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Untangling Absorption Mechanisms and Variability in Bioequivalence Studies Using Population Analysis

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Abstract

Purpose

Both inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of crossover studies.

Methods

Data from 18 bioequivalence studies were used to develop population pharmacokinetics (popPK) models to characterize the absorption and disposition processes of 14 drugs, to estimate IOV for each drug substance and to evaluate possible correlations with biopharmaceutical properties of drug substances, classified in accordance to the Biopharmaceutics Drug Disposition Classification System (BDDCS).

Results

Plasma-pharmacokinetics profiles for the 14 drugs analyzed were successfully described using popPK. The pharmacokinetic parameters that showed greater variability were first-order rate constant of absorption, duration of the zero-order absorption process, relative bioavailability and time of latency. ISCV% estimated for Cmax seems to correlate with the log-Dose-Number for Class 1, 2 and 3, despite no direct correlation was observed between popPK model residual variability (RUV) and ISCV%. Nevertheless, higher RUV estimates were observed for Class 2 drugs in comparison to Class 1 and 3.

Conclusion

Pharmacokinetic parameters related to drug absorption showed greater variability.

Ingestion of the IMP along with 240 mL of water showed to standardize gastric emptying.

Given the dependency between Cmax variability and dose-solubility ratio, for classes 2 and 4, ad libitum water intake may increase Cmax and AUC ISCV%. A water ingestion standardization until the expected Tmax of the drug is suggested.

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Conflict of Interest statement

We have no conflicts of interest to disclose.

Funding

The principal author is it supported by a University of Porto and FSE – Fundo Social Europeu, by doctoral scholarship of NORTE2020- Programa Operacional Regional do Norte-08-5369-FSE-000011.

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Authors and Affiliations

  1. MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal

    Carolina Ameijeiras Rodríguez & Luis Almeida

  2. BlueClinical, Porto, Portugal

    Sara Carolina Henriques, Luis Almeida & Nuno Elvas Silva

  3. Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    Sara Carolina Henriques & Nuno Elvas Silva

  4. Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain

    Aymara Sancho-Araiz & Iñaki F. Trocóniz

  5. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain

    Aymara Sancho-Araiz & Iñaki F. Trocóniz

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  1. Carolina Ameijeiras Rodríguez
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  2. Sara Carolina Henriques
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  3. Aymara Sancho-Araiz
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Ameijeiras Rodríguez, C., Henriques, S.C., Sancho-Araiz, A. et al. Untangling Absorption Mechanisms and Variability in Bioequivalence Studies Using Population Analysis. Pharm Res 38, 2047–2063 (2021). https://doi.org/10.1007/s11095-021-03136-3

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