Bioequivalence and Pharmacokinetics of Low-Dose Anagrelide 0.5 mg Capsules in Healthy Volunteers

Objectives: Anagrelide, an oral phosphodiesterase-3 inhibitor, is widely used to treat thrombocythemia. Evaluating the bioequivalence of low-dose formulations is essential to ensure consistent therapeutic outcomes while minimizing adverse effects, particularly cardiovascular events such as palpitations, tachycardia, and potential arrhythmias, which are known concerns with anagrelide therapy. This study aimed to compare the pharmacokinetics and bioavailability of a newly developed 0.5 mg anagrelide capsule with the reference product under fasting conditions y. Materials and Methods: In a randomized, open-label, two-period crossover design, 42 healthy Turkish male volunteers received a single oral dose (0.5 mg) of either the test or reference anagrelide capsule, with a seven-day washout period between treatments. Serial blood samples were collected over a 10 h post-dose period. Plasma concentrations of anagrelide were analyzed using a validated LC-MS/MS method. Key pharmacokinetic parameters (AUC₀-t, AUC₀-∞, Cmax, tmax, λz, t½, AUC-extrapol) were calculated and subjected to ANOVA-based bioequivalence analysis. Results: A total of 42 healthy male participants (mean age: 34.1 ± 8.9 years; BMI: 25.7 ± 2.9 kg/m²) completed the study without any protocol deviations. Pharmacokinetic analysis demonstrated that the test and reference formulations of anagrelide 0.5 mg were bioequivalent. The mean AUC₀-t values were 4533.3 ± 2379.3 pg·h/mL for the test formulation and 4515.0 ± 2392.3 pg·h/mL for the reference (p > 0.05), while the mean Cmax values were 1997.1 ± 1159.2 pg/mL and 2061.3 ± 1054.0 pg/mL, respectively (p > 0.05). The 90% confidence intervals for the geometric mean ratios of AUC₀-t (94.09-104.75%), Cmax (85.62-104.03%), and AUC₀-∞ (94.50-105.10%) were all within the predefined bioequivalence range of 80-125%, with corresponding point estimates of 99.28%, 94.37%, and 99.66%, respectively. Intra-subject variability was 14.68% for AUC₀-t and 26.98% for Cmax. No statistically significant differences were observed between the formulations for any of the primary or secondary pharmacokinetic parameters (ANOVA, p > 0.05). Regarding safety, 13 treatment-emergent adverse events were reported in 11 participants (26.2%), mostly moderate-intensity headaches, all of which resolved without complications. No serious adverse events occurred, confirming the tolerability of both formulations. Conclusions: This study demonstrates that the test and reference formulations of low-dose 0.5 mg anagrelide are bioequivalent under fasting conditions, with similar safety and tolerability profiles. The findings support the use of the test product as a safe and effective alternative.