Reviews of the productivity of the pharmaceutical industry have concluded that the current business model is unsustainable. Various remedies for this have been proposed, however, arguably these do not directly address the fundamental issue; namely, that it is the knowledge required to enable good decisions in the process of delivering a drug that is largely … Continued
In clinical practice, antifungal therapy may be switched from fluconazole to voriconazole; such sequential use poses the potential for drug interaction due to cytochrome P450 2C19 (CYP2C19)-mediated inhibition of voriconazole metabolism. This open-label, randomized, two-way crossover study investigated the effect of concomitant fluconazole on voriconazole pharmacokinetics in 10 subjects: 8 extensive metabolizers and 2 poor … Continued
As the prevalence of polypharmacy increases with our aging population, the propensity for adverse drug-drug interactions arising from the altered metabolism of co-administered medicines remains an important consideration for drug development. Mechanism-based inactivation (MBI) of the cytochrome P450 enzyme system is responsible for many clinically relevant drug-drug interactions (DDIs) due to the irreversible and long-lasting … Continued
Prediction of human volume of distribution at steady state (Vss)before first administration of a new drug candidate to humans has become an important part of the drug development process. This study examines the assumptions behind interspecies scaling techniques used to predict human Vss. from preclinical data, namely the equivalency of Vss,u. and/or fut. across species. … Continued
Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compound’s sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional … Continued
As a direct-acting inhibitor of CYP2C19 in vitro, lansoprazole is more potent than omeprazole and other proton pump inhibitors (PPIs), but lansoprazole does not cause clinically significant inhibition of CYP2C19 whereas omeprazole does. To investigate this apparent paradox, we evaluated omeprazole, esomeprazole, R-omeprazole, lansoprazole, and pantoprazole for their ability to function as direct-acting and metabolism-dependent … Continued
Assessment of time-dependent inhibition (TDI), especially CYP3A4, is an important parameter for preclinical and clinical development. The use of human liver microsomes (HLM) is the most common in vitro matrix to assess TDI, but this often leads to an overprediction of an actual effect observed clinically. Recently, the use of human hepatocytes has been hypothesized … Continued
I apologize to all my readers for such a long lapse between posts. After a very busy summer and fall, I am back to posting regularly to my blog about PK/PD topics. When analyzing PK/PD data, one of the most important plots used to visualize the data is to plot time-matched PK/PD data on a … Continued
