Factors Influencing Posaconazole Concentrations in Hospitalized Patients Receiving Delayed Release Tablets

Abstract

Specific Aims: This retrospective study sought to determine the percentage of patients who achieved a therapeutic drug serum concentration and investigated influencing factors involved in suboptimal serum concentrations among patients treated with posaconazole DRT at BUMCT/BUMCP. Electronic medical records were utilized from BUMCT and BUMCP. Methods: A list of patients with at least one serum posaconazole concentration (SPC) was obtained and evaluated for inclusion criteria. Patients included had to be hospitalized and have received at least 5 days of posaconazole treatment with DRT with doses documented in the medication administration record. Additional review was performed of covariates that might affect posaconazole absorption or disposition. Covariates included age, sex, weight, BMI, solid organ transplant, cancer, solid tumor, hematologic cancer, severe neutropenia, history of GI disease/surgery, tablet crushing, diet, feeding tube, nutritional supplement, concomitant medications (statin, metabolic inducer, acid suppression, metoclopramide, antacid, sucralfate, corticosteroid), diarrhea, mucositis, and chronic kidney disease stage. ALT, AST, bilirubin, and alkaline phosphatase were included as a marker for liver disease. Albumin was recorded, and a recently proposed equation was used to correct for hypoalbuminemia, resulting in adjusted SPC (ASPC). Posaconazole is > 98% bound, and the equation for adjustment is ASPC = SPC * 1/(0.01 + 0.99 *ALB/4.4) A low SPC was defined as < 0.7 µg/ml for prophylaxis or < 1.0 µg/ml for treatment. High SPC was defined as SPC > 5.5 µg/ml. ASPC concentrations were evaluated using the same interpretation. Results: The mean age was 60.5 ± 12.0 years. Most of the population were males (n=30, 75%). The mean height, weight, and BMI were 173 ± 10.1 cm, 82.4 ± 19.6 kg, and 27.5 ± 6.14, respectively. A history of solid organ transplant was found in 27, including lung (18), heart (2), kidney (4) and liver (3). Ten subjects had cancer including 7 with solid tumors and 3 with leukemia/lymphoma. A loading dose was utilized for 17 subjects. Most were prescribed a regular diet and nutritional supplements were ordered for half the subjects (n=20). The SPC for the initial TDM averaged 1.19 ± 0.65 µg/ml, and after adjustment for albumin, the mean ASPC was 1.79 ± 1.12 µg/ml. The initial SPC was characterized as low in 11/40 (27.5%). After adjustment for albumin, this number dropped to 7 (17.5%). No “high” concentrations were encountered. Covariates associated with low SPC included receipt of a proton pump inhibitor, diarrhea, and tube feeding; however, none of these were statistically significant. Advanced stages of chronic kidney disease were not associated with low SPC. The timing of food and nutritional supplements relative to posaconazole dose could not be explored due to lack of documentation. Conclusions: Given that free concentrations determine antifungal activity and drug disposition, use of aSPC in cases of hypoalbuminemia is recommended. We were unable to identify the factors responsible for low aSPC. More detailed PK monitoring is needed to differentiate between poor bioavailability versus rapid elimination.