Dataset Information

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

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.

SUBMITTER: Cullberg M

PROVIDER: S-EPMC5995788 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Cullberg Marie M Arfvidsson Cecilia C Larsson Bengt B Malmgren Anna A Mitchell Patrick P Wählby Hamrén Ulrika U Wray Heather H

Drugs in R&D 20180601 2

<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>AZD5069 was ...[more]

PMID: 29856004

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Project description:BACKGROUND:Excessive neutrophil presence and activation is important in a number of acute and chronic inflammatory diseases. The CXCR2 chemokine receptor is important in controlling the extravasation and activation of neutrophils. Selective antagonism of the CXCR2 receptor is a potential approach to reducing neutrophil migration and activation. Danirixin, is a small molecule, CXCR2 antagonist being evaluated as a potential anti-inflammatory medicine. METHODS:(1) First time in human (FTIH) double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and pharmacodynamics of single ascending and repeat oral doses of danirixin in healthy male subjects; (2) single-dose study of age, gender, food, and proton-pump inhibitor effects on the pharmacokinetics of danirixin in healthy adult subjects; and placebo-controlled study of the pharmacokinetics of danirixin in healthy elderly subjects. RESULTS:There were no serious adverse events and no adverse events considered to be of clinical relevance. There were no withdrawals due to adverse events. Systemic exposure following single doses of danirixin 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg increased with increasing dose. Engagement of pharmacology was demonstrated as inhibition of ex-vivo CXCL1-induced CD11b expression on peripheral blood neutrophils when compared to placebo (approximately 50% for 50 mg and 100 mg danirixin, and 72% at 200 mg). There was a 37% decrease in Cmax and a 16% decrease in AUC (0-?) following administration of danirixin in the presence of food. Cmax also decreased by 65% when danirixin 100 mg was administered following omeprazole 40 mg once daily for 5 days. The AUC (0-?) and Cmax were 50% lower in elderly subjects compared with younger subjects. CONCLUSION:The dose-dependent inhibition of agonist-induced neutrophil activation following single and repeated once daily oral administration of danirixin suggests that this CXCR2 antagonist may have benefit in neutrophil-predominant inflammatory diseases. Co-administration with food, gastric acid reducing agents, and variable exposure in the elderly have important clinical implications that need to be taken into consideration in subsequent clinical evaluations. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: NCT01209052 and NCT01209104.

Project description:Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 ?g · h/ml and 2.56 to 20.2 ?g/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (?600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.).

Dataset Information

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

Publications

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

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