Increasing sirolimus levels in a multiorgan transplant patient related to interaction with ciprofloxacin

• Published in: Clinical toxicology (Philadelphia, Pa.) Vol. 43; no. 6; p. 631
• Main Authors: Geib, A, Burns Ewald, M
• Format: Journal Article
• Language: English
• Published: 01.10.2005
• ISSN: 1556-3650

We describe a pharmacokinetic interaction between sirolimus and ciprofloxacin. A 5-year-old male was admitted for gastrointestinal bleeding. His medical history was significant for small bowel, liver, and pancreas transplant. He took multiple medications including sirolimus and ranitidine. Meropenem was started on hospital day (HD) 11, and ciprofloxacin on HD 13 for treatment of a Serratia indwelling line infection. Despite decreases in dosing, he experienced a sudden and persistent increase in sirolimus concentration to above therapeutic range (goal 10 ng/ml) after introduction of ciprofloxacin. Simultaneously, serum phosphate declined to a nadir of 1.7 mg/dl despite increasing supplementation. Physical exam and laboratory parameters otherwise remained unchanged from baseline. Sirolimus and phosphate concentrations normalized after ciprofloxacin withdrawal on HD 18. Sirolimus therapy was replaced with tacrolimus, which was continued after discharge. Calculation of mean residence time (MRT) of sirolimus did not demonstrate a substantial increase with ciprofloxacin co-administration. This implies no impairment of clearance and linear pharmacokinetics. The normalized area under the curve (AUCn) of sirolimus doubled during the last three days of ciprofloxacin. This suggests saturable elimination such as P-glycoprotein (P-GP) or P450. Sirolimus is a CYP3A4 and P-GP substrate. Ciprofloxacin is a CYP3A4 inhibitor. A pharmacokinetic interaction increased sirolimus concentration. Literature review reveals no previously reported interaction between these drugs. Dose related side effects include anemia and hyperlipidemia; hypophosphatemia, leukopenia and pulmonary fibrosis do not appear to be dose related. We recommend careful monitoring of sirolimus concentrations; and renal, pulmonary, hematologic, and metabolic parameters when sirolimus and ciprofloxacin are co-administered.