Compartmental modeling of transdermal iontophoretic transport II: in vivo model derivation and application.
OBJECTIVE
This study was aimed to develop a family of compartmental models to describe in a strictly quantitative manner the transdermal iontophoretic transport of drugs in vivo. The new models are based on previously proposed compartmental models for the transport in vitro.


METHODS
The novel in vivo model considers two separate models to describe the input into the systemic circulation: a) constant input and b) time-variant input. Analogous to the in vitro models, the in vivo models contain four parameters: 1) kinetic lag time (tL), 2) steady-state flux during iontophoresis (JSS), 3) skin release rate constant (KR), and 4) passive flux in the post-iontophoretic period (Jpas). The elimination from the systemic circulation is described by a) the one-compartment and b) the two-compartment pharmacokinetic models. The models were applied to characterize the observed plasma concentration vs. time data following single-dose iontophoretic delivery of growth hormone-releasing factor (GRF) and R-apomorphine. Moreover, the models were also used to simulate the observed plasma concentration vs. time profiles following a two-dose transdermal iontophoretic administration of alniditan.


RESULTS
The time-variant input models were superior to the constant input models and appropriately converged to the observed data of GRF and R-apomorphine allowing the estimation of JSS, KR, and Jpas. In most cases, the values of tL were negligible. The estimated JSS and the in vivo flux profiles of GRF and R-apomorphine were similar to those obtained using the deconvolution method. The two-dose iontophoretic transport of alniditan was properly simulated using the proposed time-variant input model indicating the utility of the model to predict and to simulate the drug transport by a multiple-dose iontophoresis. Moreover, the use of the compartmental modeling approach to derive an in vitro-in vivo correlation for R-apomorphine was demonstrated. This approach was also used to identify the optimum in vitro model that closely mimics the in vivo iontophoretic transport of R-apomorphine.


CONCLUSIONS
The developed in vivo models demonstrate their consistency and capability to describe the in vivo iontophoretic drug transport. This compartmental modeling approach provides a scientific basis to examine in vitro-in vivo correlations of drug transport by iontophoresis.
Nugroho
Akhmad Kharis
AK
Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden, The Netherlands.
Della-Pasqua
Oscar
O
Danhof
Meindert
M
Bouwstra
Joke A
JA
D000279:Administration, Cutaneous; D000818:Animals; D006168:Guinea Pigs; D007478:Iontophoresis / Q000379:methods; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*
D004364:Pharmaceutical Preparations