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Lactic acidosis, a potential toxicity from drug–drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report

Abstract Background Ribociclib, one of the cyclin‐dependent kinases (CDK) 4 and 6 inhibitors, in combination with endocrine therapies has been approved in the treatment of hormonal receptor positive, HER‐2 negative metastatic breast cancer worldwide. Long‐term usage of ribociclib with concomitant drugs, potential drug–drug interaction may develop which can limit the therapeutic value of CDK4/6 inhibitor. Case A 62‐year‐old with history of non‐insulin dependent diabetic, dyslipidemia, and essential hypertension was diagnosed with HR‐positive, HER‐2 negative metastatic breast cancer and treated with fulvestrant plus ribociclib. Four weeks after administration, elevated serum creatinine was observed, and then severe lactic acidosis with acute respiratory failure was subsequently reported. Ribociclib and fulvestrant were temporarily discontinued. Three days after renal replacement therapy, her clinical was stabilized. Combination ribociclib with metformin resulted in high plasma metformin levels and dangerous consequences. Hence, special precaution should be considered during concomitant treatment with sensitive transporter substrates. Conclusion Metformin associated lactic acidosis may potentially occur after combination with ribocilib, an uncommon but lethal complication from the interaction of these drugs, especially in patients who had preexisting renal impairment.

Not only long-term usage of ribociclib but also the problem of polypharmacy in the advanced breast cancer setting, potential drugdrug interactions (DDIs) may occur which can limit the therapeutic value of CDK4/6 inhibitor. Unlike palbociclib, ribociclib with a dose of 600 mg is a strong CYP3A4 inhibitor. Therefore, concomitant drugs either CYP3A4 inhibitors or CYP3A4 inducers that regularly prescribed in daily practice should be cautious. These interactions possibly will affect drug metabolisms which influence the efficacy and adverse toxicities. Additionally, previous in vitro study indicated that ribociclib has the potential to inhibit the activities of several drug transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP1B1/ 1B3), organic cationic transporter-1 and -2 (OCT1, OCT2), multidrug and toxin extrusion protein-1 (MATE1), and bile salt export pump (BSEP). However, only BCRP, OCT2, MATE1 and BSEP were inhibited at clinically relevant concentration. 6 Metformin, one of widely used oral hypoglycemic drugs, is generally excreted unchanged into urine via the renal transporters MATE1, MATE2-K, and OCT2. Therefore, inhibition of these transporters by ribociclib while metformin administers concomitantly can lead to increased metformin exposure and may deepens the harmful side effect of metformin. 7 Here, we reported clinical information of HR-positive, HER-2 negative metastatic breast cancer patient treated with fulvestrant plus ribociclib. Possible adverse events such as elevated serum creatinine and lactic acidosis were observed and discussed with the current knowledge of scientific evidence.  discontinued. Three days after renal replacement therapy, her clinical was stabilized; she was able to extubate and remove double lumen.

| CASE REPORT
Her renal function gradually recovered, and serum creatinine was reduced to 2.25 mg/dl. Additionally, her creatinine further decreased to 1.51 mg/dl in 1 month after discharge to the hospital. All changes in serum creatinine were shown in Figure 4. Drug-drug interactions from ribociclib with metformin have been reviewed previously. So, the potential reason for severe lactic acidosis is considered to be from metformin associated lactic acidosis (MALA) predisposing from prerenal acute kidney injury with drug-drug interaction from ribociclib with metformin.
Owing to her severe renal impairment persist after discharge, permanent withholding ribociclib was continued but fulvestrant monotherapy was given since December 2020. At that time, her chest CT scan in January 2020 showed progressive disease at lymph nodes, lung, and liver nodules. Fulvestrant was stopped and then capecitabine was given. Currently, she continuously received capecitabine with good performance status and response. No adverse event was observed.

| DISCUSSION
Here, we demonstrate potential lethal toxicity from co-administration of ribociclib, metformin, losartan, and amlodipine with simvastatin in advanced breast cancer patients who had preexisting renal impairment. However, no special adverse events have been identified during palbociclib treatment. Renal impairment was detected in 4 weeks after ribociclib initiation. Then, severe metabolic acidosis, lactic acidosis (blood lactate level 13.7 mmol/L) unfortunately occurred after 8 weeks of administration. After renal replacement therapy and drug interruption, she gradually recovered. Her serum creatinine turned to her baseline level previously.
In drug-drug interactions (DDIs), both palbociclib and ribociclib are substrates of the CYP3A4 enzymatic complex. 6 The co-administration of palbociclib or ribociclib with strong or moderate CYP3A4 inhibitors or inducers may be either leading a risk of increased toxicity or diminished efficacy. Slightly different in the CYP3A4 enzymatic complex between two drugs, co-administration with standard dose ribociclib may increase plasma concentrations of CYP3A4 substrates and accounts for more toxicities than palbociclib. Consistent with our report, no adverse event was observed during the administration of palbociclib. In contrast, elevation of serum creatinine and mild GI toxicities were reported a few weeks after the administration of ribociclib. Simvastatin, losartan, and amlodipine are the major CYP3A4 substrates. Taking ribociclib with these drugs affects drug metabolisms which subsequence develops toxicities as gradual renal impairment. Previously, concomitant simvastatin with palbociclib showed statin-induced rhabdomyolysis in a case study. 11 Changing ribociclib to palbociclib may report similar adverse reactions. According to effect in membrane  19 Other identified causes must also be effectively managed. Since metformin has a large distribution volume and slow rate of elimination from the deep compartment, long and multiple sessions of hemodialysis are necessary for preventing the rebound lactic acidosis in severe cases.
In resuming treatment with ribociclib, no available evidence supports using this drug in severe renal impairment (CrCl <30 ml/min).
However, only a small proportion of ribociclib is eliminated by the renal route. 9,20 Ongoing study of ribociclib in healthy patients with various degrees of renal impairment is currently recruiting participants and waiting for good outcomes.
F I G U R E 5 According to an in vitro study, ribociclib acts as inhibitors of various membrane transporters especially BRCP, OCT2, MATE1, and BSEP. Metformin is a drug substrate demonstrated in the gray color transporter. However, only OCT2 and MATE1 play potential role of DDI between ribociclib and metformin demonstrated in green star. As a result, a greater amount of metformin would accumulate in the blood causing the appearance of adverse effects. ABC, ATP-binding cassette; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; MATE1, multidrug and toxin extrusion protein; OATP, organic anion-transporting polypeptide; OCT, organic cationic transporter; P-gp, P-glycoprotein; Adapted from Ther Adv Med Oncol 2019, Vol. 11: 1-43. 8

CONSENT FOR PUBLICATION
The study has been approved by Institutional Ethical Committee.
Informed consent for publication was obtained from the patient.

ACKNOWLEDGMENTS
We sincerely thankful to our patient for giving us opportunity to treat her. Special thanks to our general medicine staff who help provided us the database.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analy-

DATA AVAILABILITY STATEMENT
The Authors allow the Journal to share all the published data, although there is not an online repository which they have been collected in.