Prediction of cyclosporine blood concentrations in hematological patients with multidrug resistance

Abstract

Pharmacokinetics and dopaminergic effect of dopamine agonist 5-OH-DPAT in vivo were determined following transdermal iontophoresis in rats based on drug concentration in plasma (Cp) and dopamine levels in striatum (CDA). Correlation of the in vitro transport with the pharmacokinetic-pharmacodynamic (PK-PD) profiles was characterized in the transport in dermatomed rat skin (DRS) and rat stratum corneum (RSC). The integrated in vivo PK-PD and in vitro transport models successfully described time course of Cp, CDA, and in vitro flux in DRS and RSC. Population value of steady-state flux (Jss) in vivo (31 nmol/cm2 · h with 95% confidence interval (CI) = 20–41) is closer to Jssin vitro in DRS (61 nmol/cm2 · h, CI = 54–67) than in vitro Jss in RSC (98 nmol/cm2 · h, CI = 79–117). On the other hand, skin release rate constant (KR) in vivo was similar to the KR in RSC (4.8/h, CI = 2.4–7.1 vs. 2.6/h, CI = 2.5–2.6). Kinetic lag time (tL) in vivo was negligible, which is close to in vitro tL in RSC (0.0 h, CI = 0.0–0.1). Based on nonlinear mixed-effect modeling, profiles of Cp and CDA were successfully predicted using in vitro values of Jss in DRS with KR and tL in RSC. A considerable dopaminergic effect was achieved, indicating the feasibility to reach therapeutically effective concentrations of 5-OH-DPAT upon transdermal iontophoresis. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association.