Phantom Lactic Acidosis Secondary to a Drug-Drug Interaction between Ribociclib and Metformin in the Setting of CKD

Introduction: Ribociclib is a CDK4 and CDK6 inhibitor widely used for treating hormone receptor-positive and human epidermal growth factor receptor 2 (HER-2)-negative metastatic breast cancers. Metformin is a biguanide, one of the most essential and primitive medications for type 2 diabetes. We present a unique drug-drug interaction between ribociclib and metformin, causing severe lactic acidosis in a 54-year-old postmenopausal woman with Invasive Ductal Carcinoma of breast, CKD stage 3, and Diabetes Case Description: A 54-year-old woman incidentally felt a mass in the left breast and was subsequently diagnosed with Invasive Ductal Carcinoma (IDC) (ER 100%, PR 10%, Her2 -ve, Ki-67 33%), histologic grade 3 with lymphovascular invasion (T1 NO M0) by core needle biopsy. She underwent lumpectomy with sentinel lymph node biopsy. She underwent re-excision and was started on radiation therapy. Iliac bone biopsy showed metastatic poorly differentiated adenocarcinoma. She was given radiation therapy to the iliac bone, resulting in theresolution of her hip pain. She was given zoledronic acid for the bony lesions, and started on Fulvestrant and Ribociclib. 5 months later, she presented with generalized weakness and nausea, workup revealed Bicarbonate at 17, AKI on CKD with creatinine elevation from baseline of 1.7 to 2.2, potassium of 5.3, with a pH of 7.34, PCO2 of 28, and lactic acid levels at 5.1. Metformin was immediately stopped. She was started on oral and IV sodium bicarbonate and fluids. Her creatinine improved to 1.7, potassium improved to 4.4, and lactic acid dropped to 2.4. She was subsequently discharged with a follow-up lactic acid and kidney function test in clinic, which remained satisfactorily close to the baseline, and the patient remained asymptomatic. Discussion: Ribociclib-induced AKI is usually reversible but may require treatment interruption or hemodialysis in severe cases. Metformin uptake from the circulation into renal epithelial cells occurs via OCT2, and from the renal cell into the lumen is mediated by MATE1 and MATE2-K. Ribociclib has the potential to inhibit OCT2 and MATE1, causing decreased renal clearance of metformin if administered together, leading to severe lactic acidosis. The use of metformin and ribociclib in consortium results in high metformin levels and subsequently, type B lactic acidosis, specifically in patients with preexisting CKD.