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

• Published in: Drugs in R&D Vol. 18; no. 2; pp. 149 - 159
• Main Authors: Cullberg, Marie, Arfvidsson, Cecilia, Larsson, Bengt, Malmgren, Anna, Mitchell, Patrick, Wählby Hamrén, Ulrika, Wray, Heather
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2018; Springer Nature B.V
• Subjects: Adolescent; Adult; Age; Age Factors; Aged; Asthma; Bioavailability; Biological Availability; Capsules - pharmacokinetics; Carbohydrates; Chronic obstructive pulmonary disease; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Drug dosages; Drug Interactions; Ethnicity; Female; Food; Food-Drug Interactions; Healthy Volunteers; Humans; Internal Medicine; Investigations; Ketoconazole - pharmacology; Male; Males; Medicine; Medicine & Public Health; Metabolism; Middle Aged; Molecules; NCT; NCT00953888; NCT01051505; NCT01083238; NCT01100047; NCT01332903; NCT01480739; NCT01735240; NCT01989520; Neutrophils; Original; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Pyrimidines - urine; Solutions - pharmacokinetics; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Sulfonamides - urine; Suspensions - pharmacokinetics; Tablets - pharmacokinetics; White people; Young Adult
• ISSN: 1174-5886; 1179-6901; 1179-6901
• DOI: 10.1007/s40268-018-0236-x

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 ( C max ) 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 C max 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 C max . 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.