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PurposePrevious studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here.MethodsUsing recently published methodologies from our laboratory to differentiate metabolic- from transporter-mediated drug-drug interactions, a critical evaluation of five published ticagrelor drug-drug interactions was carried out to investigate the purported clinical significance of enzymes and transporters in ticagrelor disposition.ResultsThe suggested CYP3A4 inhibitors, ketoconazole and diltiazem, displayed unchanged mean absorption time (MAT) and time of maximum concentration (Tmax) values as was expected, i.e., the interactions were mainly mediated by metabolic enzymes. The potential CYP3A4/P-gp inhibitor cyclosporine also showed an unchanged MAT value. Further analysis assuming there was no P-gp effect suggested that the increased AUC and unchanged t1/2 for ticagrelor after cyclosporine administration were attributed to the inhibition of intestinal CYP3A4 rather than P-gp. Rifampin, an inducer of CYP3As after multiple dosing, unexpectedly showed decreased MAT and Tmax values, which cannot be completely explained. In contrast, grapefruit juice, an intestinal CYP3A/P-gp/OATP inhibitor, significantly increased MAT and Tmax values for ticagrelor, which may be due to activation of P-gp or inhibition of OATPs expressed in intestine.ConclusionsThis study provides new insight into the role of transporter pathways in ticagrelor intestinal absorption by examining potential MAT and Tmax changes mediated by drug-drug interactions.

PurposeThe involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban.MethodsUsing recently published methodologies to discern metabolic- from transporter- mediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition.ResultsRational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance.ConclusionsInhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.

PurposeTo examine the theoretical/practical utility of the liver-to-blood partition coefficient (Kpuu) for predicting drug-drug interactions (DDIs), and compare the Kpuu-approach to the extended clearance concept AUCR-approach.MethodsThe Kpuu relationship was derived from first principles. Theoretical simulations investigated the impact of changes in a single hepatic-disposition process on unbound systemic (AUCB,u) and hepatic exposure (AUCH,u) versus Kpuu. Practical aspects regarding Kpuu utilization were examined by predicting the magnitude of DDI between ketoconazole and midazolam employing published ketoconazole Kpuu values.ResultsThe Kpuu hepatic-disposition relationship is based on the well-stirred model. Simulations emphasize that changes in influx/efflux intrinsic clearances result in Kpuu changes, however AUCH,u remains unchanged. Although incorporation of Kpuu is believed to improve DDI-predictions, utilizing published ketoconazole Kpuu values resulted in prediction errors for a midazolam DDI.ConclusionsThere is limited benefit in using Kpuu for DDI-predictions as the AUCR-based approach can reasonably predict DDIs without measurement of intracellular drug concentrations, a difficult task hindered by experimental variability. Further, Kpuu changes can mislead as they may not correlate with changes in AUCB,u or AUCH,u. The well-stirred model basis of Kpuu when applied to hepatic-disposition implies that nuances of intracellular drug distribution are not considered by the Kpuu model.

Voriconazole is the first‐line treatment for invasive aspergillosis. Its pharmacokinetics exhibit considerable inter‐ and intra‐individual variability. The purpose of this study was to investigate the effects of CYP2C19, CYP2C9, CYP3A4, and FMO3 genetic polymorphisms and sex on the pharmacokinetics of voriconazole in healthy Chinese adults receiving single‐dose and multiple‐dose voriconazole, to provide a reference for its clinical individualized treatment. A total of 123 healthy adults were enrolled in the study, with 108 individuals and 15 individuals in the single‐dose and multiple‐dose doses, respectively. Plasma voriconazole concentrations were measured using a validated LC‐MS/MS method, and pharmacokinetics parameters were calculated using the non‐compartmental method with WinNonlin 8.2. CYP2C19, CYP2C9, CYP3A4, and FMO3 single‐nucleotide polymorphisms were sequenced using the Illumina Hiseq X‐Ten platform. The results suggested that CYP2C19 genetic polymorphisms significantly affected the pharmacokinetics of voriconazole at single doses of 4, 6, and 8 mg/kg and multiple doses of voriconazole. CYP3A4 rs2242480 had a significant effect on AUC0‐∞ (area under the plasma concentration‐time curve from time 0 to infinity) and MRT (mean residence time) of voriconazole at a single dose of 4 mg/kg in CYP2C19 extensive metabolizer. Regardless of the CYP2C19 genotype, CYP2C9 rs1057910 and FMO3 rs2266780 were not associated with the pharmacokinetics of voriconazole at three single‐dose levels or multiple doses. No significant differences in most voriconazole pharmacokinetics parameters were noted between male and female participants after single and multiple dosing. For patients receiving voriconazole treatment, CYP2C19 genetic polymorphisms should be genotyped for its precision administration. In contrast, based on our study of healthy Chinese adults, it seems unnecessary to consider the effects of CYP2C9, CYP3A4, and FMO3 genetic polymorphisms on voriconazole pharmacokinetics. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19)‐associated pulmonary aspergillosis superinfection with cytokine storm is associated with increased mortality. This study aimed to establish a physiologically‐based pharmacokinetic (PK) model to investigate the disease‐drug–drug interactions between voriconazole and nirmatrelvir/ritonavir in patients with COVID‐19 with elevated interleukin‐6 (IL‐6) levels carrying various CYP2C19 phenotypes. The model was constructed and validated using PK data on voriconazole, ritonavir, and IL‐6, and was subsequently verified against clinical data from 78 patients with COVID‐19. As a result, the model predicted voriconazole, ritonavir, and IL‐6 PK parameters and drug–drug interaction‐related fold changes in healthy subjects and patients with COVID‐19 with acceptable prediction error, demonstrating its predictive capability. Simulations indicated ritonavir could increase voriconazole exposure to CYP2C19 intermediate and poor metabolizers rather than decrease it, in contrast to what is indicated in the drug package insert. However, the predicted ritonavir exposures were comparable across subjects. In patients with COVID‐19, both ritonavir and IL‐6 increased voriconazole trough concentrations, which may lead to CYP2C19 phenotype‐dependent overexposure. In conclusion, COVID‐19‐induced IL‐6 elevation and ritonavir increased voriconazole exposure, and the magnitude of interactions was influenced by CYP2C19 phenotype. Thus, caution is warranted when prescribing voriconazole concomitantly with Paxlovid in patients with COVID‐19. [ABSTRACT FROM AUTHOR]

Crop growth parameters are the basis for evaluation of crop growth status and crop yield. The aim of this study was to develop a more accurate estimation model for corn growth parameters combined with multispectral vegetation indexes (VIopt) and the differential radar information (DRI) derived from SAR data. Targeting the estimation of corn plant height (H) and the BBCH (Biologische Bundesanstalt, Bundessortenamt and CHemical industry) phenological parameters, this study compared the estimation accuracies of various multispectral vegetation indexes (VIopt) and the corresponding VIDRI (vegetation index corrected by DRI) indexes in inverting the corn growth parameters. (1) When comparing the estimation accuracies of four multispectral vegetation indexes (NDVI, NDVIre1, NDVIre2, and S2REP), NDVI showed the lowest estimation accuracy, with a normalized root mean square error (nRMSE) of 20.84% for the plant height, while S2REP showed the highest estimation accuracy (nRMSE = 16.05%). In addition, NDVIre2 (nRMSE = 16.18%) and S2REP (16.05%) exhibited a higher accuracy than NDVIre1 (nRMSE = 19.27%). Similarly, for BBCH, the nRMSEs of the four indexes were 24.17%, 22.49%, 17.04% and 16.60%, respectively. This confirmed that the multispectral vegetation indexes based on the red-edge bands were more sensitive to the growth parameters, especially for the Sentinel-2 red-edge 2 band. (2) The constructed VIDRI indexes were more beneficial than the VIopt indexes in enhancing the estimation accuracy of corn growth parameters. Specifically, the nRMSEs of the four VIDRI indexes (NDVIDRI, NDVIre1DRI, NDVIre2DRI, and S2REPDRI) decreased to 19.64%, 18.11%, 15.00%, and 14.64% for plant height, and to 23.24%, 21.58%, 15.79%, and 15.91% for BBCH, indicating that even in cases of high vegetation coverage, the introduction of SAR DRI features can further improve the estimation accuracy of growth parameters. Our findings also demonstrated that the NDVIre2DRI and S2REPDRI indexes constructed using red-edge 2 band information of Sentinel-2 and SAR DRI features had more advantages in improving the estimation accuracy of corn growth parameters. [ABSTRACT FROM AUTHOR]