Sara Carolina Henriques (1,2), Luís Almeida (2), Francisco Pimentel (2), Nuno Elvas Silva (1)
(1) Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; (2) BlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, Portugal
Objectives:
When companies are uncertain of 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. In these trials, 12 to 30 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. Analysis and interpretation of results from pilot studies usually rely on the application of the average bioequivalence approach. However, due to the small study size, these studies are inarguably more sensitive to variability.
To address and mitigate the uncertainty on the conclusions of pilot studies and on the potential of Test formulations, the ƒ2 factor was proposed as an alternative approach to the average bioequivalence methodology to assess the potential bioequivalence concerning the maximum observed concentration (Cmax) [1,2].
The ƒ2 factor has demonstrated a good relationship between avoiding type I and type II errors [1,2]. However, the proposed assessment is solely based on simulated concentration-time profiles, hence, in order to validate the ƒ2 factor method in a more diverse and realistic setting, a retrospective analysis was performed to real world pharmacokinetic data, from bioequivalence studies.
Methods:
The ƒ2 factor was applied to assess the similarity on the rate of drug absorption [1,2], using the R package ‘f2PilotBE’ [3], to pharmacokinetic data obtained from a pilot bioequivalence trial with pazopanib 400 mg. This trial was performed to support the marketing authorization of a generic pazopanib formulation (Test product) of Votrient® (Reference product). Pazopanib is recognized as a highly variable drug with an intra-subject coefficient of variability of approximately 50%.
Results:
In the pilot study with 400 mg pazopanib, involving 23 subjects, bioequivalence between the Test and Reference products was not demonstrated, using an average bioequivalence. The point estimate was above 100% and not centred (117.26%), but within the [80.00 – 125.00]% comparable bioavailability acceptance interval, along with its lower limit of the 90% confidence interval (CI). The upper limit of the 90% CI was outside the acceptance interval.
Upon applying the alternative analysis, the estimated ƒ2 factor was 53.51. According to conclusion from previous simulations, an ƒ2 factor of this dimension (>50) indicates a 90% probability that the Test product is truly bioequivalent to the Reference product in terms of Cmax, and therefore the sponsor was encouraged to proceed with a full-size pivotal study [2].
Sponsor has decided to conduct a pivotal study with 122 subjects, which would allow an a priori statistical power of at least 80% to meet the [80.00 – 125.00]% bioequivalence range. From the 122 enrolled subjects, 98 completed the study and had evaluable pharmacokinetic data for bioequivalence analysis. The increment of the number of subjects to 98, allowed the point estimate and the corresponding 90% CI to fall completely within the [80.00 – 125.00]% acceptance interval, hence showing bioequivalence.
Conclusions:
The ƒ2 factor has shown to be capable of predicting bioequivalence between two pazopanib formulations using data from a pilot study, despite the limited sample size of only 23 subjects that have been involved, considered to be low facing the high intrasubject variability known for the drug. The methodology is intended to be applied to data from other bioequivalence trials covering different BCS class drugs. Nevertheless, the ƒ2 factor has been exhibiting potential to reduce the uncertainty associated with pilot studies and to be helpful in terms of the decision to go forward with pivotal bioequivalence studies.
References:
[1] Henriques, S.C.; Albuquerque, J.; Paixão, P.; Almeida, L.; Silva, N.E. (2023). Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies. Pharmaceutics. 15(5), 1430. 10.3390/pharmaceutics15051430.
[2] Henriques, S.C.; Paixão, P.; Almeida, L.; Silva, N.E. (2023). Predictive Potential of Cmax Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ2 Similarity Factor Method. Pharmaceutics. 15(10), 2498. 10.3390/pharmaceutics15102498.
[3] Henriques, S.C.; Silva, N.E. (2024). Package “F2PilotBE”. F2 Factor Alternative Approach for Pilot Bioequivalence Studies. Available online: https://github.com/LittlePetinga/f2PilotBE.
Reference: PAGE 32 (2024) Abstr 11251 [www.page-meeting.org/?abstract=11251]
Poster: Methodology - Other topics