Bioequivalence and Relative Bioavailability of a Multiparticulate Apixaban Formulation Administered Intact or Dispersed in Yogurt

Technical Summary: Bioequivalence and Relative Bioavailability of a Multiparticulate Apixaban Formulation

Problem Statement
Apixaban, a widely used oral direct factor Xa inhibitor for thromboembolic disorders, is frequently prescribed to older adults and stroke survivors who often suffer from dysphagia (swallowing difficulties). Conventional tablet administration in these populations can lead to medication avoidance or necessitate manipulation, such as crushing tablets and dispersing them in liquids or soft foods. However, tablet crushing introduces procedural variability, potential drug loss due to retention in crushing devices, and inconsistent dose recovery. Furthermore, the interaction between crushed tablets and administration vehicles (e.g., food) may alter drug dissolution and absorption. There is a clinical need for alternative dosage forms that facilitate administration without the need for crushing while maintaining pharmacokinetic (PK) reliability.

Methodology
The investigation comprised two randomized, open-label, two-treatment, two-sequence crossover pharmacokinetic studies conducted in healthy participants, alongside an in vitro handling assessment.

• Study 1 (Bioequivalence): Compared the investigational apixaban 5 mg multiparticulate pellet formulation (administered as an intact capsule) against the reference apixaban 5 mg tablet (Eliquis®) under fasting conditions.
• Study 2 (Relative Bioavailability): Compared the pellet formulation administered as an intact capsule versus dispersed in 15 g of yogurt (with 240 mL water) under fasting conditions.
• Study Population: 36 healthy adults were enrolled in each study.
• PK Analysis: Blood samples were collected up to 72 hours post-dose. Plasma apixaban concentrations were quantified using validated UPLC–MS/MS methods. Primary endpoints were the geometric mean ratios (GMR) of maximum concentration ($C_{max}$) and area under the concentration-time curve ($AUC_t$), with bioequivalence defined as the 90% confidence interval (CI) falling within 80.00–125.00%.
• Handling Assessment: An in vitro study involving nine operators compared preparation time and dose recovery between opening the pellet capsule and crushing the reference tablet (with and without mortar rinsing).

Key Results

• Bioequivalence (Study 1): The pellet formulation administered as an intact capsule demonstrated bioequivalence to the reference tablet under fasting conditions.

  • $C_{max}$ GMR: 86.72% (90% CI: 81.41–92.38%).
  • $AUC_t$ GMR: 92.20% (90% CI: 88.56–95.98%).
  • Median $T_{max}$ was 3.00 hours for the pellet formulation versus 3.50 hours for the tablet.

• Relative Bioavailability with Yogurt (Study 2): Dispersion in yogurt altered the rate but not the overall extent of absorption compared to the intact capsule.

  • $C_{max}$ GMR: 121.36% (90% CI: 113.30–129.99%), indicating a faster absorption rate.
  • $AUC_t$ GMR: 115.37% (90% CI: 110.14–120.84%), remaining within the conventional bioequivalence range.
  • Median $T_{max}$ decreased from 4.25 hours (intact capsule) to 3.25 hours (yogurt dispersion).

• Handling and Dose Recovery:

  • Preparation Time: Opening the capsule was significantly faster than crushing the tablet. Without rinsing, preparation time was reduced by 66.4% (11.22s vs. 33.38s). When mortar rinsing was included for the tablet, the reduction was 78.2% (11.22s vs. 53.4s).
  • Dose Recovery: Direct recovery after capsule opening was 98.5% ± 2.0%, with no measurable residual drug in the rinsed capsule. Direct recovery after tablet crushing was 96.5% ± 3.0%, with an additional 2.2% ± 1.0% recovered only after rinsing the mortar and pestle.

Significance and Claims
The paper concludes that the multiparticulate apixaban pellet formulation is a viable alternative for patients with swallowing difficulties. The authors claim three primary findings:

1. Bioequivalence: The formulation is bioequivalent to the reference tablet when administered as an intact capsule under fasting conditions.
2. Yogurt Dispersion: Dispersion in yogurt maintains the extent of systemic exposure ($AUC_t$) within the standard 80–125% range, though it accelerates the absorption rate (higher $C_{max}$, earlier $T_{max}$). The authors note that while the $C_{max}$ increase is pharmacokinetically significant, the clinical relevance regarding bleeding risk is not established by these studies, citing exposure-response data that suggests a shallow relationship between exposure and bleeding.
3. Practical Utility: The capsule-opening method offers a distinct practical advantage over tablet crushing, characterized by significantly reduced preparation time and more consistent direct dose recovery without the need for equipment rinsing to achieve total dose recovery.

The authors maintain a modest stance, acknowledging that the studies were conducted in healthy volunteers rather than dysphagic patients and were not designed to evaluate clinical efficacy or bleeding outcomes. Consequently, the findings characterize the pharmacokinetic and administration properties of the formulation to support further evaluation in patient populations requiring alternative administration methods.