Clinical utility of vinblastine therapeutic drug monitoring for the treatment of infantile myofibroma patients: A case series

Infantile myofibroma is a rare, benign tumour of infancy typically managed surgically. In a minority of cases, more aggressive disease is seen and chemotherapy with vinblastine and methotrexate may be used, although evidence for this is limited. Chemotherapy dosing in infants is challenging, and vinblastine disposition in infants is unknown. We describe the use of vinblastine therapeutic drug monitoring in four cases of infantile myofibroma. Marked inter‐ and intrapatient variability was observed, highlighting the poorly understood pharmacokinetics of vinblastine in children, the challenges inherent in treating neonates, and the role of adaptive dosing in optimising drug exposure in challenging situations.

and tyrosine kinase inhibitors. 2,[4][5][6][7] Vinblastine and methotrexate are used widely in other fibrous tumours, with minimal long-term toxicity reported. 8,9 While vincristine pharmacokinetics are relatively well characterised in children, including neonates, 10 vinblastine is less well understood. 14 Vinblastine exhibits high inter-and intrapatient pharmacokinetic variability in adult populations but there is currently no published data on drug disposition in children. 11,12 Dosing of all chemotherapeutics in neonates is challenging, due to marked physiological changes impacting drug clearance, which can lead to variable drug exposures. [13][14][15] Empiric dose reductions are therefore commonly advised, without strong clinical pharmacologic data to support dosing decisions made. [13][14][15] We investigated the potential for therapeutic drug monitoring (TDM) to guide treatment in this challenging clinical situation, while generating novel data on vinblastine pharmacokinetics, in four infants receiving vinblastine for IM at different clinical centres.

Patients
Four infants are reported with an average age at first dose of vinblastine of 3.6 weeks (range 3-5.5 Figure 1B). Chemotherapy was initiated with vinblastine (initial dose 0.1 mg/kg) and methotrexate (0.5 mg/kg).

Case 3
A large tumour of the left upper arm was identified antenatally and confirmed to be IM following premature birth of a child at 36+2 weeks.
Nonmutilating surgery was not possible due to replacement of the soft tissues of the entire upper arm and extension to the chest wall ( Figure 1C). The infant was clinically unstable due to arteriovenous shunting through the tumour and therefore chemotherapy with vinblastine (initial dose 0.1 mg/kg) and methotrexate (0.7 mg/kg) was commenced.

Case 4
An infant was diagnosed with multicentric IM at 3 days of age, with subcutaneous, intramuscular, bony, liver and lung disease ( Figure 1D and E). They were treated with vinblastine (initial dose 3 mg/m 2 ) and methotrexate (15 mg/m 2 ).

Sample analysis
Samples for pharmacokinetic analysis were collected at 0.5, 2 and  Table 1 shows the pharmacokinetic parameters observed for the four case subjects, with summary vinblastine plasma concentration-time data provided in Figure S1.

Marked intra-and inter-patient variabilities in vinblastine clearance
and exposure observed in this series highlight the challenges in treating with desacetylvinblastine the only metabolite identified, 12 the isoenzyme cytochrome P450 3A4 (CYP3A4) has been shown to contribute to its metabolism in human liver microsomes. 17 In addition, vinblastine is known to be transported by P-glycoprotein, encoded by ABCB1. 18 It is therefore possible that changes in the ontogeny of these enzymes affecting expression and activity may impact on drug disposition in the first weeks of life. 19,20 However, more detailed and expansive clinical

CONCLUSIONS
Chemotherapy dosing in infants and neonates is challenging, particularly for drugs such as vinblastine, where no age-specific pharmacokinetic data exist. Adaptive dosing can potentially have a role to play in optimising drug exposure in rare conditions without established treatment guidelines, even in the absence of a defined therapeutic window, but relationships between exposure and clinical response and/or toxicity need to be determined. Marked intra-and inter-patient variabilities in vinblastine exposure were observed in the current study, providing novel clinical pharmacology data in a rare patient population. More expansive, prospective clinical pharmacology studies are required to better understand the disposition of this drug in infants and children.
Such an approach will help to support the development of evidencebased vinblastine dosing guidelines in this challenging population.