II-14 David Damoiseaux

Physiologically based pharmacokinetic model to predict chemotherapy exposure in infants through breastfeeding: paclitaxel as an example

David Damoiseaux (1), Jos H. Beijnen (1, 3), Frédéric Amant (4, 5), Alwin D.R. Huitema (1, 6, 7), Thomas P.C. Dorlo (1)

(1) Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, (2) Gynecologic Oncology Department, Amsterdam University Medical Center, Amsterdam, The Netherlands, (3) Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands, (4) Department of Gynecology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, (5) Gynecologic Oncology, UZ Leuven, Belgium, (6) Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands, (7) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

Introduction/Objectives: Little is known about infant safety when breastfed by mothers treated with cytotoxic therapy, with evidence limited to a few case reports of exposure in breast milk [1, 2]. This lack of knowledge has led to a general advice against breastfeeding during cytotoxic therapy despite overwhelming benefits that breastfeeding offers to both mothers and their children. While defining distribution to breast milk is an important to infer infant exposure, other factors, such as immature absorption and metabolism, also determine whether and to which extent the child will be exposed to the toxic effects of chemotherapy [3]. We aimed to assess the impact of the previously measured breast milk concentrations on infants by predicting systemic and local (intestinal) exposure of paclitaxel in infants through breast milk using a PBPK approach.

Methods: Paclitaxel concentrations in breast milk after maternal administration of 156 mg from a previously published case series were the input for infant breast milk dose calculations [4], based on a typical infant breast milk consumption of 150 mL/kg/day [5]. Model development using PK-Sim® (version 10) [6] and R (version 4.1.2) started from the whole-body PBPK model of intravenous (IV) paclitaxel available from the Open Systems Pharmacology GitHub repository [7]. The IV PBPK model was extended with an oral absorption component to enable predictions in infants receiving paclitaxel-containing breast milk. Absorption related parameters such as lipophilicity and specific intestinal permeability, the daily doses, administration with and without fatty food and different methods for the calculation of the partition coefficient were included. The parameter values for each parameter tested in a sensitivity analysis were 3.53 (optimized value from IV model), -10%, +10% and +25% for lipophilicity; 3.48 x 10-6 cm/min (theoretical value calculated by PK-Sim®), -10%, +10%, +50% and +200% for the specific intestinal permeability; 1, 4 and 12 times daily for the number of daily doses; administration with and without fatty food; and standard PK-Sim and Rodgers & Rowland calculation methods for partition coefficients. For safety considerations, we chose to use parameter values derived from the sensitivity analysis associated with the worst-case scenario for the infant, maximizing the plasma exposure. Finally, a population of 500 European (ICRP, 2002) infants aged 0 to 1 years were used to predict paclitaxel exposure in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel-treated mothers.

Results: The IV PBPK model extended with oral absorption was applied to the infant population. In the sensitivity analyses, the following parameter values resulted in the highest AUC0-inf of plasma paclitaxel: +10% for lipophilicity, +200% for the specific intestinal permeability, 12 breastfeeding’s per day, administration with fatty food and the Rodgers & Rowland calculation method for the partition coefficients.

The final simulation in infants using worst-case scenario parameters resulted in a median Cmax for the highest exposed individuals of 0.26, 281 and 35.1 nM in plasma, small and large intestines, respectively. Discarding the first day of breast milk after maternal paclitaxel administration resulted in a ~60% decrease in both systemic and intestinal exposure. In vitro studies report paclitaxel IC50s of 2.5-9,400 nM after 24-hour paclitaxel exposure for different cell lines [8, 9]. Since systemic Cmax in the worst-case scenario did not exceed the reported IC50s, any systemic adverse event is unlikely in infants breastfed by paclitaxel-treated. In contrast, intestinal Cmax did exceed the reported IC50s possibly resulting in local adverse events.

Conclusion: A PBPK modeling approach enabled us to predict systemic and local exposure in infants after oral administration of breast milk containing chemotherapy. Systemic exposure in the worst-case scenario is negligible and did not exceed in vitro IC50s associated with cytotoxic effects, while intestinal exposure did. Furthermore, no mutagenic effect has been identified for paclitaxel suggesting there is no risk for mutations that permanently alter the infants DNA [10]. Our findings suggest that it is relatively safe for women treated with paclitaxel to breastfeed their infant. Especially, gastrointestinal adverse events should be monitored.

References:

  1. Griffin, S.J., et al., Transfer of carboplatin and paclitaxel into breast milk. J Hum Lact, 2012. 28(4): p. 457-9.
  2. Jackson, C., et al., Breast milk paclitaxel excretion following intravenous chemotherapy-a case report. Br J Cancer, 2019. 121(5): p. 421-424.
  3. Alcorn, J. and P.J. McNamara, Pharmacokinetics in the newborn. Adv Drug Deliv Rev, 2003. 55(5): p. 667-86.
  4. Damoiseaux, D., et al., Presence of 5 chemotherapeutic drugs in breast milk as a guide for the safe use of chemotherapy during breastfeeding: results from a case series. Clin Pharmacol Ther., 2022(Accepted).
  5. Anderson, P.O. and V. Valdés, Variation of milk intake over time: clinical and pharmacokinetic implications. Breastfeed Med, 2015. 10(3): p. 142-4.
  6. Open Systems Pharmacology. PK-Sim® and MoBi® software manual. https://www.open-systems-pharmacology.org/.
  7. Open Systems Pharmacology GitHub repository. https://github.com/orgs/Open-Systems-Pharmacology/repositories.
  8. Liebmann, J.E., et al., Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines. Br J Cancer, 1993. 68(6): p. 1104-9.
  9. Georgiadis, M.S., et al., Paclitaxel cytotoxicity against human lung cancer cell lines increases with prolonged exposure durations. Clin Cancer Res, 1997. 3(3): p. 449-54.
  10. Szikriszt, B., et al., A comprehensive survey of the mutagenic impact of common cancer cytotoxics. Genome Biol, 2016. 17: p. 99.

Reference: PAGE 30 (2022) Abstr 10058 [www.page-meeting.org/?abstract=10058]

Poster: Drug/Disease Modelling - Oncology

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