Voriconazole Concentration Is Inversely Correlated with Corticosteroid Usage in Immunocompromised Patients: A Pharmacokinetic Profile

Background: Voriconazole (VRCZ) is a novel azole that exerts strong antifungal activity, and it can be administered orally or intravenously. Intra- and inter-individual variability of the VRCZ concentration in metabolism is reported. VRCZ shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are thus dependent on the administered dose. In these circumstances, drug interactions should also be considered. Hematologists commonly administer corticosteroid treatment to patients with hematological diseases, expecting an anticancer effect in some cases and an anti-inflammatory property in other cases. Against this background, we analyzed the influence of corticosteroid use on the serum VRCZ concentration using a population pharmacokinetics (PK) method.

Patients and method: This was a single-institute PK study at our hospital. We collected immunocompromised cases treated with VRCZ and with or without corticosteroid from June 2010 to August 2012 (2 yrs + 2 mos). The patients had hematological malignancies or hematological diseases such as thrombocytopenia. The inclusion criteria were: age >20 yrs, treated with corticosteroids for a hematological condition, and treated with VRCZ under a diagnosis of possible or probable fungal infection according to the IDSA criteria. VRCZ was predisposed intravenously and consequently administered orally according to its bioavailability. VRCZ was administered 2´/day for both the oral and intravenous routes. The dose was calculated according to the pharmaceutical company's manual. A double dose was used on the initial day as the loading dose. All patients concurrently treated with a corticosteroid were included in the study regardless of the administration route. We defined 'concurrent use of corticosteroid treatment' as only within 3 days before and after the initiation of VRCZ. Each corticosteroid dose was converted to a prednisolone-based dosage according to the anti-inflammatory effect (relative glucocorticoid activity). We used the total corticosteroid dose during VRCZ treatment to evaluate the contributing factors. The serum VRCZ concentration was measured at the trough point by high-performance liquid chromatography. The VRCZ concentration was measured >4 days from the initiation of VRCZ. Samples were collected just before the administration in the morning as a trough level.

Results: Fourteen cases (4 males, 10 females; median age 56 yrs, range 35-82 yrs) were investigated. The underlying diseases were acute myeloid leukemia (n=3), thrombotic thrombocytopenic purpura (n=3), chronic lymphoid leukemia (n=1), malignant lymphoma (n=1), and other immunocompromised status including autoimmune diseases (n=6). Five patients (35.7%) received chemotherapy; 12 received corticosteroid therapy. The average and median doses of corticosteroid per day were 55.7 and 80.0 mg/wk, respectively (range 0-377). A total of 27 samples were collected. The VRCZ dose ranged from 200 to 600 mg/day, administered orally for 10 patients and intravenously for four at the point of dose monitoring. The median VRCZ concentration was 2.93 mg/mL (avg. 3.00 mg/mL, 0.66-8.83 mg/mL). For the total samples as a whole, the VRCZ concentration was inversely correlated with the corticosteroid dose (r = −0.20). Conversely, 1/VRCZ concentration was weakly correlated with the corticosteroid dose (r = 0.17). We extracted two cases from whom more than four samples could be collected. In both cases, the relation between the VRCZ concentration and corticosteroid dose more clearly illustrated the inverse proportionality, with the correlation coefficients r = −0.68 and −0.77. Laboratory data evaluated simultaneously with the VRCZ concentration measurement showed no concomitance of severe liver damage; the median values of T.Bil, AST and ALT were 0.5 mg/dL (0.2-2.6), 31 IU/L (8-82) and 26 IU/l (3-82), respectively.

Discussion: Our PK study suggested that the VRCZ trough concentration is inversely correlated with corticosteroid usage in immunocompromised patients. VRCZ might be metabolized by an enzyme induced by corticosteroid in each individual. Although the inter-individual variance remains to be determined, we suggest that the VRCZ dosage be adjusted closely under therapeutic drug monitoring in cases involving corticosteroid therapy.