Focal Segmental Sclerosis Associated with the Novel Multi-tyrosine Kinase Inhibitor Ponatinib.

Ponatinib is a novel multi-tyrosine kinase inhibitor (TKI) with potent inhibitory activity against refractory chronic myeloid leukemia (CML). Despite its high clinical efficacy, ponatinib induces various adverse events due to its multi-target characteristic. However, renal complications associated with ponatinib are rare. A 76-year-old woman had a history of chronic myeloid leukemia (CML) resistant to imatinib and nilotinib. Our patient developed proteinuria and renal function deterioration during treatment with ponatinib but not with imatinib or nilotinib. We herein report the first case of a patient with secondary focal segmental glomerulosclerosis (FSGS) with partial glomerular collapse induced by ponatinib treatment.

Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients.

Physiologically based pharmacokinetic (PBPK) modeling is useful for evaluating differences in drug exposure among special populations, but it has not yet been employed to evaluate the absorption process of tacrolimus. In this study, we developed a minimal PBPK model with a compartmental absorption and transit model for renal transplant patients using available data in the literature and clinical data from our hospital. The effective permeability value of tacrolimus absorption and parameters for the single adjusting compartment were optimized via sensitivity analyses, generating a PBPK model of tacrolimus for renal transplant patients with good predictability. Next, we extrapolated the pharmacokinetics of tacrolimus for liver transplant patients by changing the population demographic parameters of the model. When the physiological parameters of a population with normal liver function were changed to those of a population with impaired hepatic function (Child-Pugh class A) in the constructed renal transplant PBPK model, the predicted tacrolimus concentrations were consistent with the observed concentrations in liver transplant patients. In conclusion, the constructed tacrolimus PBPK model for renal transplant patients could predict the pharmacokinetics in liver transplant patients by slightly reducing the hepatic function, even at three weeks post-transplantation.

Nivolumab-associated glomerular endothelial injury in a patient with gastric cancer.

A 68-year-old male with gastric cancer was treated with tegafur/gimeracil/oteracil and oxaliplatin for 6 months. Thereafter, he was treated with paclitaxel and ramucirumab for 3 months. However, neither regimen had much effect. Thus, he was treated with nivolumab for 2 months, but he developed proteinuria, microhematuria, and an acute kidney injury. A kidney biopsy revealed occasional swollen endothelial cells and proliferating mesangial cells. Few abnormal findings were seen in the tubules or interstitial tissue. Immunofluorescent staining showed segmental immunoglobulin A and complement component 3 deposition, in the mesangial area. Electron microscopy showed a small amount of electron-dense deposits in the paramesangial area and swollen endothelial cells. Mesangial interposition, the loss of endothelial cell fenestration, and subendothelial edema were also observed. Furthermore, foot process effacement and villous transformation of epithelial cells were noted. After the discontinuation of nivolumab, the patient's renal function gradually improved, and his proteinuria disappeared. Nivolumab treatment was restarted at that time because of cancer progression; however, it was ineffective. No occult blood was detected from 7 months after the administration of the last dose of nivolumab. This is a unique case, in which a kidney biopsy revealed evidence of nivolumab-associated glomerular endothelial injury.