| Summary: | 博士 === 國立臺灣大學 === 藥學研究所 === 92 === Sirolimus (SRL) solution was launched in Taiwan in 2001. It could enhance the effect of cyclosporine (CsA)-based or tacrolimus (FK)-based regimen. SRL, CsA and FK are the most potent immunosuppressants in current use. As a potent immunosuppressant, blood concentration determination is important for SRL. As 95% of the drug partitions in red blood cells, tedious extraction procedure is required. It is unstable at temperature above 25 degree Celsius and light-sensitive. Protected from light is essential in sample handling, storage and analysis. Currently, SRL blood concentrations can be analyzed by high performance liquid chromatography (HPLC) only, which makes routine blood level monitoring difficult. Fix-dose regimen of SRL was therefore recommended by manufacturer. However, clinical trial in National Taiwan University Hospital (NTUH) in 2000 revealed that frequent dosage reduction of the concurrent CsA was necessary. At that time, SRL could not be assayed domestically, and it cost US$ 1000 per sample when assayed abroad. The author therefore set up a SRL lab in NTUH. A new protocol with addition of SRL and reduced dose of CsA or FK based on the original critical pathway was designed. With blood levels of SRL, CsA and FK, as well as ADRs and effectiveness, we could individualize therapy and had better understanding of the pharmacokinetics and posology of SRL.
With the help of Wyeth-Ayerst Laboratories, a validated HPLC/UV method developed by them with small modification was set up in NTUH to determine SRL concentration in human whole blood. The accuracy and precision of the SRL assay were validated by Wyeth-Ayerst Laboratories. By reviewing the chemical properties and different HPLC-UV method of SRL, the author wrote an article to share our experience as the first SRL lab in Taiwan using HPLC-UV method, which contributed the keys to success.
The limitation of quantification was 2.5 ng/mL and the standard curve was linear at the concentration range of 2.5 to 75ng/mL. The coefficients of variation (CV) for both intraday and interday precision were less than 10%. Both intraday and interday biases were less than 6%. The recovery for SRL ranged from 98.2-105.3%.
It is recommended that SRL be taken at least 4 hours after CsA administration to minimize their interaction, but the significance of this interaction during chronic staggered administration is unclear. FK was reported not to affect SRL pharmacokinetics and can be used as a control to explore the interactions between CsA and SRL.
Twenty-two de novo kidney transplant patients were randomized to receive either CsA microemulsion capsules or FK capsules twice daily in combination with once-daily SRL solution and corticosteroids to prevent allograft rejection. SRL was administered 6 hours after the morning dose of CsA or FK. After receiving a 6-mg loading dose of SRL, participants received SRL 2 mg per day for at least 7 days, and neither the CsA nor FK dosage was adjusted for at least 3 days before and during blood sampling for pharmacokinetic profiling.
Twenty-one patients completed the study. There were no differences between the two groups in demographic data, renal and liver function, and SRL dosage during the study. The area under blood concentration-time curve, and peak and trough levels of SRL in the CsA group were 1.46 times (95% CI 1.21-1.71), 1.42 times (95% CI 1.08-1.76) and 1.42 times (95% CI 1.09-1.76), respectively, those of the FK group.
The relative bioavailability of fix-dose SRL in CsA-based regimen was 46% higher than that in FK-based regimen even though the drugs of each two-drug combination were administered 6 hours apart. Therapeutic drug monitoring of both SRL and calcineurin inhibitors is warranted irrespective of simultaneous or staggered administration.
After the availability of SRL tablet, blood monitoring and pharmacokinetic study was required because the 2 dosage forms are not bioequivalent (BE). As steady-state C0 is a reliable index of SRL exposure, a study was performed to understand the impact of SRL formulation on C0.
Twenty-two stable renal transplant recipients who had received CNI/SRL solution /steroid for more than 3 months before SRL solution converting to tablets were included. C0’s of SRL upon dosage form conversion, as well as those of each period with different dosage forms, were compared. The impacts of different CNIs and liver function on SRL levels were also assessed. With a dose of 0.03 mg/kg/day, SRL solution and tablets achieved a similar dose-adjusted C0 (2.9 ± 1.4 ng/mL/mg vs. 2.9 ± 1.3 ng/mL/mg, respectively) upon conversion. This was also true when multiple SRL C0’s obtained from different dosage form using periods were compared. C0 and dose-adjusted C0 of SRL were significantly higher in the cyclosporine-based regimen during the use of SRL solution, but not during the use of SRL tablets. Four patients with persistent liver enzyme elevation had higher dose-adjusted SRL C0, either in the solution- (p<0.01) or tablets-using period (p<0.05).
Through these years’ study, a lab using HPLC-UV to measure SRL whole blood concentration was set up. The pharmacokinetic study revealed that the AUC of SRL was higher in CsA-based regimen than FK-based regimen irrespective of staggered administration. Conversion from SRL solution to SRL tablets resulted in similar dose-adjusted C0. The dose-adjusted C0 of SRL in patients with persistent liver enzyme elevation was significantly higher than those with normal liver function.
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