Therapeutic Drug Monitoring of Blood Sirolimus and Tacrolimus Concentrations for Polypharmacy Management in a Lymphangioleiomyomatosis Patient Taking Two Cytochrome P450 3A Inhibitors

Therapeutic Drug Monitoring of Blood Sirolimus and Tacrolimus Concentrations for Polypharmacy Management in a Lymphangioleiomyomatosis Patient Taking Two Cytochrome P450 3A Inhibitors

Masaki Kumondai,¹ Masafumi Kikuchi,^1,2 Atsushi Mizuguchi,¹ Nagomi Hayashi,² Masahiro Ui,³ Takashi Hirama,³ Yoshinori Okada,³ Yu Sato,¹ Toshihiro Sato,¹ Masamitsu Maekawa^1,2 and Nariyasu Mano^1,2

¹Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi, Japan
²Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
³Department of Thoracic Surgery, Tohoku University Hospital, Sendai, Miyagi, Japan

Patients with lymphangioleiomyomatosis (LAM) and lung transplantations are treated with multiple drugs, such as tacrolimus, mycophenolate mofetil, prednisolone, and itraconazole, for long-term suppression of rejection response and prevention of infection. Additional drugs are required when lung transplant recipients develop graft complications. Therefore, managing polypharmacy is critical because of drugdrug interactions caused by various factors, including drug-metabolizing enzymes such as cytochrome P450 3A (CYP3A). The patient was a 48-year-old woman (height 144.9 cm and weight 38.4 kg) who underwent lung transplantation for LAM. Mycophenolate mofetil, tacrolimus (target blood concentration, 4.0-8.0 ng/mL), and prednisolone were administered for immunosuppression, and itraconazole and clarithromycin were administered to manage graft infection. The patient developed unilateral lymphedema, predominantly in the left leg; therefore, sirolimus was initiated with a target blood concentration of 3.0-5.0 ng/mL. In addition to 1.0 mg/day of sirolimus, tacrolimus (0.3 mg/day), itraconazole (100 mg/day), and clarithromycin (800 mg/day) were added. Blood sirolimus concentrations ranged from 18.8 to 36.9 ng/mL on days 6 to 9; thus, treatment with sirolimus was stopped because of over-target blood concentrations. Blood concentrations of sirolimus and tacrolimus were successfully managed without adverse events using therapeutic drug monitoring (TDM) and azole anti-fungal substitution of azithromycin instead of clarithromycin although sirolimus concentration was relatively lower compared to the target range. Thereby, frequent TDM, management of polypharmacy that influences CYP3A activity, and possibly CYP3A genotyping should be appropriately conducted for personalized medicine.

Key words —— cytochrome P450 3A; drugdrug interactions; lung transplantation; lymphangioleiomyomatosis; therapeutic drug monitoring

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Tohoku J. Exp. Med 2023 May, 260(1), 29-34.

Correspondence: Masaki Kumondai, Ph.D., Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: masaki.kumondai.d5@tohoku.ac.jp