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Letermovir (MK‐8228/AIC246) is a cytomegalovirus (CMV) DNA terminase complex inhibitor for CMV prophylaxis in adult patients undergoing hematopoietic stem cell transplant. It is cytochrome P450 (CYP) 3A inhibitor and inhibits organic anion transporting polypeptide 1B1/3 and breast cancer resistance protein transporters. Atorvastatin (ATV), a commonly used treatment for hypercholesterolemia, is a substrate of organic anion transporting polypeptide 1B1, potentially breast cancer resistance protein, and CYP3A. As letermovir may be coadministered with ATV, the effect of multiple‐dose letermovir 480 mg once daily on the pharmacokinetics of single‐dose ATV 20 mg and its metabolites (ortho‐hydroxyatorvastatin [o‐OH‐ATV] and para‐hydroxyatorvastatin [p‐OH‐ATV]) was evaluated in an open‐label trial in healthy female adults (N = 14). ATV area under the plasma concentration–time curve from time 0 to infinity and maximum plasma concentration (Cmax) increased ≈3‐fold with letermovir coadministration. The time to ATV Cmaxalso increased, while apparent clearance decreased. The exposures of o‐OH‐ATV and p‐OH‐ATV were comparable in the presence versus absence of letermovir; however, o‐OH‐ATV Cmaxdecreased by 60% with coadministration, while p‐OH‐ATV Cmaxwas similar. Due to the increase in ATV exposure with letermovir coadministration, statin‐associated adverse events such as myopathy should be closely monitored following coadministration. The dose of ATV should not exceed 20 mg daily when coadministered with letermovir.

Detachment of epithelial cells from the glomerular capillary wall correlates with the massive increase in protein leakage across the capillary wall that is characteristic of many renal diseases. We introduce the hypothesis that this detachment process involves three classes of physical events acting at the subcellular level: the receptor-mediated binding of epithelial cells to basement membrane, the transglomerular hydraulic pressure gradient acting to lift the cells off the basement membrane, and a receptor-receptor co-operativity induced by mechanical deformations of the epithelial cell surface. After presenting the available evidence, we explore the hypothesis by means of a simplified, quantitative model of the detachment process. The model is developed by mapping between the stochastic events of cell adhesion receptor binding and the equilibrium statistical mechanics of the Ising model. Monte Carlo simulations predict cell attachment under normal conditions, as expected from experimental data, and detachment at lower receptor binding affinity and/or increased pressure gradient. The normal attached state in the model is found to be particularly sensitive to changes in the receptor-binding affinity. The amount of resistance the cell surface offers to deformation forces is a key determinant of whether the detachment of small clusters of receptors spreads to involve large areas of the plasma membrane, precipitating bulk detachment. Copyright 1993, 1999 Academic Press