IVIVC modelling can speed up the drug development process
IVIVC can serve as a surrogate for human bioavailability, bioequivalence studies and speed up the drug development process
Want to have a certain confidence in the potential drug release of your product during your product development? An in vitro in vivo correlation (IVIVC) can help you reach this goal.
The Food and Drug Administration (FDA) guidance indicated that IVIVC has been defined as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form (usually the rate or extent of drug release) and an in-vivo response” (e.g., amount of drug absorbed). IVIVC describes the relationship between the drug in vitro dissolution characteristics and the in vivo bioavailability response of an extended/modified release (ER) drug product. Both FDA[i] and EMA[ii] guidelines on ER drug products outlines the details of IVIVC model development and assessment of evaluate predictability, internal and external validation process, use IVIVC to establish specifications for dissolution, and apply an IVIVC as a surrogate for bioequivalence (BE) studies.
Advantage of IVIVC
In vitro dissolution testing is a critical process for control and quality assurance as well as an indicator for the in vivo drug performance with the help of a surrogate for human BE study- IVIVC model.
A validated IVIVC model allows predicting in vivo absorption based on the in vitro dissolution data. It can support both New Drug Applications (NDA) during the initial approval process and Abbreviated New Drug Applications (ANDA) for the scale-up and/or post-approval modifications, allow to seek for biowaiver of long and expensive BE studies. The IVIVC developed from two or more formulations/release rates (at least 10% for the percentage dissolved among the formulations) allows for a different level of process/manufacturing changes, thus, this should be taken into the sponsor’s consideration when planning a IVIVC in the development program. A biowaiver for lower strengths during the initial approval or new strength post-approval can be provided based on the IVIVC developed with the highest strength.
Additionally, the IVIVC is a useful tool for setting dissolution specifications. In general, the performance of the in vivo lots will be used to set the dissolution specification in vitro, while the in vitro dissolution test is only a quality control test without in vivo significance. However, the add-in of the IVIVC model allows in vitro dissolution test contributes as a meaningful predictor for formulation performance in vivo, while dissolution specifications can be used to minimize the potential that the releasing lots would be different from in vivo performance. This approach is recommended for many ER formulations, the drug dissolution from the formulation is the reason for the absorption rate in vivo and the IVIVC can provide the relation between the in vivo and in vitro dissolution specifications, beyond batch-to-batch quality control.
Levels of IVIVC
There are three primary IVIVC categories, known as Levels A, B, and C (there is also a Multiple Level C correlation). The majority of Investigational New Drug applications (IND) and NDAs used Level A. Level C can be useful in the early stages of development and is the second most common. Level B and Multiple Level C correlations are comparatively rare.
- Level A: Level A correlation uses a two-stage procedure approach including deconvolution followed by a comparison of the drug absorbed fraction to the drug dissolved fraction. A level A model can also be developed based on a convolution procedure in which the predicted plasma concentration from the model and those observed from the in vivo study are compared directly. This model requires a point-to-point relationship between in vitro dissolution and the in vivo input rate.
- Level B: A level B correlation uses all the in vitro and in vivo like model A. However, this is not considered to be a point-to-point correlation as it used the mean in vitro dissolution time to compare either to the mean residence time or the mean in vivo dissolution time. This model, therefore, does not uniquely reflect the actual in vivo concentration curve.
- Level C: A level C correlation develops a single-point relationship between a dissolution parameter and pharmacokinetic parameter which means that it does not reflect the concentration-time curve and therefore, is not suitable to define the performance of an ER product. Thus, a level C model is not feasible to justify for a biowaiver but to establish a dissolution specification.
- Multiple level C: A multiple-level C correlation establishes the relationship of one or several pharmacokinetic parameters to the amount of drug dissolved at several time points in the dissolution profile. A multiple level C correlation can be used to justify a biowaiver if it can correlate the amount of dissolved, at all time points that affect the in vivo performance of any change in the dissolution can be assessed, with the primary PK parameters such as Cmax and AUC.
BioPharma Can Help You Navigate Through the IVIVC Roadmap
BioPharma can assist you throughout both the NDA and ANDA journey with the addition of IVIVC analyses. BioPharma’s Pharmacometric Team has experience in conducting in vivo clinical trials to facilitate further IVIVC modeling, developing an IVIVC model for your product using in vitro and in vivo data, providing scientific advice related to your product.
We offer a full-service package including designing, conducting in vivo trials with two, three, or more different release rates formulations to obtain differences in absorption profiles together with reference product required for IVIVC deconvolution, either the IV or oral IR product; and developing IVIVC modeling based on this in vivo study and your in vitro dissolution data. We will assess the PK parameters and compare the differences in Cmax and AUC between each formulation (i.e. formulations that differ by a given percentage in vitro should show a corresponding difference in vivo) and make a recommendation for your investigational formulations/release rates for your product development. The IVIVC model we use is validated using internal/external predictability based on the prediction error as per regulatory guidance.
With the many advantages of IVIVC, we can assist with the optimization of your formulation development, streamlining product development and manufacturing with our experience. Contact Us to Schedule a Discovery Call.
[ii] EMA (2014). Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms, EMA/CHMP/EWP/280/96 Rev1 – https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-clinical-evaluation-modified-release-dosage-forms_en.pdf
About BioPharma Services
BioPharma Services, Inc., a Think Research Corporation company, is a full-service Contract Research Organization (CRO) based in Toronto, Canada, specializing in Phase I/IIa and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.