Hypercalcemia in children with APL caused by interactions between voriconazole and all-trans retinoic acid: A case report and literature review.

Rationale: All-trans retinoic acid (ATRA) and voriconazole (VRZ) are pivotal drugs for the treatment of acute promyelocytic leukemia (APL) and invasive fungal infections, respectively. When ATRA is co-administered with VRZ, clinically significant drug interactions may occur due to alterations in drug metabolism and clearance.

Patient concerns: We report a case of hypercalcemia caused by the interaction between ATRA and VRZ in a child with APL.

Diagnoses and interventions: A 14-year-old boy received arsenictrioxide (ATO) for APL and VRZ for invasive fungal infections, followed by planned maintenance therapy with ATRA monotherapy and combination of ATRA and ATO. He experienced no adverse reactions during the concurrent use of ATO and VRZ, while on the 12th day of combined ATRA and VRZ administration, his blood calcium levels significantly increased, accompanied by a series of symptoms. Following the discontinuation of VRZ and continuation of ATRA monotherapy, and subsequent maintenance chemotherapy with ATRA and ATO, his blood calcium levels decreased and remained within the normal range.

Outcomes: We reviewed the published literature and excluded primary hyperparathyroidism or ectopic parathyroid hormone secretion as the cause of hypercalcemia in the child. He did not use other cytochrome inhibitors that may affect ATRA metabolism other than VRZ. Multiple measurements of VRZ trough concentrations ranged from 1.2 to 3 μg/mL. According to the Drug Interaction Probability Scale (5 points) and Naranjo Probability Scale (4 points), the drug interaction between VRZ and ATRA is probable. The hypercalcemia and other clinical manifestations may be caused by the inhibition of ATRA metabolism by VRZ.

Lessons: During clinical use of ATRA, it is necessary to closely monitor the adverse drug interactions such as hypercalcemia and limit the use of drugs that may affect cytochrome P450 enzyme such as VRZ.