Publications by authors named "M E Dowty"
Physiologically-based pharmacokinetic (PBPK) modeling offers a viable approach to predict induction drug-drug interactions (DDIs) with the potential to streamline or reduce clinical trial burden if predictions can be made with sufficient confidence. In the current work, the ability to predict the effect of rifampin, a well-characterized strong CYP3A4 inducer, on 20 CYP3A probes with publicly available PBPK models (often developed using a workflow with optimization following a strong inhibitor DDI study to gain confidence in fraction metabolized by CYP3A4, f, and fraction available after intestinal metabolism, Fg), was assessed. Substrates with a range of f (0.
View Article and Find Full Text PDFAbrocitinib is a selective Janus kinase 1 inhibitor approved for the treatment of atopic dermatitis. It is metabolized primarily by cytochrome P450 (CYP) 2C19 (approximately 53%) and CYP2C9 (approximately 30%), which form 2 active metabolites. The pharmacologic activity of abrocitinib is attributable to the unbound exposures of abrocitinib and those metabolites with active moiety area under the plasma concentration-time curve (AUC) considered the best measure of the total pharmacological effect.
View Article and Find Full Text PDFArticle Synopsis
- - Ritlecitinib is an oral medication being developed for treating moderate-to-severe alopecia areata, functioning as an irreversible inhibitor of specific kinases.
- - A study using advanced mass spectroscopy explored how ritlecitinib is absorbed, distributed, metabolized, and eliminated in the body, revealing key pharmacokinetic parameters like a clearance rate of 43.7 L/h and a bioavailability of 64%.
- - The research found that ritlecitinib binds to plasma proteins and is mainly cleared through urine, with metabolic processes involving various cytochrome P450 enzymes and glutathione-related conjugation playing significant roles.
Article Synopsis
- * To gain regulatory approval for the MR microsphere, researchers needed to establish bioequivalence (BE) with the IR solution, which was achieved by conducting physiologically-based pharmacokinetic (PBPK) virtual BE trials instead of traditional clinical ones.
- * The trials showed that the MR microsphere (10 mg once daily) is bioequivalent to the IR solution (5 mg twice daily) after both a single and multiple doses, highlighting a new method that minimizes unnecessary testing on healthy volunteers while aiding in drug formulation development.
Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of C-brepocitinib (∼300 nCi). The average mass balance recovery was 96.
View Article and Find Full Text PDF