Frano Mihaljevic, Géraldine Cellière, Jonathan Chauvin, Claude Magnard, Pauline Traynard, Monika Twarogowska
Simulations Plus, Lixoft Division, Antony, France
Objectives: Post-approval changes in manufacturing processes or approvals of new strengths of a drug product require expensive and often long bioequivalence trials. However, an established mathematical correlation between in vitro and in vivo data (in vitro/in vivo correlation, IVIVC) can be used to waive bioequivalence studies in certain cases. Here we present how to establish a point-to-point (level A) correlation between in vitro (dissolution) and in vivo (drug concentration) data using Monolix and PKanalix, software from the MonolixSuite, on a dataset containing pharmacokinetic profiles and dissolution profiles of three different bimodal release formulations and an immediate release formulation of D,L-threo-methylphenidate (MPH) [1, 2].
Methods: In vivo data was obtained through a four-treatment, four-period, single-dose, randomized crossover study, which enrolled 17 participants [1, 2]. The establishment of level A in vitro/in vivo correlation was done in several steps:
- The pharmacokinetic profile of immediate release MPH formulation was modeled using a first order absorption model with lag time, one compartment and linear elimination.
- A double Weibull function was used to characterize dissolution data of three different bimodal release formulations.
- The pharmacokinetic data of three different bimodal release MPH formulations was fit to a convolution-based IVIVC model containing a general time-scaling equation. In the IVIVC model, the pharmacokinetic parameters estimated by modeling immediate release data were used to characterize distribution and elimination processes and double Weibull parameters estimated through modeling dissolution data were used to characterize absorption. A unique set of time scaling parameters was obtained for all three bimodal release formulations in a one-step procedure.
- NCA metrics for both predicted and observed data were obtained and prediction errors for those metrics were calculated to assess the internal predictability of the IVIVC model, according to the criteria published by Food and Drug Administration (FDA) [3].
The process was done using software from the MonolixSuite: Monolix was used for modeling pharmacokinetic and dissolution data and PKanalix was used for subsequent calculations of NCA metrics used to assess if IVIVC model based predictions are acceptable.
Results: The time scaling equation was successfully obtained and the FDA internal predictability criteria for level A (point-to-point) correlations between in vitro and in vivo data were successfully met for Cmax, AUCinf and partial AUCs noted in Draft Guidance on Methylphenidate Hydrochloride published by FDA [4].
Conclusions: We demonstrated that Monolix can be successfully used for modeling dissolution data, as well as for estimating parameters of an IVIVC equation. We have shown the ability of PKanalix to be used for a purpose of demonstrating the validity of the obtained IVIVC equation through NCA metrics calculation used for prediction error calculation.
References:
[1] Wang, Y. et al. In vitro dissolution and in vivo oral absorption of methylphenidate from a bimodal release formulation in healthy volunteers. Biopharm. Drug Dispos. 25, 91– 98 (2004).
[2] Gomeni R, Fang LL, Bressolle-Gomeni F, Spencer TJ, Faraone SV, Babiskin A. A general framework for assessing in vitro/in vivo correlation as a tool for maximizing the benefit-risk ratio of a treatment using a convolution-based modeling approach. CPT Pharmacometrics Syst Pharmacol. 2019; 8(2): 97- 106.
[3] US Food and Drug Administration. Guidance for industry: extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations <https://www.fda.gov/downloads/drugs/guidances/ucm070239.pdf > (1997).
[4] US Food and Drug Administration. Draft guidance on methylphenidate hydrochloride. <https://www.accessdata.fda.gov/drugsatfda_docs/psg/Methylphenidate%20Hydrochloride_draft_Oral%20tab%20ER_RLD%2021121_RC07-18.pdf> (2018).
Reference: PAGE 30 (2022) Abstr 10161 [www.page-meeting.org/?abstract=10161]
Poster: Methodology - Other topics