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In certain scenarios, in vitro dissolution tests can replace in vivo bioequivalence studies. This is particularly true when a drug product, though available in varying strengths, maintains proportional similarity in its active and inactive ingredients. In such cases, the need for in vivo bioequivalence studies for lower strength variants may be waived, provided dissolution tests and in vivo studies on the highest strength yield satisfactory results.Bioequivalence can be indicated through...
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Physiological and compartmental models are valuable tools used in studying biological systems. These models rely on differential equations to maintain mass balance within the system, ensuring an accurate representation of the dynamic processes at play.
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It is not uncommon for complete drug pharmacokinetic profiles to remain elusive in pharmacokinetics. This necessitates certain educated assumptions by pharmacokineticists to determine appropriate dosage regimens without comprehensive pharmacokinetic data from animal or human studies. One prevalent assumption is setting the bioavailability factor, denoted as F, to 1 or 100%. This assumption caters to the scenario where a drug doesn't achieve full systemic absorption, resulting in the patient...
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Virtual Bioequivalence Assessment of Long-Acting Injectable Suspensions Using PBPK Modeling: Part 2. Type I Error and

Natalie M Morris1, Masoud Jamei2, Khondoker Alam3

  • 1Certara Predictive Technologies (CPT), Certara UK Limited, Simcyp Division, level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK. Natalie.Morris@certara.com.

The AAPS Journal
|April 2, 2026
PubMed
Summary
This summary is machine-generated.

Virtual bioequivalence (VBE) assessments using physiologically-based pharmacokinetic (PBPK) models require careful control of statistical type I error. Safe space for formulation design is limited, emphasizing the interplay between critical quality attributes and statistical power in bioequivalence studies.

Keywords:
PBBM/PBPK modelbioequivalence safe spacelong-acting injectable suspensionpaliperidone palmitatestatistical type I errorvirtual bioequivalence

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Area of Science:

  • Pharmacokinetics and Drug Delivery
  • Pharmaceutical Sciences
  • Biostatistics

Background:

  • Physiologically-based pharmacokinetic (PBPK) models are increasingly used for virtual bioequivalence (VBE) assessments.
  • Controlling statistical type I error and defining the 'safe space' for formulation attributes are critical in VBE.
  • Long-acting injectable suspensions, like paliperidone palmitate (PP), present unique challenges in bioequivalence (BE) evaluation.

Purpose of the Study:

  • To analyze statistical type I error and safe space calculations in VBE assessments for 3-month long-acting paliperidone palmitate (PP) injectable suspensions.
  • To investigate the relationship between formulation critical quality attributes (CQAs) and bioequivalence outcomes using PBPK modeling.
  • To provide insights into formulation design considerations for achieving bioequivalence.

Main Methods:

  • Utilized a previously published PBPK model for 3-month PP injectable suspensions.
  • Estimated type I error for the two-one-sided t test (TOST) in virtual parallel BE trials via simulated BE boundaries.
  • Employed Monte Carlo simulations to combine type I error limits with power calculations for safe space estimation.

Main Results:

  • The simulated BE boundaries for mean particle radius extended over 5 µm.
  • Acceptable statistical power (≥80%) was achieved only when mean particle radius was within 1 µm of the reference formulation.
  • Type I error calculations in PBPK models are more complex than power calculations, requiring prior determination of CQA BE boundaries.

Conclusions:

  • This study is the first to address the intersection of type I error control and safe space estimation in PBPK modeling for VBE.
  • Controlled type I error in VBE assessments is achievable under specific conditions.
  • The 'safe space' for formulation design is influenced by both formulation characteristics and the statistical power of bioequivalence studies.