Furthermore, the proportion of subtherapeutic em C /em min is comparable (17.0% in our study em vs /em . are observed with the use of the delayed\released tablet formulation (70C90%) 7, 20, 21. Marked variability in posaconazole exposure is still observed in PK studies of the delayed\released tablet formulation 10, 11, 22, 23, 24. Individuals receiving 300?mg daily have a median posaconazole em C /em min concentration of 1 1.08C1.89?mg?l?1 at constant state having a concentration range of 0.1C7.89?mg?l?1. Our data are consistent with these observations. We observed a median em C /em min 1.17?mg?l?1, with a range of 0.17C4.53?mg?l?1 and an overall CV of 50.4%. The degree of inter\ and intra\individual variability were 43.9% and 29.3%, respectively, similarly to those previously reported 22. Furthermore, the proportion of subtherapeutic em C /em min is comparable (17.0% in our study em vs /em . 8.6%, 15.4% and 29% in other studies) 10, 23, 25. Recognition of clinical factors associated with posaconazole exposure is definitely of great medical concern, as posaconazole underexposure was associated with the event of breakthrough IFIs both in experimental animal models 26 and in some clinical studies 5, 27. Although the new delayed\launch formulation seems to be less prone to suboptimal absorption, the pharmacokinetic variability of posaconazole may depend also on additional factors that impact CL. Our study demonstrates the use of PPIs and/or the use of steroids at dosages 0.7?mg?kg?1 daily are significant risk factors for drug underexposure. The effects of PPIs on intragastric pH is definitely dose\dependent and is related to the relative potency of each drug 28. It should be acknowledged that, in a different way from what we did in the current study, only a minority of the studies that previously assessed the influence of PPIs on posaconazole tablet exposure specified the type and dosage of the PPI. Different choices and/or different dosages of the PPIs may clarify why only some of the actual\world studies on posaconazole tablets still found co\administration of these drugs as being a risk element of low posaconazole levels, similarly to us. A retrospective study carried out among 157 individuals with haematological malignancies treated with posaconazole tablets showed that at multivariate analysis the use of PPIs ( em P /em ?=?0.015) was a risk factor for subtherapeutic posaconazole concentrations 11. In that study, other risk factors were the presence of diarrhoea ( em P /em ? ?0.001), low baseline albumin concentrations ( em P /em ?=?0.011) and body weight 90?kg ( em P /em ?=?0.047) 11 . Body weight and diarrhoea were significant risk factors for drug underexposure also in an earlier retrospective investigation 10. Conversely, in a recent retrospective study carried out among 48 haematological malignancy individuals who experienced 325 posaconazole em C /em min measurements, no significant relationship between the use of PPIs and the risk of suboptimal exposure with posaconazole tablets was observed at multivariate analysis 25. Related findings were recorded in another group of haematological individuals 20, in lung transplanted individuals 29 and in healthy volunteers receiving a 400?mg daily dose 8. The presence of gastro\intestinal mucositis is not associated with the risk of posaconazole underexposure during the use of delayed\launch tablets in two earlier studies 23, 24. Probably the most novel Rabbit Polyclonal to Caspase 7 (p20, Cleaved-Ala24) aspect of our analysis was the finding that corticosteroids may be a risk element for low posaconazole exposure in individuals with haematological malignancy. Posaconazole is definitely metabolized by UGT1A4 12. Intermediate or high dose steroids may have upregulated the activity of this enzyme and resulted in improved CL. This assumption is based on previous studies showing that UGT1A4 may be upregulated by steroids (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013) in pregnancy.Indeed, we notice that collinearity between steroids and HSCT might have prevented HSCT from becoming identified as an independent risk factor in our study, in a different way from what was observed by additional authors 25. Overall, our findings suggest that TDM of posaconazole tablet could be especially important for individuals receiving both PPI and steroids. We recognize that our study has several limitations. for individuals with haematological malignancies who receive induction chemotherapy or for HSCT recipients with GVHD requiring immunosuppression 3. A target em C /em min? ?0.7?mg?l?1 is advocated 15. Approximately 50% of individuals receiving standard dose of the oral suspension (200?mg every 8?h) achieve this target 15. In contrast, higher rates of target attainment are observed with the use of the delayed\released tablet formulation (70C90%) 7, 20, 21. Marked variability in posaconazole exposure is still observed in PK studies of the delayed\released tablet formulation 10, 11, 22, 23, 24. Individuals receiving 300?mg daily have a median posaconazole em C /em min concentration of 1 1.08C1.89?mg?l?1 at constant state having a concentration range of 0.1C7.89?mg?l?1. Our data are consistent with these observations. We observed a median em C /em min 1.17?mg?l?1, with a range of 0.17C4.53?mg?l?1 and an overall CV of 50.4%. The degree of inter\ and intra\individual variability were 43.9% and 29.3%, respectively, similarly to those previously reported 22. Furthermore, the proportion of subtherapeutic em C /em min is comparable (17.0% in our study em vs /em . 8.6%, 15.4% and 29% in other studies) 10, 23, 25. Recognition of clinical factors (R)-Sulforaphane associated with posaconazole exposure is definitely of great medical concern, as posaconazole underexposure was associated with the event of breakthrough IFIs both in experimental animal models 26 and in some clinical studies 5, 27. Although the new delayed\launch formulation seems to be less prone to suboptimal absorption, the pharmacokinetic variability of posaconazole may depend also on additional factors that impact CL. Our study shows that the use of PPIs and/or the use of steroids at dosages 0.7?mg?kg?1 daily are significant risk factors for drug underexposure. The effects of PPIs on intragastric pH is definitely dose\dependent and is related to the relative potency of each drug 28. It should be acknowledged that, (R)-Sulforaphane in a different way from what we did in the current study, only a minority of the studies that previously assessed the influence of PPIs on posaconazole tablet exposure specified the type and dosage of the PPI. Different choices and/or different dosages of the PPIs may explain why only some of the real\world studies on posaconazole tablets still found co\administration of these drugs as being a risk factor of low (R)-Sulforaphane posaconazole levels, similarly to us. A retrospective study conducted among 157 patients with haematological malignancies treated with posaconazole tablets showed that at multivariate analysis the use of PPIs ( em P /em ?=?0.015) was a risk factor for subtherapeutic posaconazole concentrations 11. In that study, other risk factors were the presence of diarrhoea ( em P /em ? ?0.001), low baseline albumin concentrations ( em P /em ?=?0.011) and body weight 90?kg ( em P /em ?=?0.047) 11 . Body weight and diarrhoea were significant risk factors for drug underexposure also in an earlier retrospective investigation 10. Conversely, in a recent retrospective study carried out among 48 haematological malignancy patients who had 325 posaconazole em C /em min measurements, no significant relationship between the use of PPIs and the risk of suboptimal exposure with posaconazole tablets was observed at multivariate analysis 25. Similar findings were documented in another group of haematological patients 20, in lung transplanted patients 29 and in healthy volunteers receiving a 400?mg daily dose 8. The presence of gastro\intestinal mucositis is not associated with the risk of posaconazole underexposure during the use of delayed\release tablets in two previous studies 23, 24. The most novel aspect of our analysis was the finding that corticosteroids may be a risk factor for low posaconazole exposure (R)-Sulforaphane in patients with haematological malignancy. Posaconazole is usually metabolized by UGT1A4 12. Intermediate or high dose steroids may have upregulated the activity of this enzyme and resulted in increased CL. This assumption is based on previous studies showing that UGT1A4 may be upregulated by steroids (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013) in pregnancy leading to an increased elimination of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2622, which is a substrate for UGT1A4 30. UGT1A4 contains http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=606 response elements, which by acting as xenobiotic receptor for a wide range of compounds, including steroids, may induce the glucuronidation (R)-Sulforaphane process 30, 31. This hypothesis is usually supported by a retrospective analysis conducted among 52 haematologic patients by Chin em et al /em . 23. These authors found at multivariate analysis that patients not receiving treatment for GVHD [including also high\dose steroids (either 1?mg?kg?1 daily.