Sirolimus Pharmacokinetics Variability Points to the Relevance of Therapeutic Drug Monitoring in Pediatric Oncology

Abstract

Sirolimus is widely used in transplantation, where its therapeutic drug monitoring (TDM) is well established. Evidence of a crucial role for sirolimus in the PI3K/AkT/mTor pathway has stimulated interest in its involvement in neoplasia, either as monotherapy or in combination with other antineoplastic agents. However, in cancer, there is no consensus on sirolimus TDM. In the RAPIRI phase I trial, the combination sirolimus + irinotecan was evaluated as a new treatment for refractory pediatric cancers. Blood sampling at first sirolimus intake (D1) and at steady state (D8), followed by LC/MS2 analysis, was used to develop a population pharmacokinetic model (Monolix® software). A mono-compartmental model with first-order absorption and elimination best fit the data. The only covariate retained for the final model was “body surface area” (D1 and D8). The model also demonstrated that 1.5 mg/m2 would be the recommended sirolimus dose for further studies and that steady-state TDM is necessary to adjust the dosing regimen in atypical profiles (36.4% of the population). No correlation was found between sirolimus trough concentrations and efficacy and/or observed toxicities. The study reveals the relevance of sirolimus TDM in pediatric oncology as it is needed in organ transplantation.

Predictors of sirolimus pharmacokinetic variability identified using a nonlinear mixed effects approach: a systematic review

“…Most SRL PopPK studies were performed on various types of transplant patients, including kidney transplants, 9,15,17,20,26 heart transplants, 19 pancreatic islet transplants, 18 and bone marrow transplants, 22 while cancer was the second most disease in which SRL PopPK studies were conducted, 21,27,28,[33][34][35] which included renal cell carcinoma, Kaposiform hemangioendothelioma, and several types of advanced Predictors of sirolimus pharmacokinetic variability identified using a nonlinear mixed effects approach e15 a wider IIV range than the k a (11.4% to 103.0%). As for the V d , the estimated values ranged from 88.9 to 3670 L for those with the 1-compartment structure, with the magnitude of IIV of 5.5% to 115.5%.…”

“…17 The sample sizes of the included studies ranged from 6 to 127 subjects, with half of the included studies retrospectively conducted using data from a clinical trial [19][20][21]23,34,37 and TDM data, [26][27][28]36 while the rest of the studies were prospective. 9,15,17,18,22,24,25,29,33 Most studies used sparse sampling strategy, 9,18,20,23,24,[26][27][28][29]36 whereas six and four studies employed an intensive sampling approach 15,17,22,25,34,35 and a mixture of both intensive and sparse sampling. 19,21,33,37 Concerning bioassay, most studies used liquid chromatography with tandem mass spectrometry (LCMS/MS), 17,[19][20][21][23][24][25]…”

“…9,15,17,18,22,24,25,29,33 Most studies used sparse sampling strategy, 9,18,20,23,24,[26][27][28][29]36 whereas six and four studies employed an intensive sampling approach 15,17,22,25,34,35 and a mixture of both intensive and sparse sampling. 19,21,33,37 Concerning bioassay, most studies used liquid chromatography with tandem mass spectrometry (LCMS/MS), 17,[19][20][21][23][24][25]33,34,37 mass spectrometry (MS), 15,22,33,35 or high performance liquid chromatography with ultraviolet detector (HPLC/UV), 18,20 whereas the rest utilized various types of immunoassays. 9,[26][27]…”

“…Most studies conducted a PopPK model using NONMEM ® software, except for four studies in which Phoenix NLME, 25,29 Monolix, 35 and P-Pharm 15 were used. Ten studies developed a model with a 1-compartment structure, 9,[18][19][20]24,[27][28][29]35,36 while nine studies used a 2-CMT disposition, 15,17,21,22,25,26,33,34,37 and the other one that explored the developmental trajectory of CL SRL employed a sigmoidal E max model.…”

“…Most studies conducted a PopPK model using NONMEM ® software, except for four studies in which Phoenix NLME, 25,29 Monolix, 35 and P-Pharm 15 were used. Ten studies developed a model with a 1-compartment structure, 9,[18][19][20]24,[27][28][29]35,36 while nine studies used a 2-CMT disposition, 15,17,21,22,25,26,33,34,37 and the other one that explored the developmental trajectory of CL SRL employed a sigmoidal E max model. 23 The first-order absorption process was used in all models, except studies by Djebli et al 17 and Wu et al 21 in which the Erlang distribution and the Michaelis-Menten kinetics were used to explain the absorption process.…”