Christian Dr Zurth

Simultaneous Estradiol and Levonorgestrel Transdermal Delivery from a 7-day Patch: In Vitro and In Vivo Drug Deliveries of Three Formulations

ABSTRACT A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara ProTM.

The Pharmacokinetic/Pharmacodynamic Research Tool (PRESTO): An Advanced Concept for Rational Drug Development

In Germany in 1995 an intercompany expert working group was formed to define a flexible structure for a modern database system, named the Pharmacokinetic/Pharmacodynamic RESearch TOol (PRESTO), which handles pharmacokinetic/pharmacodynamic (PK/PD) results of entire research and development (R&D) projects, thus going beyond the information available in laboratory or clinical data systems generally present in most companies. PRESTO consists of two main modules: a database and an analysis system. The database part of PRESTO is designed for storing and managing PK and PD study data. Associated information such as biochemistry, toxicokinetic, physico-chemistry, and clinical chemistry data can also be handled to aid the interpretation of results, if necessary. The database will be used as a source for all kinds of pharmacokinetic, pharmacodynamic, and biometric evaluations. The extraction of data across studies to prepare meta-analyses is an essential feature of this system. The analysis system part of PRESTO provides uniform graphical interfaces to the database and to commercially available and proprietary data analysis programs (noncompartmental, compartmental PK, effect modeling, population PK/PD) as well as statistical software packages. The database part is then additionally used as a repository of the results from these evaluations. PRESTO is designed to a modular concept and a flexible data model, and offers configuration to site-specific needs. The concept supports filfillment of Good Clinical Practice/Good Laboratory Practice requirement