Pharmacokinetics of the Oral Selective CXCR2 Antagonist AZD5069: A Summary of Eight Phase I Studies in Healthy Volunteers

Marie Cullberg, Cecilia Arfvidsson, Bengt Larsson, Anna Malmgren, Patrick Mitchell, Ulrika Wählby Hamrén, Heather Wray, Marie Cullberg, Cecilia Arfvidsson, Bengt Larsson, Anna Malmgren, Patrick Mitchell, Ulrika Wählby Hamrén, Heather Wray

Abstract

Objective: The aim of this study was to summarise the pharmacokinetic findings from eight phase I studies in healthy volunteers given oral AZD5069, a selective small-molecule CXCR2 antagonist.

Methods: 240 healthy volunteers across eight phase I studies received single (0.1-200 mg) or multiple once- or twice-daily (10-120 mg) oral AZD5069 as solution, suspension, capsules or tablets. Pharmacokinetics were evaluated using non-compartmental analysis methods.

Results: AZD5069 was rapidly absorbed (time to maximum concentration ~ 2 h) under fasting conditions. A high-fat, high-calorie meal delayed and reduced the peak plasma AZD5069 concentration (Cmax) by 50%, but total exposure (AUC) was unchanged (fed:fasting geometric mean ratio 90% confidence interval within 0.80-1.25). The plasma concentration of AZD5069 declined with an initial half-life of 4 h and terminal half-life of 11 h. Steady-state plasma concentrations were achieved within 2-3 days and accumulation was ~ 1.1-fold with twice-daily dosing. Systemic exposure was approximately proportional to dose. Intra- and inter-subject variability in AUC was 3-11 and 29-64%, respectively. Less than 5% of the AZD5069 dose was excreted as parent drug in the urine. Elderly subjects had 39% higher AZD5069 AUC and 21% higher Cmax than younger adults. Japanese subjects had similar or slightly higher exposure to AZD5069 than Caucasian subjects. Co-administration with ketoconazole resulted in 2.1-fold higher AUC and 1.6-fold higher Cmax. All formulations had similar bioavailability.

Conclusions: AZD5069 demonstrated predictive linear pharmacokinetics with low intra- and moderate inter-subject variability and no major influences from ethnicity, age, food or formulation. Half-life data indicated suitability for twice-daily dosing. CLINICALTRIALS.

Gov identifiers: NCT00953888, NCT01051505, NCT01083238, NCT01100047, NCT01332903, NCT01480739, NCT01735240, NCT01989520.

Conflict of interest statement

Funding

All studies were sponsored and funded by AstraZeneca. David Candlish, of InScience Communications, Tattenhall, UK, provided editorial and medical writing assistance, which was funded by AstraZeneca.

Conflicts of Interest

All authors are full-time permanent employees of AstraZeneca.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the studies.

Figures

Fig. 1
Fig. 1
Boxplots of dose-normalised AUC (area under plasma concentration–time curve) by dose and study (see Table 1 for acronyms) following: a single-dose; and b repeated-dose (bid) administration of AZD5069
Fig. 2
Fig. 2
Arithmetic mean plasma AZD5069 concentration–time profiles following a single oral administration of 0.1–200 mg (SAD study). Inserted graph shows the same data on a logarithmic y-axis scale
Fig. 3
Fig. 3
AUC and Cmax versus dose following single-dose (a) and repeated-dose (bid) (b) administration of AZD5069. Red symbols represent data from the SAD study and blue symbols from the MAD study. Lines and equations are based on regression analysis (see Sect. 2.6 for details). AUC area under plasma concentration–time curve, Cmax peak plasma concentration
Fig. 4
Fig. 4
Geometric mean (± SD) plasma concentration versus time profiles of AZD5069 when administered alone on Day 1 and in combination with ketoconazole on Day 3 of a 5-day treatment period with ketoconazole 400 mg daily (DDI study) on a linear scale (a) and a log scale (b)

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