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PHC-011 Dual Absorption in Intranasal Administration: A New Pharmacokinetic Model
  1. C Neef1,
  2. N Veldhorst-Janssen1,
  3. N Punt2,
  4. PHM Van der Kuy3,
  5. M Marcus4
  1. 1Maastricht University Medical Center, Clinical Pharmacy & Toxicology, Maastricht, The Netherlands
  2. 2Maastricht University, Toxicology, Maastricht, The Netherlands
  3. 3Orbis Medical Center, Pharmacy, Sittard-Geleen, The Netherlands
  4. 4Maastricht University Medical Center, Anaesthesiology, Maastricht, The Netherlands

Abstract

Background The role of pharmacokinetic modelling is important in the development of new formulations. Some of these models are related to a particular dosage form, others are similar to models that have already been developed. Intranasal (IN) administration can be an example of a dosage form with a specific pharmacokinetic model, especially when it is applied to create a systemic effect.

Purpose To design a pharmacokinetic model that adequately describes a dual absorption profile of the concentration-time curve for intranasal administration.

Materials and Methods A strategy to predict dual absorption was developed to describe the pharmacokinetics of an intranasal administration (model1 and model2). A programme for fitting and simulation was developed (SIMLAB). Midazolam nasal spray was used as an example for this model. To validate the final pharmacokinetic model, Monte Carlo simulations were performed.

Results We had trouble fitting the observations to a single one-compartment dual absorption model. In many cases a flip-flop condition occurred in which the fitted absorption rate was lower than the estimated elimination rate, and the elimination rate showed an unrealistic value. To prevent this flip-flop condition, we used the absorption parameters from the associated observations. We developed the following model: the model superposes two one-compartment absorption models where the dose is split up over the two compartment inputs and the concentration-time curves are separated by using different lag-times (t0). Monte Carlo simulations resulted in a plasma concentration-time profile, indicating the median concentration and the 5th–95th percentile ranges. Biphasic profiles were observed starting at a parameter error of 15%, increasing to 13.6% of biphasic profiles at a parameter error of 50%. When increasing the difference between a parameter in Model 1 and Model 2, the contribution of t0 to creating a local minimum exceeded the contribution of ka. The AUC of the measured and estimated curve was 201.6 µg/L*h and 201.3 µg/L*h, respectively.

Conclusions The model developed is able to fit concentration-time curves showing individual dual absorption curves adequately.

No conflict of interest.

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