Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests

Twelves, Christopher; Dobbs, Nicola; Gillies, H.; James, Christopher; Rubens, Robert; Harper, Peter

doi:10.1007/s002800050809

Cited by 28 publications

(8 citation statements)

References 15 publications

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“…20, 21 However, the therapeutic efficacy of this relatively insoluble small-molecule drug is limited by its low bioavailability and short-plasma half-life, necessitating frequent dosing. 22 In addition, the often life-threatening side effects (cardiotoxicity, 23 bone marrow suppression, 24, 25 infertility, 26 etc.) that accompany the use of doxorubicin, including latent development of leukemia after prolonged treatment, 27 deem this an undesirable chemotherapeutic agent.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and in vitro activity of ROMP-based polymer nanoparticles

et al. 2009

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A new type of polymer nanoparticle (PNP) containing a high density of covalently linked doxorubicin, attached via a non-cleavable amine linkage (amine-linked Dox-PNP) was prepared. Together with a previously reported cleavable carbamate-linked Dox-PNP, this new amine-linked Dox-PNP was subsequently evaluated against free doxorubicin for its cytotoxicity and inhibitory effects on SKNSH wild-type and SKrDOX6 doxorubicin-resistant human neuroblastoma cell lines. Analogous cholesterol-containing PNPs (Chol-PNPs) and indomethacin-containing PNPs (IND-PNPs) were also synthesized and used as the non-cytotoxic controls. While neither cell line was affected by Chol-PNPs or IND-PNPs, SKrDOX6 doxorubicin-resistant cells exhibited similar cytotoxic responses to free doxorubicin and both amine- and carbamate-linked Dox-PNPs, suggesting that doxorubicin or the doxorubicin-containing polymer must be the active agent in the latter case. SKNSH wild-type cells also responded to both Dox-PNPs, albeit at a higher apparent concentration than free doxorubicin alone. The growth of SKNSH wild-type cells was significantly inhibited upon incubation with carbamate-linked Dox-PNPs, as with free doxorubicin, over a 7-day period. In comparison to free doxorubicin, carbamate-linked Dox-PNPs produced a longer (72-h) period of initial inhibition in SKrDOX6 doxorubicin-resistant cells.

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Section: Resultsmentioning

confidence: 99%

Synthesis and in vitro activity of ROMP-based polymer nanoparticles

et al. 2009

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“…In addition, in this study, a negative correlation between Alb and AUC/D of DXR was found in elderly patients. It has been reported that DXR clearance (CL) correlates with various liver function test values, including Alb 25,26 . DXR is eliminated primarily by hepatic metabolism and biliary excretion.…”

Section: Discussionmentioning

confidence: 99%

Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy

Nakagawa

Takahata

Hyodo

et al. 2021

Sci Rep

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Abstract(R-)miniCHOP therapy, which delivers approximately half-doses of the (R-)CHOP regimen, has shown efficacy and safety in patients who are more than 80 years old. This study aimed to compare the area under the plasma concentration–time curves (AUCs) of vincristine (VCR), doxorubicin (DXR), and cyclophosphamide (CPA) between (R-)CHOP and (R-)miniCHOP regimens. The AUCs were compared between patients aged 65–79 years receiving (R-)CHOP therapy and those aged 80 years and older receiving (R-)miniCHOP therapy. Age was not an independent variable for predicting the dose-adjusted AUCs (AUC/Ds) of cytotoxic anticancer drugs. The median AUCs of DXR and CPA were significantly smaller in the (R-)miniCHOP group than in the (R-)CHOP group (168.7 vs. 257.9 ng h/mL, P = 0.003, and 219.9 vs. 301.7 µg h/mL, P = 0.020, respectively). The median AUCs of VCR showed the same trend but the difference was not significant (24.83 vs. 34.85 ng h/mL, P = 0.135). It is possible that the AUCs of VCR, DXR, and CPA in patients aged 80 years and older receiving (R-)miniCHOP therapy may be lower than those in patients 65–79 years old receiving (R-)CHOP therapy.

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“…Therefore, the present study might have missed possible influence of xenograft tumors, similar to other diseases or disease statuses ( Li et al, 2019 ), as well as sex ( Franconi and Campesi, 2014 ) on the PK properties of Dox or Sor (e.g., volume of the central compartment), whereas the differences in PK among mouse strains seem minimal ( Barr et al, 2020 ). Indeed, it has been reported that doxorubicin clearance was relatively higher in men ( n = 6) than in women ( n = 21) (59 vs. 27 l•h −1 •m −2 ) ( Dobbs et al, 1995 ), and abnormal liver functions tended to correlate with lower levels of doxorubicin clearance ( Twelves et al, 1998 ). Baseline body weight was identified as a statistically significant covariate for variable sorafenib distributional volume among patients with solid tumors ( Jain et al, 2011 ), whereas no association was found between organ function and systemic sorafenib exposure, including patients with severe liver and kidney impairment ( Miller et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine In Vivo Synergism

Choi

Zhang

Liu

et al. 2021

J Pharmacol Exp Ther

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Understanding pharmacokinetic (PK)-pharmacodynamic (PD) relationships is essential in translational research. Existing PK-PD models for combination therapy lack consideration of quantitative contributions from individual drugs, whereas interaction factor is always assigned arbitrarily to one drug and overstretched for the determination of in vivo pharmacologic synergism. Herein, we report a novel generic PK-PD model for combination therapy by considering apparent contributions from individual drugs coadministered. Doxorubicin (Dox) and sorafenib (Sor) were used as model drugs whose PK data were obtained in mice and fit to two-compartment model. Xenograft tumor growth was biphasic in mice, and PD responses were described by three-compartment transit models. This PK-PD model revealed that Sor (contribution factor = 1.62) had much greater influence on overall tumor-growth inhibition than coadministered Dox (contribution factor = 0.644), which explains the mysterious clinical findings on remarkable benefits for patients with cancer when adding Sor to Dox treatment, whereas there were none when adding Dox to Sor therapy. Furthermore, the combination index method was integrated into this predictive PK-PD model for critical determination of in vivo pharmacologic synergism that cannot be correctly defined by the interaction factor in conventional models. In addition, this new PK-PD model was able to identify optimal dosage combination (e.g., doubling experimental Sor dose and reducing Dox dose by 50%) toward much greater degree of tumor-growth inhibition (>90%), which was consistent with stronger synergy (combination index = 0.298). These findings demonstrated the utilities of this new PK-PD model and reiterated the use of valid method for the assessment of in vivo synergism. Significance Statement A novel pharmacokinetic (PK)-pharmacodynamic (PD) model was developed for the assessment of combination treatment by considering contributions from individual drugs, and combination index method was incorporated to critically define in vivo synergism. A greater contribution from sorafenib to tumor-growth inhibition than that of coadministered doxorubicin was identified, offering explanation for previously inexplicable clinical observations. This PK-PD model and strategy shall have broad applications to translational research on identifying optimal dosage combinations with stronger synergy toward improved therapeutic outcomes.

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Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests

Cited by 28 publications

References 15 publications

Synthesis and in vitro activity of ROMP-based polymer nanoparticles

Synthesis and in vitro activity of ROMP-based polymer nanoparticles

Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy

A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine In Vivo Synergism

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