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Population pharmacokinetic analysis of oxaliplatin in adults and children identifies important covariates for dosing

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Abstract

Purpose

To characterize the determinants of variability for oxaliplatin pharmacokinetics including age, renal function, and hepatic function in children and adults.

Methods

Oxaliplatin pharmacokinetic data were combined from phase I and II clinical trials: three pediatric trials (Peds1–3) and two adult NCI organ dysfunction studies (Hepatic and Renal). A population pharmacokinetic model was developed utilizing platinum ultrafiltrate concentrations to characterize changes in oxaliplatin disposition with age and organ dysfunction along with other potential sources of oxaliplatin pharmacokinetic variability.

Results

A total of 1,508 concentrations from 186 children and adults were used in the study. The data were well described by a three-compartment model. Serum creatinine (SCR) was an independent predictor of clearance (CL) while age was an independent predictor of volume of distribution. Although age was a significant covariate on CL in the univariate analysis, age effects on CL were entirely accounted for by SCR. Gender, hepatic function, and race had no effect on CL or volume of distribution. Median CL values were 0.58 (Hepatic), 0.34 (Renal), 0.78 (Peds1), 0.74 (Peds2), and 0.81 (Peds3) (L/h/kg0.75). Monte Carlo simulations of the final model with 130 mg/m2 yielded median AUC values of: 14.2 (2–6 years), 16.8 (6–12 years), 16.5 (12–18 years), and 17.3 (>18 years) (µg h/mL).

Conclusions

Renal function had the greatest effect on CL with a small age effect seen on the distribution of oxaliplatin. Young pediatric patients had higher CL values than adults as a result of better renal function.

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Acknowledgments

The authors would like to thank Dr. Percy Ivy from the National Institutes of Health and Dr. Paul Juniewicz from Sanofi-Aventis for assistance with the project. We would like to thank the Children’s Oncology Group and the Pediatric Brain Tumor Consortium for providing the ADVL0421 and PBTC-010 data sets, respectively. This study was supported by grants from the National Institutes of Health (EVC: U54 HD071600-01, TWS: U01 CA062505, P30 CA033572), St. Jude Cancer Center Support Grant CA21765, the American Lebanese Syrian Associated Charities (ALSAC), and Kaiser Santa Clara.

Conflict of interest

Edmund Capparelli served in a consultant/advisory role at Trius Pharmaceuticals, The Medicines Company, and Cempra. Maryam Fouladi received funding from Genentech and Roche. There are no additional disclosures or potential conflicts of interest to report.

Ethical standard

The previously completed clinical trials from which data were utilized for the current analysis were approved by ethics committees at each respective institution and were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent was obtained from patients, parents, or guardians for all participants in the studies.

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Authors and Affiliations

  1. University of California San Diego, 9500 Gilman Drive, MC 0657, La Jolla, CA, 92093-0657, USA

    Mina Nikanjam & Edmund V. Capparelli

  2. St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

    Clinton F. Stewart

  3. Janssen Research and Development, 1400 McKean Road, SH-32-2-1, PO Box 776, Spring House, PA, 19477, USA

    Chris H. Takimoto

  4. City of Hope, 1500 E Duarte Rd, Duarte, CA, 91010, USA

    Timothy W. Synold

  5. Zeis Children’s Cancer Center, Mission Hospitals, 21 Hospital Drive, Asheville, NC, 28801, USA

    Orren Beaty

  6. Children’s Hospital of Cincinnati, 3333 Burnet Ave, Cincinnati, OH, 45229, USA

    Maryam Fouladi

Authors
  1. Mina Nikanjam
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  2. Clinton F. Stewart
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  3. Chris H. Takimoto
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  4. Timothy W. Synold
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  5. Orren Beaty
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  6. Maryam Fouladi
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  7. Edmund V. Capparelli
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Corresponding author

Correspondence to Edmund V. Capparelli.

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Nikanjam, M., Stewart, C.F., Takimoto, C.H. et al. Population pharmacokinetic analysis of oxaliplatin in adults and children identifies important covariates for dosing. Cancer Chemother Pharmacol 75, 495–503 (2015). https://doi.org/10.1007/s00280-014-2667-6

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  • DOI: https://doi.org/10.1007/s00280-014-2667-6

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