Mycophenolic acid pharmacokinetics in lung transplant recipients with cystic fibrosis.

BACKGROUND: Lung transplantation is an established treatment for cystic fibrosis (CF) patients with end-stage lung disease. Current immunosuppression includes the prodrug mycophenolate mofetil (MMF), which has led to improved transplant outcomes. Given the pancreatic insufficiency and malabsorption in CF patients, some transplant centers give higher doses of MMF to these patients based on lower predose levels (C(0)), even though C(0) values correlate poorly with mycophenolic acid (MPA) exposure. The focus of this pilot study was to determine the pharmacokinetics (PK) of MPA in CF when compared with noncystic fibrosis (NCF) lung transplant recipients. METHODS: Five CF and 5 NCF patients had 3 separate PK analyses performed through our clinical research center. In addition to MMF, all patients were on tacrolimus and prednisone and were diabetic on insulin. Twelve-hour total serum concentration-time profiles of MPA and MPA glucuronide (MPAG) were obtained after oral administration of MMF. Concentrations of total MPA and MPAG were determined by a validated liquid chromatography-tandem mass spectrometry method. PK parameters of MPA were calculated by the noncompartmental method. Student t test or Mann-Whitney test was used to assess the differences in the PK parameters between the 2 cohorts. RESULTS: CF patients were significantly younger (30.6 versus 59.4 years; P < 0.001) and had significantly lower serum albumin (3.8 versus 4.1 g/dL; P = 0.0018) than NCF patients. CF patients had significantly lower MPA area under the curve (47.7 versus 83.1 mg·h·L(-1); P = 0.016) and MPAG area under the curve (569 versus 911 mg·h·L(-1); P = 0.047) when compared with NCF patients. In addition, C(0) (2.6 versus 4.6 mg/L; P = 0.026) and maximum serum concentration (9.2 versus 20.3 mg/L; P = 0.016) were significantly lower, and apparent oral clearance (0.26 versus 0.13 L·h·kg(-1); P = 0.009) was significantly higher in CF patients. T(max) was delayed in CF patients but not significantly. No difference between CF and NCF patients was observed for intra- and interindividual variability. CONCLUSIONS: Given these results, the lower MPA exposure in CF patients may impact transplant outcome in this lung transplant population.

Standardization of LC-MS for therapeutic drug monitoring of tacrolimus.

BACKGROUND: LC-MS is increasingly used for therapeutic drug monitoring of tacrolimus. A recent summary from an international proficiency-testing scheme demonstrated that the mass spectrometry respondents were the largest method group. However, these methods lack standardization, which may explain the relatively poor interlaboratory agreement for such methods. This study aimed to provide one path toward the standardization of tacrolimus quantification by use of LC-MS. METHODS: A 40-member whole blood tacrolimus proficiency panel was circulated to 7 laboratories, 4 in the US and 3 in Europe, offering routine LC-MS-based quantification of tacrolimus. All laboratories used a common LC-MS platform and followed the manufacturer's instructions that accompanied an LC-MS reagent kit intended for tacrolimus quantification in whole blood samples. Four patient pools were prepared that had sufficient volume to allow comparison with a tacrolimus reference measurement procedure. RESULTS: For the 40-member panel, the standardized MassTrak LC-MS assay demonstrated excellent agreement with a validated LC-MS method used by Analytical Services International (y = 1.02x - 0.02; r = 0.99). The CVs for the pooled patient samples ranged from 2.0% to 5.4%. The mean difference from the reference measurement procedure ranged from 0.4% to 4.4%. CONCLUSIONS: Tacrolimus assay standardization, which must include all facets of the analysis, is necessary to compare patient results between laboratories and to interpret consensus guidelines. LC-MS can provide accurate and precise measurement of tacrolimus between laboratories.

Gender Authorship in the Field of Clinical Chemistry.

BACKGROUND: Gender underrepresentation has long existed in the science, technology, engineering, and mathematics fields. While there are upward trends in many areas of the life and health sciences, some disciplines are underrepresented in female author numbers, including first and corresponding authors. This study evaluated the participation by women as authors in the field of clinical chemistry. METHODS: Clinical Chemistry and The Journal of Applied Laboratory Medicine were selected for data collection. Data were classified into four categories: total number of authors for each article, number of female authors for each article, whether the first author was female, and whether the corresponding author was female. From these data, the percentages of female authors, articles with female first authors, articles with female corresponding authors, and articles where a female was either first or corresponding author were calculated. RESULTS: Both journals had ≥40% total female authorship, ≥45% female first author, and 64% female first or corresponding author. The 40% female author number matched the percentage of female doctoral degree, board certified clinical chemists, and the 39% female PhDs and MDs in academic clinical pathology departments. Compared with a selected group of science or medicine journals and gender reports, Clinical Chemistry and The Journal of Applied Laboratory Medicine exceeded most journals and gender reports in female total authorship, first author, and corresponding author. CONCLUSIONS: Women are well represented as authors in these two clinical chemistry journals. Both journals compare favorably against other scientific/medical journals. Female authorship in these two journals also parallels gender composition of the field of clinical chemistry.

Ultraperformance liquid chromatography-tandem mass spectrometry assay for iohexol in human serum.

BACKGROUND: Iohexol is an iodinated contrast dye that has been shown to be useful in the estimation of glomerular filtration rate (GFR) in patients with suspected renal insufficiency. We developed and validated an ultraperformance liquid chromatography (UPLC)-triple quadrupole mass spectrometry (MS/MS) assay for quantifying iohexol in human serum. METHODS: Sample preparation involved dilution of 50 microL serum with 400 microL water, followed by protein precipitation with zinc sulfate and methanol containing the structural analog ioversol as the internal standard. After 1:20 dilution of the supernatant with water, 5 microL was injected into the UPLC-MS/MS system. Chromatography was performed using a Waters Oasis HLB 5-microm particle size, 2.1 x 20 mm column maintained at 50 degrees C. We used a 1-step acetonitrile/0.1% formic acid gradient to elute the compounds of interest at a common retention time of 0.96 min. The multiple reaction monitoring transitions used for integration and quantification were m/z 821.7-->803.7 for iohexol and m/z 807.9-->589.0 for ioversol in the electrospray positive ionization mode. RESULTS: The assay was linear from 2.5 mg/L (lower limit of quantification) to 1500 mg/L iohexol, with a mean extraction efficiency of >99%. Recovery of nominal target concentrations was 99%-102%. Interassay imprecision ranged from 7.9% at a concentration of 2.5 mg/L to 4.1% at 1000 mg/L. Ion suppression studies showed no matrix effects on the ionization of the 2 compounds. CONCLUSIONS: This rapid UPLC-MS/MS method can be successfully used for quantifying iohexol in human serum.