Bioequivalence and Bioavailability Forum

Hi BE-proff,

❝ If I need to compare kinetics of immediate-release tablet and modified-release medication how to plan a study?

I guess you are talking BE and not PK (modeling)?

❝ Which parameters are to be used?

Nitpicking: PK parameters are estimated by a PK model. PK metrics are obtained by NCA/SHAM.

• AUC_0–τ (if there is circadian variability in PK and the drug is administered more than once additionally AUC_0–24).
  
• C_ss,max (descriptively t_ss,max).
  
• For originators C_ss,min (the minimum within the dosage interval τ) and for generics C_ss,τ (the concentration at the end of τ).
  
• %PTF (the Peak-to-Trough Fluctuation in percent): 100(C_max–C_min)/C_av, where C_av is the average concentration within the dosage interval given by C_av = AUC_0–τ/τ.
  
• In Russia T>75%C_max: The time interval where the concentration is ≥75% of C_max. In the literature also called “Plateau Time” (t_75%) or “Peak Occupancy Time” (POT-25: the time period during which concentrations are within 25% of C_max). It’s variability may be high.
  You can try to convince regulators to assess the more stable “Half Value Duration” (HVD) aka POT-50 (time period during which con­cen­trations are within 50% of C_max) instead. Good luck.

❝ How to determine how many days and how often tablets are to be taken?

If linear PK is applicable, 5–7 times t_1/2 (AFAIK, only ANVISA requires 10×t_1/2 ~99.9% of steady state). Exact for the one-compartment model and approximate for >1 compartments. In theory steady state (output = input) is reached after infinite time. We don’t want to wait that long, right? Formula to estimate the percentage of steady state reached: 100(1–½ⁱ), where i is the i-th dose administered.
As said above all this is valid for linear PK only (check the literature). For nonlinear PK it might get extremely complicated (see this thread) and designing an MD study without knowing the kind of nonlinearity and establishing a PK model first might be almost impossible.

❝ How to determine what time point must be in PK-session?

You need to have single dose data (preferably of your own study). Some people design the MD dose study already based on literature data of the IR formulation and black magic assumptions about the new MR formulation. Not a good idea!
Based on SD data you could use a method called Nonparametric Superposition (see this thread for software and this post for an example). Essentially at every dosing you stack the single dose profile on top of the expected concentrations of previous doses estimated by λ_z. If the software allows that you may explore different sampling schedules (i.e., interpolating time points not existing in the SD profiles). Remember that a precise estimate of C_ss,max is crucial. Since t_ss,max for IR and MR will be different, try to find a sampling schedule which will give you sufficient information about both.

❝ A lot of questions...

Some answers, I do hope.

Hi BE-proff,

Be aware of some new document on the MOH site (Russian version of Q&A)
I'm translating with google the 2nd question:
Q: What recommendations by volume of preclinical and clinical studies for drug registration state for medical use in the dosage form of the sustained release?

A: To develop the formulation reconstituted drug sustained-release program will require an extended preclinical and clinical studies, exceeding the volume of research needed to confirm the bioequivalence study drug sustained-release formulation registered comparison drug preparatas sustained release.
One of the conditions for pre-clinical research should be the introduction of the test drug to animals without compromising the integrity of the dosage form. In addition, should be provided in a recovery period, studied the local tolerance (irritant effect on the gastrointestinal tract). It is advisable to examine the pharmacokinetics of the drug both in comparison with immediate release formulations.
For new drugs with sustained release, containing known pharmaceutical substances registered as the drug from immediate release, first of all, necessary to carry out pharmacokinetic studies in single (fasting and post-prandial) and multiple dose (in order to examine the exposure in the equilibrium state). It may require different doses of the study drugs and dosages. Displacement further studies depends on the linearity of the pharmacokinetics of the pharmaceutical agent in the therapeutic dose range, cumulation pharmaceutical substance in the body, the proportional composition of additional doses to the main dosage, the influence on the dosage form solutions of ethanol, and others. It is also necessary to consider the function of the gastrointestinal tract in particular groups | patients who are the target population.

So some doubts are coming to regulators that current guidelines are not enough for MR drugs
Waiting for next version of Q&A...