Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus

Rapamycin is active against B-precursor leukemiain vitroandin vivo, an effect that is modulated by IL-7-mediated signaling

“…By 4-5 days of culture, all of the cells treated (even with the lowest concentration of rapamycin) were dead (data not shown). By comparison, typical serum levels of patients on rapamycin are 8-12 ng͞ml, showing that this effect is pharmacologically relevant (59). Rapamycin was tested in several murine and human T and B cell leukemia lines, including Jurkat, BJAB, J558L, Nalm 6, and Nalm 16, and had similar growth-inhibitory effects in each cell line tested (V.I.B., unpublished data).…”

mTOR inhibitors: An overview

“…Mean graft half-life after transplantation remains almost unchanged for 2 decades, and chronic rejection is still a major problem after kidney and heart transplantation (graft vascular disease), liver transplantation (vanishing bile duct syndrome), and lung transplantation (obliterative bronchiolitis). Such side effects as nephrotoxicity are so common that elevated creatinine levels of 150 to 170 mol/L and deterioration of kidney function are accepted as normal, 79,113 resulting in high morbidity and mortality rates over time. 114 Inhibitors of mTOR, sirolimus and RAD, are a new class of immunosuppressive agents that could solve some of these problems.…”

“…76 In contrast to cyclosporine A, sirolimus trough concentrations are stable over time and strongly correlated with 24-hour exposure (area under the curve [AUC] 0-24h ; r 2 ϭ 0.19 v r 2 ϭ 0.96). 79,80 Furthermore, sirolimus whole-blood concentrations are linear and dose proportional between 3 and 12 mg/m 2 . 76 There is no significant effect on C max (maximal concentration) or AUC by sex, age, or ethnic origin.…”

“…There are indications that trough concentrations greater than 15 ng/mL have a high risk for thrombocytopenia and hyperlipidemia, and trough concentrations less than 6 ng/mL are associated with an increased incidence of acute rejection. 79,[85][86][87][88] Because of the long half-life of sirolimus, trough levels obtained 5 to 7 days after dose adjustments should be sufficient. 79 Assays for pharmacodynamic monitoring are developed by measuring p70 S6 kinase activity 89 and 3 H-thymidine incorporation 90,91 and detecting expression of proliferating nuclear antigen/SG 2 M and T-cell surface activation molecules by flow cytometry (R.E.…”

Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs

“…1 B and C). The doses of each agent that, when used in combination, caused profound inhibition were below typical therapeutic serum levels of each drug (8,32). Drug interaction analyses indicated that inhibition was synergistic (Fig.…”