Verapamil as a culprit of palbociclib toxicity

Introduction

Hormone therapy is currently the mainstay treatment for hormone receptor (HR) positive breast cancer. ¹ A promising drug, palbociclib, received accelerated approval as a first line treatment when used with the aromatase inhibitor, letrozole, for postmenopausal women with HR positive advanced or metastatic breast cancer. ² Palbociclib inhibits cyclin dependent kinase 4 (CDK 4) and cyclin dependent kinase 6 (CDK 6), which halts cancer cells from progressing from the G1 phase to the S phase, ultimately leading to cell-cycle arrest. ³ CYP3A4 plays a major role in the metabolism of palbociclib and therefore strong CYP3A4 inducers and inhibitors should be avoided in combination with this drug. ⁴

Palbociclib has also been described as a substrate of the efflux transporters, permeability-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). ³ These efflux membrane pumps prevent accumulation of various foreign substances and toxins.^3,5 P-gp transporters are found mostly on epithelial cells lining the colon, small intestine, pancreatic ductules, bile ductules, kidney proximal tubules, and the adrenal glands. ⁵ P-gp can recognize a whole host of molecules and can eliminate them into bile, gastrointestinal lumen, and urine. ⁵ It also plays a role in extruding compounds out of hepatocytes leading to decreased effectiveness of a drug. ⁵ Similarly, BCRP transporters are found in liver hepatocytes, intestine, renal proximal tubular cells, and brain vasculature contributing to the distribution and elimination of various drugs. ⁶ These transporters also play a role in the blood–brain barrier and prevent toxic accumulation of compounds. ³

Numerous agents interact with the CYP isoenzymes and efflux transporters; therefore, clinicians need to be wary of potential and known drug interactions.^6,7 The following case report describes a potential drug interaction with the CYP3A4 and P-gp substrate potential of palbociclib with an agent with known inhibition qualities of the same isoenzyme and efflux pump.

Case report

A 68-year-old female with a medical history of hypertension treated with verapamil and Stage IV, Grade 3 ER+, PR+, HER 2 non-amplified invasive ductal carcinoma was recently started on letrozole and palbociclib. She completed her first cycle of palbociclib as part of a three-week on and one-week off regimen. She developed grade 4 neutropenia (absolute neutrophil count 0.41 × 10⁹/L) with her first cycle of palbociclib. After beginning her second cycle, she presented to the Emergency Department (ED) with fever of 103°F, general malaise, grade 3 stomatitis, and periorbital and lip swelling. She reported decreased oral intake due to painful mouth ulcers and was only able to tolerate a liquid diet. Her symptoms began the following day after taking palbociclib. In the ED, a complete blood count revealed leukopenia of 1.3 × 10⁹/L with an absolute neutrophil count of 0.55 × 10⁹/L. She also had a normocytic anemia with hemoglobin of 11.3 g/dL. Comprehensive metabolic panel showed transaminitis with aspartate aminotransferase of 99 international units/L and alanine aminotransferase of 75 international units/L. Medications from home included palbociclib, letrozole, verapamil, albuterol inhaler, calcium carbonate, cholecalciferol, citalopram, vitamin B12, cyclosporine ophthalmic emulsion, dicyclomine, multivitamin, naproxen sodium, pantoprazole, potassium chloride, promethazine-codeine, rosuvastatin, and tizanidine.

Review of her vital signs displayed hypotension, which was treated with 1.5 L of normal saline. Her palbociclib was held for leukopenia and the verapamil held due to hypotension. Since palbociclib was the only new medication addition taken the day prior to her symptoms, there was a concern that palbociclib was the inciting agent of her presentation. For the treatment of her hypertension, her verapamil was switched to amlodipine due to concern of a drug interaction between palbociclib and verapamil. Her stomatitis and periorbital and lip edema dissipated over the next five days.

Repeat lab work performed one week later demonstrated a white blood cell count 4.3 × 10⁹/L with an absolute neutrophil count of 1.72 × 10⁹/L. Her liver function tests had worsened to an aspartate aminotransferase of 303 international units/L and an alanine aminotransferase of 309 international units/L, and there was concern for possible liver metastasis. However, positron emission tomography scan demonstrated an unremarkable liver and the acute hepatitis panel was negative. The amlodipine was continued and she was restarted on palbociclib at a reduced dose approximately one month later with no side effects reported. Lab work performed three weeks later displayed a normal white blood cell count of 5.5 × 10⁹/L with an absolute neutrophil count of 2.86 × 10⁹/L and resolving transaminitis.

Discussion

Our patient developed febrile neutropenia, periorbital edema, grade 3 stomatitis with lip swelling, grade 3 aspartate aminotransferase and grade 2 alanine aminotransferase elevations that were likely induced by increased levels of palbociclib in the setting of CYP3A4 and P-gp inhibition.^2,5,8 Efflux membrane transporters such as P-gp are overexpressed in cancer cells and prevent chemotherapeutic agents from reaching their target intracellular concentrations. ⁵ These adenosine triphosphate-dependent transporters are significant barriers at preventing effective cancer treatments. ⁵ Verapamil, a calcium channel blocker, is one drug that acts as a P-gp inhibitor, which may have prevented the efflux of intracellular palbociclib. ⁵

P-gp and BCRP play a role in the blood brain barrier and can limit the delivery of chemotherapeutic drugs.^9,10 Several studies have evaluated palbociclib’s role in the treatment of breast cancer found in the central nervous system (CNS).^9,10 Since palbociclib is a substrate of P-gp and BCRP, the strong inhibition qualities of these CNS efflux pumps prevent palbociclib from residing within the CNS. ⁹ One study examined mechanisms behind the decreased effectiveness of palbociclib in brain tumors by using in vivo studies in transgenic mice. ⁹ The results demonstrated a ∼115-fold increase in brain exposure to palbociclib in mice deficient of efflux transporters in comparison to wild-type mice. ⁹ In this study, P-gp and BCRP were responsible for palbociclib’s limited distribution within the CNS. ⁹

There are three main mechanisms for inhibition of efflux transporters, which include blocking the drug binding site either competitively, non-competitively, or allosterically; affecting adenosine triphosphate hydrolysis; or interfering with the cell membrane lipids. ⁵ Of P-gp and BCRP, verapamil primarily is an inhibitor of P-gp.^11,12 Inhibitors are classified as first, second, or third generation based on their specificity, affinity, and toxicity. ⁵ Verapamil is considered a first-generation P-gp inhibitor. ⁵ In one study, oral administration of verapamil was shown to increase plasma level, prolong elimination of half-life, and increase volume of distribution of doxorubicin via inhibition of P-gp. ¹³ Another study found total body clearance of paclitaxel was markedly decreased after co-treatment with verapamil. ¹⁴

It is not surprising that our patient presented with a grade 4 neutropenia. In the PALOMA-1 trial, over 50% of patients had grade 3 and 4 neutropenia with exposure to palbociclib. ¹⁵ However, what is unique about our patient’s presentation is that she presented with febrile neutropenia, which was not reported in the PALOMA-1 trial and was less than 1% in the palbociclib arm of the subsequent PALOMA-3 trial.^15–17

There is an increased risk for stomatitis with the use of CDK4/6 inhibitors as was observed in one systematic review and meta-analysis. ¹⁸ In the PALOMA-1 study, at least 10% of patients receiving palbociclib and letrozole had stomatitis but most were only grade 1 or 2. ⁴ Our patient presented with a grade 3 stomatitis as she had mouth ulcers, swelling, and was only able to consume liquids. ⁸ The incidence of grade 3 or 4 stomatitis was less than 1% in the PALOMA studies. ¹⁶ One retrospective study performed at a single institution investigated treatment-related adverse events of palbociclib and endocrine therapy. ¹⁶ Interestingly, severe cases of mucositis/stomatitis typically involved swelling of the tongue and lips. ¹⁶ In addition to our patient’s lip swelling, her periorbital edema was also suspected to have been the result of elevated levels of palbociclib due to the timing of her presentation.

In the PALOMA-3 trial, grade 3 increase of aspartate aminotransferase was reported to be 3% and grade 2 increase of alanine aminotransferase was reported to be 4% in the palbociclib arm. ¹⁷ Transaminitis is more commonly seen with ribociclib and abemaciclib, two other cyclin-dependent kinase inhibitors used in hormone sensitive breast cancer.^19,20 Both are known substrates of CYP3A4, but abemaciclib is also a substrate for P-gp.^21–23 Ribociclib and abemaciclib have drug labeling dosing recommendations for drug induced liver injury.^19,20 In one study involving rats, palbociclib displayed a dose responsive effect on aspartate aminotransferase and alanine aminotransferase levels. ²⁴ As discussed earlier, P-gp plays a role in extruding compounds out of hepatocytes; therefore, if this efflux transporter were blocked, then increased intracellular concentrations of palbociclib might explain our patient’s transaminitis. ⁵

Interestingly, the above-mentioned side effects were not observed with amlodipine and palbociclib. This is likely due to amlodipine’s lack of significant interaction with P-gp.^6,25,26 Moreover, her other medications were continued without further side effects observed. Our patient’s febrile neutropenia, grade 3 stomatitis with lip swelling, periorbital edema, and transaminitis was hypothesized from elevated levels of palbociclib secondary to verapamil’s inhibition of P-gp and CYP3A4.^2,5,27 First-generation P-gp inhibitors, like verapamil, can interact with P-gp substrates leading to alterations of its pharmacokinetics and increased adverse effects. ⁵ In addition, verapamil is a moderate CYP3A4 inhibitor and when combined with a CYP3A4 substrate, such as palbociclib, it can lead to increased levels of plasma palbociclib resulting in increased adverse effects.^2,4,27 Verapamil’s inhibition of both P-gp and CYP3A4 is suspected to have led to the adverse side effects seen in our patient.^5,2,27