Population Pharmacokinetics of Everolimus in Relation to Clinical Outcomes in Patients With Advanced Renal Cell Carcinoma.

BACKGROUND: Everolimus has been used for the treatment of unresectable or metastatic renal cell carcinoma (RCC). Here, we measured blood concentrations of everolimus to obtain the population pharmacokinetic parameters and to examine the relationship between blood concentration and clinical outcomes. METHODS: Twenty-two Japanese patients were enrolled. Blood samples were collected before and 2, 4, 8, and 24 hours after drug administration on days 1 and 8 of everolimus therapy (5 or 10 mg) from inpatients; occasional samples were collected from outpatients. Blood concentrations of everolimus were measured by high-performance liquid chromatography with tandem mass spectrometry. Population pharmacokinetic analysis was conducted using the NONMEM software. RESULTS: Everolimus pharmacokinetics was best described by a 2-compartment model with population mean estimates of apparent oral clearance of 10.0 L/h and an interindividual variability of 42.4%. There was no relationship between overall best responses and the predicted trough concentrations at day 8. The predicted trough concentration in patients who terminated everolimus treatment owing to adverse drug reactions (ADRs) was significantly higher than in patients who stopped the treatment owing to disease progression or other reasons (27.6 ± 3.1 versus 15.7 ± 2.3 ng/mL; mean ± SEM). Patients who terminated the treatment owing to ADRs had significantly shorter time-to-treatment failure than other patients (112 versus 187 days, median). CONCLUSIONS: This study reports the first population pharmacokinetic parameters of everolimus in patients with RCC. Individual dose adjustment based on everolimus blood concentrations helps to avoid early drug cessation due to ADRs.

Exposure-toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Sorafenib has various adverse events that can cause treatment discontinuation or dose reduction. The aim of this study was to compare the safety profile between renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) patients receiving sorafenib under real-life practice conditions. Furthermore, we investigated the relationship between sorafenib exposure and clinical outcomes. METHODS: A total of 91 Japanese cancer patients (RCC, n = 21; HCC, n = 70) treated with sorafenib were enrolled. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0. Single blood samples were collected at each clinic visit and serum sorafenib concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The incidence of adverse events was analyzed according to cancer type and sorafenib concentration. RESULTS: Hand-foot skin reaction (HFSR) was the most common adverse event among RCC (76 %) and HCC (66 %) patients. Elevations in hepatic transaminases and pancreatic amylase developed more frequently in patients with RCC than in those with HCC (p < 0.05), while hyperbilirubinemia and thrombocytopenia were observed more often in HCC patients than in RCC patients (p < 0.05). Pharmacokinetic data were available from 52 patients (RCC, n = 16; HCC, n = 36). HCC patients showed significantly higher dose-normalized concentrations than RCC patients (p = 0.0184). Sorafenib concentrations were significantly greater in patients with grade ≥2 HFSR and hypertension than in those not experiencing the adverse events (p = 0.0045 and 0.0453, respectively). Furthermore, receiver operating characteristic curves revealed optimal cutoff concentrations of sorafenib to predict grade ≥2 HFSR (5.78 µg/mL) and hypertension (4.78 µg/mL). In addition, a trend of prolonged overall survival was observed in HCC patients who achieved a maximal sorafenib concentration of ≥4.78 µg/mL during treatment compared with those who did not achieve the threshold concentration (12.0 vs. 6.5 months; log-rank p = 0.0824). CONCLUSIONS: The results of this study suggest that the safety and pharmacokinetic profiles of sorafenib differ between Japanese cancer patients with RCC and HCC. Furthermore, the serum sorafenib concentration could be used as a guide to avoiding the development of severe HFSR while allowing prediction of the incidence of grade ≥2 hypertension in patients with RCC and HCC, and may potentially be related to the clinical efficacy of sorafenib for HCC.

Tolerable sorafenib therapy for a renal cell carcinoma patient with hemodialysis: a case study.

Sorafenib (Nexavar(®)) has been approved for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma. There is little information on the dosage adjustment of sorafenib for patients with end-stage renal failure. Herein, we have examined the effect of hemodialysis on the pharmacokinetics of sorafenib and its major active metabolite, M-2, and assessed sorafenib-related toxicity throughout the therapy. The patient was a 54-year-old man who was diagnosed with advanced RCC. Pharmacokinetic analysis was carried out on days 9 and 183. The patient had stable disease on day 77 and showed progression on day 181. He has received about 6 months of continuous treatment with sorafenib 800 mg/day without any clinically relevant toxicity. The pharmacokinetic parameters of sorafenib such as C (max) and AUC(0-12) on day 183 were in the range of the reference values reported in patients with normal renal function. Our results suggest that sorafenib administered at a dose of 400 mg twice per day was well tolerated, at least for 6 months, for a patient undergoing hemodialysis.

Prospective evaluation of the bayesian method for individualizing tacrolimus dose early after living-donor liver transplantation.

Tacrolimus is widely used to prevent acute rejection after transplantation, but achieving therapeutic blood concentrations of tacrolimus is often difficult because of large pharmacokinetic variability. In this study, the applicability of the Bayesian method to individualize tacrolimus dose was prospectively examined. Twenty adult recipients (Bayesian group) and another 20 adult patients (control group), all of whom underwent living-donor liver transplantation, were enrolled in this study. In the Bayesian group, the dose of tacrolimus during the first 3 and 4 weeks after surgery was adjusted with the Bayesian method using a population pharmacokinetic model, targeting a trough level of 5 to 12 ng/mL. The interindividual variability in tacrolimus concentrations was significantly reduced in the Bayesian group compared with the control group (average percentage coefficient of variation for all occasions, 32% vs 44% and 31% vs 39% in the first 3 and 4 weeks, respectively). In addition, more patients achieved the target concentrations in the Bayesian group than in the control group (average for all occasions, 85% vs 59% and 83% vs 70% in the first 3 and 4 weeks, respectively). These findings suggest that the Bayesian method can be used to calculate maintenance doses of tacrolimus in adult patients early after living-donor liver transplantation.