Géraldine Cellière (1), Joel Owen (2) , Pauline Traynard (1), Claude Magnard (1), Monika Twarogowska (1)
(1) Simulations Plus, Lixoft division, Antony, France. (2) Simulations Plus, Cognigen division, USA
Objectives: Long-acting injectables (LAI) have been developed to offer prolonged drug release and thus improve treatment adherence. Approximately 30 LAI drug products are currently approved by the FDA. However, only one of these has an approved generic formulation because the long terminal half-life and high inter-individual variability result in risky bioequivalence trials with long duration and low power [1,2]. Here we propose a novel BE design combined with a model-integrated approach to reduce the duration of bioequivalence trials for LAIs.
Methods: The novel design we propose is a 2-treatment, 2-period, 1-sequence “reduced crossover” with no or limited washout. The data of the second period takes into account the second dose and the carryover from the first dose and can thus not be directly compared to the data of the first period. Therefore, we apply a model-based correction of the data of the second period. To do so, individual parameters are estimated on the data of the first period (reference formulation, for which a population model is usually available) and used to predict the carryover concentration into the second period. The predicted carryover concentration is then subtracted from the second period data before usual BE analysis. The method is applicable in the case of a single dose design (i.e on healthy volunteers), and linear PK.
The procedure is exemplified with Buprenorphine LAI, using a published model [3]. To be valuable, the proposed procedure needs to have a properly controlled type I error (probability of wrongly concluding bioequivalence, i.e patient risk) and a sufficiently high power (probability of correctly concluding bioequivalence).
To calculate the empirical type I error and power, many BE trials with the proposed “reduced crossover” design are simulated under the null hypothesis (no bioequivalence) or the alternative hypothesis (bioequivalence) and submitted to the analysis procedure. For comparison, power and type I error is also calculated for classical crossovers with washout period and parallel designs.
Results: For Bubrenorphine LAI, a classical crossover design with washout would last 20 months due to the long half-life, and lead to many dropouts. A parallel design would be shorter but require at least 250 individuals per arm to achieve a 80% power. These challenges impede the development of generics for LAIs. We thus investigated the power, duration and type I error of the proposed reduced crossover design with no washout. Several inter-dose intervals were tested: 3, 4, 5 or 6 months. The 3 months inter-dose interval does not provide sufficient data to properly estimate the individual parameters during the first period and leads to an inflated type I error, which is not acceptable. However, with an inter-dose interval of 4 months (or higher), the type I error is properly controlled and the power is above 90% with 30 individuals. This reduced crossover design is thus three times shorter than the traditional crossover and requires a 10 times smaller sample size compared to a parallel trial.
Conclusions: The proposed model-integrated reduced crossover bioequivalence design and the associated analysis procedure is shown to provide a high power for a reasonable study duration and sample size, with a properly controlled type I error. It alleviates the current challenges for the development of LAI generics and represents a hope for the community.
The analysis procedure is implemented as an R script, relying on the MonolixSuite. It can easily be applied to other LAIs.
References:
[1] Zhao, L. et al. (2019) ‘Generating Model Integrated Evidence for Generic Drug Development and Assessment’, Clinical Pharmacology and Therapeutics, 105(2), pp. 338–349.
[2] Sharan, S. et al. (2021) ‘Model-Informed Drug Development for Long-Acting Injectable Products: Summary of American College of Clinical Pharmacology Symposium’, Clinical Pharmacology in Drug Development, 10(3), pp. 220–228. [3] Jones, A. K. et al. (2021) ‘Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials’, Clinical Pharmacokinetics. Springer International Publishing, 60(4), pp. 527–540.
Reference: PAGE 30 (2022) Abstr 10175 [www.page-meeting.org/?abstract=10175]
Poster: Methodology - New Modelling Approaches