{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:15:17Z","timestamp":1776914117635,"version":"3.51.2"},"reference-count":16,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bluepharma-Ind\u00fastria Farmac\u00eautica, S.A."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: When companies are uncertain about the potential of a new formulation to be bioequivalent to a Reference product, it is common practice to carry out downsized pilot studies as a gatekeeping in vivo strategy to decide whether to move forward or not with a full-size pivotal study. However, due to the small study size, these studies are inarguably more sensitive to variability. Objectives: To address and mitigate the uncertainty of the conclusions of pilot studies concerning the maximum observed concentration (Cmax), the f2 factor was proposed as an alternative approach to the average bioequivalence statistical methodology. Methods: In this work, the alternative methodology is applied to pharmacokinetic data from pilot bioequivalence trials performed with pazopanib 200 mg and 400 mg. Results: Despite the small sample size, and very high intra-subject variability, the f2 factor demonstrated the potential for predicting bioequivalence. The positive results were confirmed in the full sized pivotal studies. Conclusions: In conclusion, this alternate methodology shows promise in reducing uncertainty associated with pilot studies and aiding in decisions to go forward with pivotal bioequivalence studies.<\/jats:p>","DOI":"10.3390\/pharmaceutics16121579","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T06:44:05Z","timestamp":1733899445000},"page":"1579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Unveiling the Potential of Cmax\u00a0f2 Factor Applied to Pilot Bioavailability\/Bioequivalence Studies\u2014A Case Study with Pazopanib Drug Products"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9649-4823","authenticated-orcid":false,"given":"Sara Carolina","family":"Henriques","sequence":"first","affiliation":[{"name":"BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal"},{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0446-8239","authenticated-orcid":false,"given":"Ana","family":"Leblanc","sequence":"additional","affiliation":[{"name":"BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8898-7625","authenticated-orcid":false,"given":"S\u00e9rgio","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Bluepharma-Ind\u00fastria Farmac\u00eautica, S.A., S\u00e3o Martinho do Bispo, 3045-016 Coimbra, Portugal"},{"name":"Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5828-8535","authenticated-orcid":false,"given":"Marlene","family":"Fonseca","sequence":"additional","affiliation":[{"name":"BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5993-5132","authenticated-orcid":false,"given":"Francisco Lu\u00eds","family":"Pimentel","sequence":"additional","affiliation":[{"name":"BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4861-8649","authenticated-orcid":false,"given":"Luis","family":"Almeida","sequence":"additional","affiliation":[{"name":"BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal"},{"name":"Department of Biomedicine, Unit of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal"},{"name":"MedInUP\u2014Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9478-0110","authenticated-orcid":false,"given":"Nuno Elvas","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Henriques, S.C., Albuquerque, J., Paix\u00e3o, P., Almeida, L., and Silva, N.E. (2023). Alternative Analysis Approaches for the Assessment of Pilot Bioavailability\/Bioequivalence Studies. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15051430"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Henriques, S.C., Paix\u00e3o, P., Almeida, L., and Silva, N.E. (2023). Predictive Potential of Cmax Bioequivalence in Pilot Bioavailability\/Bioequivalence Studies, through the Alternative f2 Similarity Factor Method. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15102498"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1208\/s12248-015-9744-6","article-title":"Pilot and Repeat Trials as Development Tools Associated with Demonstration of Bioequivalence","volume":"17","author":"Fuglsang","year":"2015","journal-title":"AAPS J."},{"key":"ref_4","unstructured":"US Food and Drug Administration (FDA) (2024, July 05). 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Available online: https:\/\/github.com\/saracarolinahenriques\/f2PilotBE.","DOI":"10.3390\/pharmaceutics15102498"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/12\/1579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:52:07Z","timestamp":1760115127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/12\/1579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,11]]},"references-count":16,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["pharmaceutics16121579"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16121579","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,11]]}}}