OpenLB
Open Library of Bioscience
Advanced Search
Asia-Pacific journal of clinical oncology
Feb, 2023;19 (1): 9-26.

Population pharmacokinetics of doxorubicin: A systematic review.

Janthima Methaneethorn, Kanokkan Tengcharoen, Nattawut Leelakanok, Rowan AlEjielat
Author Information
  1. Janthima Methaneethorn: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand. ORCID
  2. Kanokkan Tengcharoen: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.
  3. Nattawut Leelakanok: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Burapha University, Sean Suk, Thailand.
  4. Rowan AlEjielat: Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.
PMID: 35415961 DOI: 10.1111/ajco.13776

Abstract

Because of the high interindividual pharmacokinetic variability, several population pharmacokinetic (PopPK) models of doxorubicin (DOX) were developed to characterize factors influencing such variability. However, significant predictors for DOX pharmacokinetics identified using PopPK models varied across studies. Thus, this review aims to summarize PopPK models of DOX and its metabolites (if any) as well as significant covariates influencing DOX (and its metabolites) pharmacokinetic variability. A systematic search from PubMed, CINAHL Complete, Science Direct, and SCOPUS databases identified 503 studies. Of these, 16 studies met the inclusion criteria and were included in this review. DOX pharmacokinetics was described with two- or three-compartment models. Most studies found a significant increase in DOX clearance with an increase in body surface area from the median value of 1.8 m . Moreover, this review identified that while a 10-year increase in patient age resulted in a decrease in DOX clearance in adults and the elderly, younger children had lower DOX clearance compared to older children. Further, low DOX exposure was observed in pregnant women, and thus dosage adjustment is required. Concerning model applicability, predictive performance assessment of these published models should be performed before implementing such models in clinical practice.

Keywords

anticancer doxorubicin doxorubicinol nonlinear mixed effects population pharmacokinetics

References

  1. Speth P, Van Hoesel Q, Haanen C. Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet. 1988;15(1):15-31.
  2. Joerger M, Huitema ADR, Meenhorst PL, Schellens JHM, Beijnen JH. Pharmacokinetics of low-dose doxorubicin and metabolites in patients with AIDS-related Kaposi sarcoma. Cancer Chemother Pharmacol. 2005;55(5):488-496.
  3. Ahmad N, Ahmad R, Alam MA, Ahmad FJ. Enhancement of oral bioavailability of doxorubicin through surface modified biodegradable polymeric nanoparticles. Chem Cent J. 2018;12(1):65.
  4. Siebel C, Lanvers-Kaminsky C, Würthwein G, Hempel G, Boos J. Bioanalysis of doxorubicin aglycone metabolites in human plasma samples-implications for doxorubicin drug monitoring. Sci Rep. 2020;10(1):18562.
  5. Licata S, Saponiero A, Mordente A, Minotti G. Doxorubicin metabolism and toxicity in human myocardium: role of cytoplasmic deglycosidation and carbonyl reduction. Chem Res Toxicol. 2000;13(5):414-420.
  6. Kontny NE, Würthwein G, Joachim B, Boddy AV, Krischke M, Fuhr U, et al. Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years. Cancer Chemother Pharmacol. 2013;71(3):749-763.
  7. Eksborg S, Strandler HS, Edsmyr F, Näslund I, Tahvanainen P. Pharmacokinetic study of i.v. infusions of adriamycin. Eur J Clin Pharmacol. 1985;28(2):205-212.
  8. Andersen A, Holte H, Slørdal L. Pharmacokinetics and metabolism of doxorubicin after short-term infusions in lymphoma patients. Cancer Chemother Pharmacol. 1999;44(5):422-426.
  9. Piscitelli SC, Rodvold KA, Rushing DA, Tewksbury DA. Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther. 1993;53(5):555-561.
  10. Frenay M, Milano G, Renee N, Pons D, Khater R, François E, et al. Pharmacokinetics of weekly low dose doxorubicin. Eur J Cancer Clin Oncol. 1989;25(2):191-195.
  11. DOXORUBICIN HYDROCHLORIDE [package insert]. Pfizer Labs; 2013.
  12. Gil P, Favre R, Durand A, Iliadis A, Cano J, Carcassonne Y. Time dependency of adriamycin and adriamycinol kinetics. Cancer Chemother Pharmacol. 1983;10(2):120-124.
  13. Pérez-Blanco JS, Santos-Buelga D, Fernández de Gatta MD, Hernández-Rivas JM, Martín A, García MJ. Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma. Br J Clin Pharmacol. 2016;82(6):1517-1527.
  14. Joerger M, Huitema ADR, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, et al. Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG. Clin Pharmacokinet. 2007;46(12):1051-1068.
  15. Wong AL, Seng KY, Ong EM, Wang LZ, Oscar H, Cordero MT, et al. Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients. Breast Cancer Res Treat. 2014;144(1):143-152.
  16. Völler S, Boos J, Krischke M, Würthwein G, Kontny NE, Boddy AV, et al. Age-dependent pharmacokinetics of doxorubicin in children with cancer. Clin Pharmacokinet. 2015;54(11):1139-1149.
  17. Callies S, de Alwis DP, Wright JG, Sandler A, Burgess M, Aarons L. A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). Cancer Chemother Pharmacol. 2003;51(2):107-118.
  18. Kunarajah K, Hennig S, Norris R, Lobb M, Charles B, Pinkerton R, et al. Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles? Cancer Chemother Pharmacol. 2017;80(1):15-25.
  19. Thomson AH, Vasey PA, Murray LS, Cassidy J, Fraier D, Frigerio E, et al. Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours. Br J Cancer. 1999;81(1):99-107.
  20. Wilde S, Jetter A, Zaigier M, Rietbrock S, Menzel H, Sieber M, et al. Population pharmacokinetics of cyclophosphamide, doxorubicin and etoposide in 30 patients with BEACOPP chemotherapy. Int J Clin Pharmacol Ther. 2002;40(12):586-588.
  21. Janssen JM, Van Calsteren K, Dorlo TPC, Halaska MJ, Fruscio R, Ottevanger P, et al. Population pharmacokinetics of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women with cancer: a study from the International Network of Cancer, Infertility and Pregnancy (INCIP). Clin Pharmacokinet. 2021;60(6):775-784.
  22. Kumar VS, Kaushik HK, Kumar SB, Reddy NY, Reddy N, Kumaraswamy T, et al. Population pharmacokinetics of doxorubicin in Indian cancer patients using NONMEM. Clin Res Regul Aff. 2009;26(4):93-100.
  23. Freyer G, Tranchand B, Ligneau B, Ardiet C, Souquet PJ, Court-Fortune I, et al. Population pharmacokinetics of doxorubicin, etoposide and ifosfamide in small cell lung cancer patients: results of a multicentre study. Br J Clin Pharmacol. 2000;50(4):315-324.
  24. Wilde S, Jetter A, Rietbrock S, Kasel D, Engert A, Josting A, et al. Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin's lymphoma and its effect on myelotoxicity. Clin Pharmacokinet. 2007;46(4):319-333.
  25. Escudero-Ortiz V, Ramón-López A, Duart MJ, Pérez-Ruixo JJ, Valenzuela B. Populational pharmacokinetics of doxorubicin applied to personalised its dosing in cancer patients. Farmacia Hospitalaria. 2012;36(4):282-291.
  26. van Hasselt JGC, van Calsteren K, Heyns L, Han S, Mhallem Gziri M, Schellens JHM, et al. Optimizing anticancer drug treatment in pregnant cancer patients: pharmacokinetic analysis of gestation-induced changes for doxorubicin, epirubicin, docetaxel and paclitaxel. Ann Oncol. 2014;25(10):2059-2065.
  27. Brendel K, Dartois C, Comets E, Lemenuel-Diot A, Laveille C, Tranchand B, et al. Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? Clin Pharmacokinet. 2007;46(3):221-234.
  28. Liang S, Brundage RC, Jacobson PA, Blaes A, Kirstein MN. Pharmacokinetic-pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer. Br J Clin Pharmacol. 2016:773-783.
  29. Thompson PA, Rosner GL, Matthay KK, Moore TB, Bomgaars LR, Ellis KJ, et al. Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study. Cancer Chemother Pharmacol. 2009;64(2):243-251.
  30. Liu Z, Martin J, Orme L, Seddon B, Desai J, Nicholls W, et al. Gender differences in doxorubicin pharmacology for subjects with chemosensitive cancers of young adulthood. Cancer Chemother Pharmacol. 2018;82(5):887-898.
  31. Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, et al. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci USA. 1988;85(10):3585-3589.
  32. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989-1008.
  33. Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Womens Health. 2005;14(1):19-29.
  34. Jeong H. Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes. Expert Opin Drug Metab Toxicol. 2010;6(6):689-699.
  35. Kivisto KT, Kroemer HK, Eichelbaum M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br J Clin Pharmacol. 1995;40(6):523-530.
  36. Feghali M, Venkataramanan R, Caritis S. Pharmacokinetics of drugs in pregnancy. Semin Perinatol. 2015;39(7):512-519.
  37. Erman A, Neri A, Sharoni R, Rabinov M, Kaplan B, Rosenfeld JB, et al. Enhanced urinary albumin excretion after 35 weeks of gestation and during labour in normal pregnancy. Scand J Clin Lab Invest. 1992;52(5):409-413.
  38. Cheung CK, Lao T, Swaminathan R. Urinary excretion of some proteins and enzymes during normal pregnancy. Clin Chem. 1989;35(9):1978-1980.

MeSH Term

Pregnancy
Adult
Child
Humans
Female
Adolescent
Aged
Models, Biological
Doxorubicin
Databases, Factual

Chemicals

Doxorubicin
Systematic Review Journal Article Review

Word Cloud

Created with Highcharts 10.0.0DOXmodelspharmacokineticsstudiesreviewpharmacokineticvariabilityPopPKsignificantidentifiedincreaseclearancepopulationdoxorubicininfluencingmetabolitessystematicchildrenhighinterindividualseveraldevelopedcharacterizefactorsHoweverpredictorsusingvariedacrossThusaimssummarizewellcovariatessearchPubMedCINAHLCompleteScienceDirectSCOPUSdatabases50316metinclusioncriteriaincludeddescribedtwo-three-compartmentfoundbodysurfaceareamedianvalue18mMoreover10-yearpatientageresulteddecreaseadultselderlyyoungerlowercomparedolderlowexposureobservedpregnantwomenthusdosageadjustmentrequiredConcerningmodelapplicabilitypredictiveperformanceassessmentpublishedperformedimplementingclinicalpracticePopulationdoxorubicin:anticancerdoxorubicinolnonlinearmixedeffects

Similar Articles

Cited By