P14 Fluctuation of sirolimus dosing in a child (neonatal to infancy) with cardiac rhabdomyomas
Authors: Brooks Teresa , Whiteley Sarah , Morris Stephen 
Published: April 2023

Introduction

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor and well-known for its anti-tumour effect increasing the tumour disappearance rate of rhabdomyoma. Cardiac rhabdomyomas are a rare condition associated with tuberous sclerosis. They present antenatally as benign tumours which grow for six months postnatally. Mostly, the tumours regress without treatment. Rhabdomyomas are problematic when they cause cardiac arrhythmias and obstruction to cardiac blood flow. Larger tumours can cause life-threatening obstruction of the ventricular outflow tracts or cardiac dysfunction; only treatment options are surgical resection or sirolimus. Sirolimus undergoes metabolism in the intestinal wall and liver. Sirolimus is primarily metabolised by O-demethylation and/or hydroxylation via CYP3A4 and P-glycoprotein forming metabolites which are pharmacologically inactive. These metabolic pathways and enzymes can mature at different ages, although the exact timings and effect this has on medications is unknown.

Situation

A 10-day 39/40 neonate (3.75kg) with antenatal diagnosis of multiple cardiac rhabdomyomas; including potential life-threatening obstruction of the left ventricular outflow tract and moderate obstruction of the right ventricular outflow tract. To avoid surgical resection a treatment course of sirolimus was commenced to prevent further growth of the tumours and lead to a reduction in size. Sirolimus is unlicensed in this indication/cohort and dosing experience is limited. Dosing of 0.25 mg (1 mg/m2) daily with a target blood concentration of 5–15ng/mL was used based on the prospective cohort study.1This led to a concentration of 16.2ng/mL after 4 days and 19.8ng/mL after a further week, with two doses omitted and dose reduced to 0.12 mg (0.48 mg/m2) daily. Three further doses were omitted and the dose reduced to 0.05 mg (0.2 mg/m2) daily giving stable concentrations of 5–7ng/mL until approximately 3 months of age when concentrations dropped to 2.9ng/mL. At this point multiple dosage increases were needed to maintain concentrations within the target range, with a final dose of 0.5 mg (1.47 mg/m2) daily (infants weight 5.99kg) being sufficient, ten times the original dose required to maintain target concentrations.

Lessons Learnt

It is theorised that a metabolic pathway involved in the metabolism of sirolimus may have matured during the neonatal to infant period, causing an increased clearance rate. CYP3A4 activity is very low at birth and gradually increases to adult activity throughout infancy.2There is a large increase in activity of CYP3A4 during the first 3 months of life, with nearly no activity during the first few days3which may have contributed to the initial high sirolimus concentrations observed in this patient. However as this is a single case interpatient variability could play a role. The medication was well tolerated with few side effects. Mild neutropenia (1.33 109/L) was observed with high sirolimus concentrations, but resolved when sirolimus concentrations returned to the target range. It is clear from this case that close blood concentration monitoring is required for neonates and infants requiring sirolimus treatment in order to achieve target concentrations consistently and to reduce the risk of toxic concentrations which could lead to dose dependent adverse effects.

References

Chen X-Q, Wang Y-Y, Zhang M-N, Lu Q, Pang L-Y, Liu L-Y, Li Y-F, Zou L-P. Sirolimus can increase the disappearance rate of cardiac rhabdomyomas associated with tuberous sclerosis: a prospective cohort and self-controlled case series study.The Journal of Paediatrics2021;233:150–155.

Anker J, Reed MD, Allergaert K, Kearns GL. Developmental pharmacokinetics in pediatric populations.The Journal of Clinical Pharmacology2018;58(S10):S10-S25. Available online: https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.1284 [Accessed 09/06/22]

Lu H, Rosenbaum S. Developmental pharmacokinetics in paediatric populations.The Journal of Pediatric Pharmacology and Therapeutics2014;19:262–276. Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341411/