Therapeutic drug monitoring and dose adaptation of cisplatin in a newborn with hepatoblastoma: a case report

Abstract

Purpose

Chemotherapy dosing in neonates represents a major clinical challenge because of a lack of clinical pharmacology information in this patient population. In this study, we investigate the use of cisplatin dose adaptation based on therapeutic drug monitoring in a 2-week-old neonate with localized hepatoblastoma.

Methods

Cisplatin concentrations were determined in plasma and ultrafiltrate samples collected on each of six cycles of a monotherapy regimen, beginning with a dose of 1.6 mg/kg at 16 days of age. Pharmacokinetic data were analyzed to generate clearance (CL) and area under the curve (AUC0–∞) for each administration. Toxicity and clinical response were monitored.

Results

The first cisplatin dose (1.6 mg/kg) resulted in an AUC0–∞ of 535 µg/mL · min, was well tolerated and associated with a good response. This AUC was, therefore, considered as an appropriate target for this patient. Increases in cisplatin CL were observed across consecutive treatment cycles, and, therefore, dose was gradually increased to finally reach 2.5 mg/kg on the sixth cycle. Treatment was well tolerated over the six courses and resulted in a good response, with the patient remaining in remission at 15 months. Cisplatin CL was significantly correlated to age (p = 0.013) and weight (p = 0.013).

Conclusions

Our study provides useful data on the pharmacokinetics of cisplatin monotherapy in neonates treated within the first few weeks of life. These data provide a reference point to support clinicians in determining appropriate dosing regimens for neonates and support the implementation of therapeutic drug monitoring in such challenging patients.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    Meyers RL, Maibach R, Hiyama E et al (2017) Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration. Lancet Oncol 18:122–131

    Article  PubMed  Google Scholar 

  2. 2.

    Stocker JT (2001) Hepatic tumors in children. Clin Liver Dis 5:259–281 (viii–ix)

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Dall’Igna P, Brugieres L, Christin AS et al (2018) Hepatoblastoma in children aged less than six months at diagnosis: a report from the SIOPEL group. Pediatr Blood Cancer 65. https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/28921839

  4. 4.

    Zsiros J, Brugieres L, Brock P et al (2013) Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 14:834–842

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Veal GJ, Errington J, Hayden J et al (2015) Carboplatin therapeutic monitoring in preterm and full-term neonates. Eur J Cancer 51:2022–2030

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Veal GJ, Errington J, Sastry J et al (2016) Adaptive dosing of anticancer drugs in neonates: facilitating evidence-based dosing regimens. Cancer Chemother Pharmacol 77:685–692

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Perilongo G, Maibach R, Shafford E et al (2009) Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 361:1662–1670

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    LeRoy AF, Wehling ML, Sponseller HL et al (1977) Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochem Med 18:184–191

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Burger H, Loos WJ, Eechoute K et al (2011) Drug transporters of platinum-based anticancer agents and their clinical significance. Drug Resist Updat 14:22–34

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Sweeney DE, Vallon V, Rieg T et al (2011) Functional maturation of drug transporters in the developing, neonatal, and postnatal kidney. Mol Pharmacol 80:147–154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Lickteig AJ, Cheng X, Augustine LM et al (2008) Tissue distribution, ontogeny and induction of the transporters Multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci 83:59–64

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Bardin C, Veal G, Paci A et al (2014) Therapeutic drug monitoring in cancer—are we missing a trick? Eur J Cancer Oxf Engl 1990 50:2005–2009

    CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Fabienne Thomas.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from the parents of the patient to take blood samples to perform individualized dosing.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 300 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Thomas, F., Veal, G.J., El Balkhi, S. et al. Therapeutic drug monitoring and dose adaptation of cisplatin in a newborn with hepatoblastoma: a case report. Cancer Chemother Pharmacol 82, 361–365 (2018). https://doi.org/10.1007/s00280-018-3625-5

Download citation

Keywords

  • Cisplatin
  • Hepatoblastoma
  • SIOPEL
  • Pharmacokinetics
  • Neonate