Abstract
Abstract 5066
Aim:
Currently, it is not fully elucidated how ethnicity influences the pharmacokinetic (PK) profile of anagrelide. The aim of this retrospective analysis was to compare the PK profile of anagrelide in healthy Japanese and Caucasian volunteers.
Methods:
Retrospective analyses were conducted on two phase I studies with anagrelide: a study of healthy Japanese volunteers (study A) and healthy Caucasian volunteers (study B). In study A, healthy males received anagrelide (0. 5, 1. 0 or 2. 0 mg) or placebo under fasted or fed conditions. In study B, healthy volunteers received a single 1. 0 mg dose under fasted conditions. PK analysis of anagrelide was conducted as part of these original studies. The calculated PK parameters were maximum plasma concentration (Cmax), time for Cmax (tmax), area under plasma concentration from time zero to time infinity (AUC0-inf) and terminal-phase disposition half-life (t1/2).
Results:
PK data for healthy Japanese males (n=6) aged 20–35 years, with a body weight of 50–80 kg and receiving 1. 0 mg anagrelide in study A were compared with PK data for healthy Caucasian volunteers (n=10, 8 male and 2 female) aged 40–69 years, with a body weight of 56–100 kg and receiving 1. 0 mg anagrelide in study B. Single-dose PK parameters under fasted conditions across both studies are shown in the Table for anagrelide and its metabolite 2-amino-5, 6-dichloro-3, 4-dihydroquinazilone (RL603).
Compared with Caucasian volunteers, healthy Japanese volunteers exhibited similar Cmax, and slightly higher AUC0-inf for anagrelide. In contrast, Cmax and AUC0-inf for the inactive metabolite RL603 were considerably higher in Japanese volunteers. Five adverse events (AEs) were reported in 3 volunteers in study A and 9 AEs in 3 volunteers in study B: 5 and 3 AEs, respectively, were considered possibly related to treatment. The most commonly reported AEs were headache and nausea. No serious AEs were observed during either study.
Discussion:
The PK analyses conducted on volunteers receiving a single 1 mg dose showed that under fasted conditions anagrelide was rapidly absorbed with similar Cmax and tmax between Japanese and Caucasian volunteers. The slightly higher AUC0-inf of anagrelide in Japanese volunteers may be an artefact of the high inter-subject variability, which is common with drugs such as anagrelide that exhibit extensive pre-systemic metabolism. It remains unclear as to why Japanese volunteers had higher RL603 Cmax and AUC0-inf values than Caucasian individuals.
Analyses of PK data from studies of patients with essential thrombocythaemia (ET) (Okamoto et al, manuscript in preparation; Besses et al, Int J Clin Pharmacol Ther, 2012, manuscript in press) noted that compared with non-Japanese patients, Japanese patients also had slightly higher Cmax (2. 81±0. 99 vs 5. 88±4. 58 ng/mL) and AUC (6. 8±2. 4 vs 16. 3±6. 5 ng·h/mL) for anagrelide. Overall, across both ethnic groups, patients with ET had higher anagrelide exposures than healthy volunteers. However, within the Japanese population, Cmax and AUC0-inf values were only slightly higher in patients with ET than in volunteers, which may suggest that the PK exposures of anagrelide did not differ substantially between these Japanese cohorts.
Conclusion:
Anagrelide exhibits high inter- and intra-subject variability, which makes it difficult to compare PK exposures in studies with small populations. The PK data across all these studies indicate that the first-pass metabolism of anagrelide may be marginally lower in the Japanese population than in Caucasian individuals; however these differences do not translate to different clinical outcomes with respect to the observed treatment-related AEs associated with anagrelide therapy. Despite the small differences observed in metabolism of anagrelide, it is well tolerated in Japanese populations and ethnicity-specific dosing regimens are not required.
Disclosures:
Kanakura: Shire: Consultancy. Hodgson:Shire Pharmaceutical Development Ltd: Employment. Troy:Shire Development, LLC: Employment. Abhyankar:Shire Pharmaceuticals: Employment. Smith:Shire Pharmaceuticals: Employment. Besses:Shire: Honoraria; Novartis: Honoraria.
WS06-3 Administration of ELX-02 to healthy volunteers demonstrates dose-linearity and proportionality as well as low inter-subject variability
