonidine is well absorbed after oral administration. The major clearance pathway for moxonidine in humans is via renal elimination. Furthermore, seven metabolites were identified with three metabolites unique to humans.

Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval.

AIMS: To investigate the pharmacokinetics and pharmacodynamics of dofetilide 1 mg twice daily continuously for 24 days compared with intermittent single dose treatments. METHODS: A randomized, single-blinded, placebo-controlled, parallel-group, multiple-dose study design was utilized. Healthy male volunteer subjects were randomized into three groups. Group 1 received dofetilide 1.0 mg twice daily for 23 days and once on day 24. Group 2 received matching placebo capsules under the same regimen as group 1. Group 3 received a single dose of dofetilide 1.0 mg on days 1, 5, 10, 17, and 24 with identical placebo capsules administered at all other times to match the dosing pattern of the other groups. RESULTS: Continuous administration of dofetilide resulted in the achievement of steady-state concentrations by day 5. Pharmacokinetic parameters following intermittent treatment showed no accumulation. Maximum daily QTc interval (mean +/- s.e. mean) increased in response to continuous twice-daily dofetilide from baseline (373 +/- 5) to day 2 (453 +/- 9) but thereafter decreased slightly, but not beyond day 5, by which time the mean maximum QTc was 440 +/- 7 ms. In contrast, single doses of dofetilide in the intermittently treated group led to reproducible increases in QTc. Thus mean (+/- s.e. mean) maximum QTc increased from a baseline of 387 +/- 7-467 +/- 14, 467 +/- 18, 469 +/- 14 and 458 +/- 10 ms on days 5, 10, 17 and 24, respectively. In view of the pharmacokinetic accumulation on continuous dosing, the attenuation of responsiveness is best represented by the slope of the QTc vs plasma concentration relationship. In the continuously treated group, an initial decrease in the value of the mean slope between day 1 (14.2 +/- 1.7 ms/ng ml(-1)) and day 5 (9.1 +/- 0.8 ms/ng ml(-1)) did not progress beyond day 5. The mean difference in slopes (95% CI) between the intermittent and continuously treated groups were 4.4 (1.3, 7.4) on day 5, 4.9 (1.6, 8.2) on day 10, 5.2 (1.1, 9.2) on day 17 and 4.4 (0.4, 8.4) on day 24. CONCLUSIONS: With continuous twice-daily administration the QT interval responsiveness to dofetilide is greater after the first dose than it is at steady state. After day 5 the relationship between dofetilide plasma concentration and its QT interval effect is predictable and stable over time.