Effects of Concomitant Administration of PXR Ligand Drugs on the Anticoagulant Effects of Warfarin.

We encountered cases in which the anticoagulant effects of warfarin (CYP2C9 substrate) were reversibly attenuated by the concomitant administration of rifampicin or bosentan, which are potent pregnane X receptor (PXR) ligands. The purpose of the present study is to report the previous case with rifampicin, and to evaluate the changes in the warfarin anticoagulant effects when withdrawing or switching bosentan treatment. The former is a case study of a 4-year-old girl undergoing warfarin treatment. The latter is a longitudinal study of 20 pediatric patients receiving stable warfarin treatment. The prothrombin time and international normalized ratio (PT-INR) values were extracted from the medical records and normalized by the daily-dose per body size as an index for the warfarin anticoagulant effects. Rifampicin treatment resulted in a 52.0% decrease in the anticoagulant index. On the other hand, 10 of 20 patients started bosentan and their anticoagulant index was reduced by a median of 2.00. Bosentan was withdrawn in 4 of 20 patients and their anticoagulant index increased by a median of 3.67. Six of 20 patients switched from bosentan to macitentan, which is considered not to activate PXR in clinical settings. However, switching from bosentan to macitentan resulted in a median of 2.25 reduction of the anticoagulant index rather than recovery of the response to warfarin. This study suggests not only the possibility of heterogeneity in the response to PXR activation and deactivation, but also the importance of long-term monitoring of drug-drug interactions when switching from bosentan to macitentan.

Pharmacokinetic Variability of Caffeine in Routinely Treated Preterm Infants: Preliminary Considerations on Developmental Changes of Systemic Clearance.

The purpose of this study was to clarify the variability of serum concentrations of caffeine (CAF) in preterm infants, and to deliberate on a better explanation for developmental changes of systemic clearance during the neonatal period. Forty-nine serum samples were obtained from 23 preterm neonates (age, 34.1 ± 18.8 d), and additive blood sampling was conducted periodically for 10 of the 23 patients after discontinuation of CAF treatment. The concentrations of CAF and its major metabolites were determined by liquid chromatography-tandem mass spectrometory. The serum concentrations of CAF were within therapeutic levels (5-25 µg/mL) in 37 samples and exceeded 25 µg/mL in the rest of the 12 samples, although no sample was in the toxic range (> 50 µg/mL). The inter- and intra-individual variability of the concentration to dose (C/D) ratio corrected for body surface area (BSA) was more negatively associated with postmenstrual age (PMA) rather than postnatal age (PNA). The serum concentrations of major metabolites were much smaller than those of CAF throughout the study, suggesting that the contribution of hepatic metabolism to drug elimination was small in the preterm infants under 241 d of PMA. The mean values for elimination half-life and oral clearance estimated in the 10 patients were 124.6 ± 44.6 h and 2.26 ± 0.73 mL/min/1.73 m2, respectively. Consequently, we confirmed that the exposure to CAF was considerably variable and provided additive insight that the C/D ratio corrected for patient's BSA and PMA are promising for describing and understanding the developmental change of clearance in preterm infants.