Stability of Sirolimus (Rapamycin) in Whole Blood

Salm, Paul; Tresillian, Michael; Taylor, Paul J.; Pillans, Peter I.

doi:10.1097/00007691-200008000-00010

Cited by 15 publications

(5 citation statements)

References 8 publications

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“…Blood samples were frozen at −80°C for 1 month prior to analysis, which might have adversely affected measurement of the rapamycin concentration in those samples. Results of other studies 24,25 indicate that the rapamycin concentration is not substantially affected in blood samples stored frozen at −80°C for 90 days and subsequently thawed. Therefore, we do not believe that blood sample storage prior to analysis significantly affected measurement of blood rapamycin concentration in the present study.…”

Section: Discussionmentioning

confidence: 80%

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Larson

Allstadt

Fan

et al. 2016

ajvr

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Objective To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. Animals 5 healthy purpose-bred hounds. Procedures The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and non-compartmental analyses. Results Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. Conclusions and Clinical Relevance Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in ng/mL. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, needs to be determined.

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Section: Discussionmentioning

confidence: 80%

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Larson

Allstadt

Fan

et al. 2016

ajvr

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“…Regarding long term stability, the present study highlights the possibility of storing samples up to 90 days at -20°C without significant variations, since an increment in drug concentrations <7% was found. In previous studies, Salm reported a substantial constancy of Siro concentrations in samples stored at -80°C for 6 weeks after one, two or three freezethaw cycles (9), while Streit reported a significant decrease after storing samples at -40°C for 6 months and after two freeze-thaw cycles (11). It is worth of note that in both previous trials the Authors used storage temperatures much lower than those presently worked.…”

Section: Discussionmentioning

confidence: 95%

“…In Table I 9 ) containing sirolimus (panels a-c) and everolimus (panels d-f In Fig. 3 LT o ' r = 0.786.…”

Section: Long Term Stabilitymentioning

confidence: 99%

“…reported a stability at 4°C or 30°C in light and dark up to 8 days, with a percentage decrease less than 10% for control at 15.0 ug/l; moreover, samples stored at -80°C for 6 weeks were stable after one, two or three freeze-thaw cycles (9). Besides, Siro was found to be stable in blood for 30 days ifstored at 4°C or 30°C (10), and a significant reduction in Siro blood concentrations was reported for samples stored at -40°C for 6 months which had undergone two freeze-thawing cycles (11).…”

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confidence: 95%

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Stability of Sirolimus and Everolimus Measured by Immunoassay Techniques in Whole Blood Samples from Kidney Transplant Patients

Capone¹,

Gentile²,

Polichetti³

et al. 2008

Int J Immunopathol Pharmacol

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The measurement of blood concentration of immunosuppressive drugs is strongly recommended because of the narrow therapeutic range. An important aspect in the therapeutic monitoring of a drug is its possible degradation. This paper is aimed at investigating the stability of two widely-used immunosuppressants, sirolimus and everolimus. Short (storage at 30 degrees C for 3 or 7 days) and long term (storage at -20 degrees C for 0-90 days with a single freeze-thaw cycle) stability of sirolimus and everolimus in whole blood samples from kidney transplant patients were examined by using MEIA and FPIA. Sirolimus and everolimus samples stored at 30 degrees C in light for up to a week showed a decrement in concentration of 5.2 percent and 6.1 percent, respectively. Our findings on long term stability for both sirolimus and everolimus highlight the possibility of storing samples at -20 degrees C for up to 90 days, without the need to use lower storage temperatures. The results have important implications for patients living far from laboratories where drug concentration is measured or when the storing of blood samples is needed for pharmacokinetic studies.

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“…When using LC-MS/MS, it has been shown that blood samples retain their analytical integrity for up to 3 days at 30°C when kept in the dark [30]. At 35°C, there was a 9 % loss of the drug after 3 days of storage and a 13 % loss after 6 days [29].…”

Section: Hplc With Mass Spectrometric (Ms) Detectionmentioning

confidence: 99%

Drug Monitoring of Sirolimus and Everolimus/Drug-Monitoring von Sirolimus und Everolimus

Armstrong¹,

Streit²

2003

LaboratoriumsMedizin

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Sirolimus (Rapamune â ) and everolimus (Certican TM ) are macrocyclic lactones with a novel mechanism of immunosuppressive action that act in synergy with the calcineurin inhibitors cyclosporine and tacrolimus. Both sirolimus and everolimus are rapidly absorbed (t max 1±2 h), but they have a relatively low systemic bioavailability. Sirolimus has a prolonged half-life (ca. 60 h) and is therefore administered once daily, whereas everolimus has a shorter half-life (ca. 17.5 h) and is normally given twice daily. Both drugs show substantial inter-and intraindividual variation in their pharmacokinetics. They are metabolized by the cytochrome P-450 3A (CYP3A) system and they are also substrates for P-glycoprotein. Drug-drug interactions are therefore observed with inhibitors or inducers of CYP3A/P-glycoprotein. The major side effects associated with sirolimus and everolimus appear to be hypercholesterolaemia, hypertriglyceridaemia, thrombocytopenia and leucopenia. However, in contrast to the calcineurin inhibitors, they are not nephrotoxic. Several analytical procedures based on HPLC-UV, liquid chromatography-mass spectrometry (LC-MS), or liquid chromatography-tandem mass spectrometry (LC-MS/ MS) have been described for the quantification of sirolimus. In the case of everolimus, LC-MS and LC-MS/MS methods have been reported. As yet, immunoassays are not available. A provisional therapeutic range for trough whole-blood sirolimus concentrations, measured using a chromatographic procedure, in renal transplant recipients receiving cyclosporine and corticosteroids as concomitant immunosuppression is 4±12 mg/L. If cyclosporine therapy is discontinued, a target trough range of 12±20 mg/L is recommended. A therapeutic range for everolimus has not yet been established. A significantly increased risk of acute rejection has been documented at everolimus trough levels below 3 mg/L when used in combination with cyclosporine and steroids. Zusammenfassung: Sirolimus (Rapamune â ) und Everolimus (Certican TM ) sind cyclische Makrolide mit einer a,b-Diketoamid-Bindung. Sie weisen einen anderen Mechanismus der Immunsuppression als die bisher verwendeten Calcineurin-Inhibitoren (Cyclosporine und Tacrolimus) auf, welche jedoch mit einer synergistischen Wirkung in Kombinationstherapie eingesetzt werden ko Ènnen. Sirolimus und Everolimus werden beide schnell adsorbiert (t max 1±2 Std), haben jedoch eine geringe Bioverfu Ègbarkeit. Sirolimus wird aufgrund seiner relativ langen Halbwertszeit (ca. 60 Std) nur einmal ta Èglich gegeben, wa Èhrend Everolimus mit einer ku Èrzeren Halbwertszeit (ca. 17,5 Std) zweimal ta Èglich gegeben wird.

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Stability of Sirolimus (Rapamycin) in Whole Blood

Cited by 15 publications

References 8 publications

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Stability of Sirolimus and Everolimus Measured by Immunoassay Techniques in Whole Blood Samples from Kidney Transplant Patients

Drug Monitoring of Sirolimus and Everolimus/Drug-Monitoring von Sirolimus und Everolimus

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