Current Issue : January-March Volume : 2026 Issue Number : 1 Articles : 5 Articles
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....
Background: Epinephrine is currently the only vasopressor recommended during neonatal cardiopulmonary resuscitation (CPR). Rapid vasopressor administration is critical during CPR; however, establishing vascular access can take several minutes and requires extensive skills and/or training. The intramuscular (IM) route provides rapid drug administration and does not require special skills, training, or equipment. We aimed to compare various doses of IM epinephrine to intravascular (IV) epinephrine in a healthy neonatal piglet model. Method: Fifteen newborn piglets (1–3 days of age) underwent anesthesia, intubation via a tracheostomy, and randomization to 0.02 mg/kg IM epinephrine, 0.1 mg/kg IM epinephrine, or 0.02 mg/kg IV epinephrine. Hemodynamic and cardiac function parameters were continuously recorded throughout the experiment. Blood was collected prior to drug administration and throughout the experiment for pharmacokinetic and pharmacodynamic analysis. Results: Dose-dependent changes in hemodynamic and cardiac function parameters were observed following IM epinephrine administration. Greater changes were observed with 0.1 mg/kg IM epinephrine, while there were little to no changes with 0.02 mg/kg IM epinephrine. Pharmacokinetic parameters were not different between 0.02 mg/kg IV epinephrine or 0.1 mg/kg IM epinephrine. Conclusions: IM epinephrine dose of 0.1 mg/kg was more effective in producing systemic hemodynamic and cardiac function changes compared to the lower IM dose 0.02 mg/kg....
Buntanetap is an orally bioavailable small molecule that has been shown to improve cognitive function in patients with Alzheimer’s and Parkinson’s diseases and holds promise for use in other neurodegenerative conditions. Until now, a crystalline anhydrate (Form A) has been used in preclinical and clinical studies. However, a novel dihydrate crystal (Form B) was recently discovered, offering improved solid-state stability without compromising its absorption, systemic exposure, and metabolism. We sought to evaluate the pharmacokinetic (PK) profile of Form B and compare it to the well-characterized PK profile of Form A in a series of studies conducted in mice, dogs, and humans. Our data revealed that although the two forms are distinct and do not interconvert, they exhibit comparable PK profiles both within and across species. Consistent with previous reports, Form A and Form B alike reached fast peak plasma concentrations (<2 h), demonstrated efficient partitioning into brain tissue, and were fully cleared by 12 h post-dose. Furthermore, metabolic profiling showed that both forms produced identical PK profiles for the primary metabolites, N1- and N8-norbuntanetap, confirming that Form B retains the established metabolic characteristics of Form A. These findings support the continued development of Form B for future clinical use, as it combines enhanced solid-state stability with a preserved PK profile essential for buntanetap’s therapeutic efficacy....
Faldaprevir (FDV) is a novel NS3/NS4A inhibitor used in the treatment of hepatitis C infection in an interferon-free regimen. This study evaluated the safety, tolerability, and pharmacokinetics of FDV following a single dose in healthy male subjects and assessed the effect of food on FDV bioavailability. In the placebo-controlled, randomized, single-blind, single-increasing-dose part of the study (Part 1), 64 healthy male subjects were randomized to receive FDV in PEG/ TRIS/meglumine solution at one of eight dose levels (4–1,200 mg, n = 6 per dose group) or placebo (n = 2 per dose group). In Part 2, the effect of food on the relative bioavailability (rBA) of 480 mg FDV in solution was evaluated in an openlabel, crossover comparison, with and without a high-fat breakfast, in an additional 10 subjects (8 FDV and 2 placebo). Following single doses of 4–1,200 mg FDV, geometric mean (gMean) Cmax and AUC0-inf were 3.57–16500 ng/mL and 254–402000 h*ng/mL, respectively, displaying more than dose-proportional increases in exposure. FDV was slowly absorbed, with gMean t1/2 and median tmax of 15.5–39.2 h and 4.0–14.0 h, respectively; both were dose dependent. The urinary excretion of FDV was less than 0.1% of the dose. A high-fat breakfast increased systemic exposure to FDV in solution by 14%. FDV was generally well tolerated; subjects who experienced adverse events (AEs) recovered without sequelae, and no serious AEs were reported. Indirect (unconjugated) bilirubin of >3.0 mg/dL was observed in two subjects at 480 mg and five subjects at 1,200 mg. In conclusion, at single doses of 4–1,200 mg in healthy male subjects, FDV showed dose-dependent pharmacokinetics and was generally considered safe and well tolerated. Food had no clinically relevant effect on the rBA of FDV....
Aim: To investigate the pharmacokinetics effects of a middle cerebral artery occlusion (MCAO) model on senkyunolide I (SEI) in pseudo germ-free rats after oral co-administration of Chuanxiong and warfarin. Methods: Rats were divided randomly into WC_H, WS_H, WC_HF, WS_HF, WC, WS, WC_F, and WS_F groups (W, warfarin; C, Chuanxiong; S, SEI; H, rats without an MCAO operation; F, pseudo germ-free). Pseudo germ-free rats were orally administered ciprofloxacin hydrochloride (50 mg/kg, twice a day) for 3 consecutive days, and the MCAO operation was carried out on the third day. Chuanxiong (10 g/kg) or SEI (7.5 mg/kg) and warfarin sodium (0.5 mg/kg) were orally administered only once on the fourth day. The plasma concentrations of SEI were determined by UPLC-MS/MS. Stool samples were collected for gut microbiota analyses. The coronal thin slices of the brain were dyed with triphenyl- 2H-tetrazolium chloride. Results: Compared to the WC_H group, the AUC0-t and Cmax of the WC group increased 2.08- and 1.79-fold (P < 0.001), respectively. Compared with the WS_H group, the AUC0-t and Cmax of the WS group decreased by 6.24% and 22.64% (P < 0.001), respectively. Compared to the WC_HF group, the AUC0-t and t1/2z of the WC_F group decreased by 60.95% and 35.26% (P < 0.01), respectively. Compared with the WS_HF group, the AUC0-t and Cmax of the WS_F group decreased by 2.87% and 8.54% (P < 0.001), respectively. Compared to the WC_H group, the AUC0-t and Cmax of the WC_HF group increased by 85.03% and 82.48% (P < 0.001), respectively. Compared with the WS_H group, the AUC0-t and Cmax of the WS_HF group increased 1.40-and 2.43-fold (P < 0.001), respectively. Compared to the WC group, the AUC0-t and t1/2z of the WC_F group decreased by 45.81% and 79.44% (P < 0.001), respectively. Compared with the WS group, the AUC0-t and t1/2z of the WS_F group decreased by 35.86% and 79.74% (P < 0.001), respectively. Conclusion: Both the MCAO operation and the pseudo germ-free condition significantly changed the pharmacokinetics characteristics of SEI after oral co-administration with warfarin and Chuanxiong or SEI. It is a promising way to understand the potential pharmacokinetics of herb–drug interactions from the angle of the gut microbiota....
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