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Abstract

Aim:

To determine effects of Coenzyme Q10 (CoQ10) supplementation in breast cancer patients receiving doxorubicin treatment.

Methods:

Phase I randomized, placebo-controlled, cross-over, dose-finding study among women with stage I-III breast cancer receiving 4 cycles of doxorubicin plus cyclophosphamide. The study was designed to test effects on doxorubicin pharmacokinetic parameters when administering up to the maximum tolerated dose of CoQ10 of 1200 mg/day. Eligible patients were randomized to Arm A (CoQ10 after Cycle 3, followed by placebo after Cycle 4) or Arm B (placebo after Cycle 3, followed by CoQ10 after Cycle 4). CoQ10 concentrations and total antioxidant capacity (TAC) were measured before and after chemotherapy cycles. Non-compartmental pharmacokinetic parameters of doxorubicin and its active metabolites were measured with and without CoQ10. Paired t-tests assessed intra-patient differences in pharmacokinetic parameters, serum CoQ10 concentrations, TAC, and adverse events.

Results:

Six patients received 300 mg/day of CoQ10 (Arm A [n = 3], Arm B [n = 3]). One patient received 600 mg/day of CoQ10 but was discontinued due to non-adherence. Serum CoQ10 concentrations were increased in patients receiving 300 mg/day (mean ± SD change: CoQ10, 1.6 ± 0.9 µg/mL; placebo, −0.01 ± 0.3 µg/mL; P = .01). There were no clinically significant pharmacokinetic interactions between 300 mg/day CoQ10 and doxorubicin and no differences in TAC or adverse events during treatment and nontreatment periods. The trial was closed early due to slow accrual.

Conclusion:

300 mg/day of CoQ10 with doxorubicin did not change doxorubicin pharmacokinetics and was not associated with treatment-related adverse events. Future studies should evaluate the long-term effects of CoQ10 at 300 mg/day and safety studies should examine higher doses.

Trial registration:

ClinicalTrials.gov: NCT00976131.

Keywords

coenzyme Q10 doxorubicin pharmacokinetics breast cancer

Introduction

In 2023, an estimated 297 790 women will be diagnosed with invasive breast cancer in the US, and there are currently more than 3 million breast cancer survivors.^1
-3 Doxorubicin (Adriamycin), an anthracycline, plus cyclophosphamide (AC) is standard neoadjuvant and adjuvant therapy for early-stage breast cancer.^4
-6 However, despite the benefits of these therapies in preventing breast cancer recurrence and improving overall survival, 3%-20% of breast cancer patients develop acute and chronic cardiomyopathic changes and congestive heart failure due to doxorubicin therapy, as assessed by changes in left ventricular ejection fraction (LVEF), especially when doxorubicin cumulative doses exceed 450 mg/m² and/or are co-administered with other cardiotoxic medications such as trastuzumab.^7
-10 It is well established that doxorubicin cardiotoxicity is a cumulative dose-related effect.¹¹ Once a dose threshold is reached, irreversible myocyte damage occurs, likely due to increased myocyte mitochondrial reactive oxygen species (ROS), which is exacerbated by further exposure to doxorubicin and trastuzumab.¹² There has been longstanding interest in identifying possible cardioprotective agents for use during anthracycline treatment. While a recent meta-analysis shows that dexrazoxane is effective in preventing or decreasing cardiotoxicities adult oncology patients treated with anthracyclines, the results were not consistent in pediatric patients, and adverse event data were not of high quality in both populations.¹³ The authors concluded that more research is needed before making any definitive conclusions. Moreover, while dexraxozane is may be efficacious for reducing cardiotoxicity in anthracycline-treated patients, it has had low clinical uptake to date given some of these concerns.

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a lipid soluble antioxidant that may protect cardiac myocytes against mitochondrial ROS. CoQ10 is synthesized in the mitochondria and in most intracellular membranes, and is ingested via foods such as meat, poultry, fish, soybean and canola oils, and dietary supplements. CoQ10 plays an integral part in generating intracellular adenosine triphosphate (ATP) within the mitochondrial inner membrane and in quenching intracellular oxidative stress.¹² During doxorubicin treatment, there is an acute rise in plasma CoQ10,¹⁴ and following treatment there is a marked decrease in the CoQ10 content of cardiac and skeletal muscle.¹⁵ The decrease in CoQ10 within muscle tissue is caused when doxorubicin reduces to its semiquinone and the semiquinone displaces CoQ10 in the cardiac myocyte mitochondrial inner membrane. Thus, it has been proposed that CoQ10 supplementation prior to and during doxorubicin treatment may prevent oxidative-stress induced cardiotoxicities.¹²

Although CoQ10 is not known to be a strong chelator nor an enzyme inhibitor or inducer, we hypothesized a possible drug-drug interaction effect in doxorubicin treated patients because the antioxidant properties of compounds such as CoQ10 could interfere with the pro-oxidant actions of chemotherapeutic agents.^16,17 We previously conducted an in vitro study that supported the hypothesis that CoQ10 does not alter the cytotoxicity of doxorubicin,¹⁸ however that single study is not conclusive. No prospectively conducted, placebo-controlled trials have evaluated the safety of CoQ10 administration during doxorubicin treatment and whether it confers a protective effect against cardiotoxicity in early stage breast cancer patients.

To begin to fill this gap, we conducted a phase I randomized, placebo-controlled, cross-over study of intra-patient differences in doxorubicin and its active metabolites, comparing patients with and without administration of CoQ10, and to screen for effects associated with CoQ10 administration. We hypothesized that CoQ10 administration during doxorubicin treatment would be safe and would not affect concentrations of doxorubicin active metabolites and total antioxidant capacity (TAC). Measuring difference in both doxorubicin concentrations and TAC may be able to address some of the concerns of use of antioxidant supplements during chemotherapy.

Methods

Participants

Participants were screened and recruited from the outpatient Breast Medical Oncology Clinic at Columbia University Medical Center (CUMC) between December 2010 and August 2012 with the target of a maximum of 18 evaluable patients. Eligible participants included women aged 21 years or older who spoke English and/or Spanish, were diagnosed with stage I-III breast cancer, and were scheduled to receive at least 4 cycles of dose-dense (every 2 weeks) doxorubicin therapy in the neoadjuvant or adjuvant setting. Patients receiving neoadjuvant dose-dense doxorubicin therapy were permitted to have prior trastuzumab and/or taxane chemotherapy. Patients receiving adjuvant dose dense doxorubicin therapy were required to have single lumen implanted venous access device (i.e., single port) if they had a history of unilateral breast cancer and double lumen implanted venous access device (i.e., double port) if they had a history of bilateral breast cancer. Participants were required to have an ECOG performance status ≤ 2 (Karnofsky > 60%), normal organ and marrow function prior to initial doxorubicin/cyclophosphamide treatment, and normal left ventricular ejection fraction (LVEF) via multigated acquisition scan (MUGA) or echocardiogram. The institutional lower limit for a normal LVEF was ≥50%.

Exclusion criteria included history of CoQ10 supplement use within 30 days of initiating study drug, history of anthracycline use or radiation therapy in the previous 5 years, uncontrolled or significant co-morbid illness, pregnant, breast-feeding, or planning to become pregnant during the study. Patients were excluded if they experienced any significant treatment toxicities related to first or second dose of doxorubicin/cyclophosphamide chemotherapy or biologic therapy that did not resolve to less than a CTCAE 3.0 grade 3 non-hematologic toxicity. Patients were excluded if they were using any other investigational agent, or had severe medical, psychological, or sociological conditions that might interfere with the participant’s ability to follow the protocol or achieve study objectives. Patients were also excluded if they reported use of an over-the-counter nutritional vitamin greater than 5 times the recommended dietary allowance, any form of antioxidant supplements, U.S. Food and Drug Administration (FDA)-approved cardioprotective drugs (i.e., dexrazoxane), or use of warfarin. Due to the use of opaque coloring in a fish-based softgel shell, additional exclusion criteria included titanium dioxide allergy, fish allergy, reporting a tilapia dietary restriction, or following Kosher dietary practices.

A baseline questionnaire collected data on demographics, health history, and fruit and vegetable intake. As part of routine clinical care, prior to doxorubicin/cyclophosphamide treatment all participants received routine blood tests to evaluate organ and marrow function and an echocardiogram to assess LVEF. Prior to enrollment, premenopausal women were screened for pregnancy via urine or serum pregnancy test. Organ and marrow function tests were conducted prior to study initiation. Prior to beginning study drug, blood was collected to measure trough CoQ10 concentrations and total antioxidant capacity. Baseline symptoms were assessed during prior to receiving cycle 2 doxorubicin/cyclophosphamide treatment.

The CUMC Institutional Review Board approved the protocol and informed consent process (initial IRB approval September 2, 2009, CUMC IRB-AAAD8521). The study was administered in English and Spanish. All participants provided written informed consent.

Study Drug

CoQ10 softgel capsules and a matching rice bran oil placebo were manufactured by CanCap Pharmaceutical Ltd. (Richmond, BC, Canada) and distributed by Thorne Research (Sandpoint, ID). Softgel capsule shells were manufactured from fish (tilapia gelatin made from the skins), and softgel shells were rendered opaque using titanium dioxide. CanCap Pharmaceutical holds a Site License and Establishment License from Health Canada. Thorne Research adheres to FDA recommended Current Good Manufacturing Processes (CGMPs) for dietary supplements. CoQ10 was administered in 150 mg capsules with food. The planned dosing at the 3 dose levels was as follows: 300 mg dose level, two 150 mg capsules once per day with food; 600 mg dose level, two 150 mg capsules 2 times per day with food; and 1200 mg dose level, four 150 mg capsules 2 times per day with food. The placebo was administered with the matching number of capsules and timing. CoQ10 and placebo capsules were dispensed by the CUMC Research Pharmacy. The trial was conducted under IND# 105119.

Study Design

Randomization. The study schema is depicted in Figure 1. In this phase I trial, a randomized, cross-over design was used to account for potential differences in cycle effects. At each dose level, 6 participants were planned to be randomized to Arm A (n = 3, Cycle 3 with CoQ10, followed by Cycle 4 with placebo) or Arm B (n = 3, Cycle 3 with placebo, followed by Cycle 4 with CoQ10); however, only a total of 7 patients were accrued. Participants, study staff, and investigators were blinded to randomization assignment; only the research pharmacy knew the study assignment. The randomization list was developed by the trial biostatistician using a random number generator and then provided to the research pharmacy.

Figure 1.

Design of randomized, controlled cross-over study design.

Routine doxorubicin/cyclophosphamide treatment. Dose-dense doxorubicin infusions were administered every 2 weeks for 4 cycles. For the 2 doxorubicin cycles administered during this study (Cycles 3 and 4), doxorubicin therapy was administered via infusion at 60 mg/m² over 30 minutes via an I.V. push, followed by a 45-minutes infusion of cyclophosphamide 600 mg/m². This dose remained fixed for all cycles unless toxicity necessitated any dose reduction. Anti-emetics were used as needed. Routine hematological assessment was performed 0-3 days prior to Cycles 2, 3 and 4. In order to receive dose-dense doxorubicin/cyclophosphamide neoadjuvant/adjuvant infusion (administered in all cycles) and the subsequent CoQ10/placebo study drug (study drug was administered following Cycle 2 for pharmacokinetic draws during Cycle 3 infusion and study drug was administered following Cycle 3 for pharmacokinetic draws during Cycle 4 infusion), the following parameters had to be met: absolute neutrophil count (ANC) ≥ 1500/µl before starting Cycle 1 and ANC ≥ 1000/µl prior to Cycles 2, 3 and 4; platelets ≥ 100 000/µl; total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN); aspartate transaminase (AST) (or serum glutamic-oxaloacetic transaminase, SGOT)/alanine aminotransferase (ALT) (or serum glutamic-pyruvic transaminase, SGPT) ≤ 2.5 X institutional ULN; and serum creatinine within normal institutional limits. In order to continue participation in the study, up to 3 weeks were allowed between Cycles 2 and 3 and between Cycles 3 and 4, based on the discretion of the medical oncologist.

Coenzyme Q10 administration and adherence. Beginning on the morning of Cycle 2 Day 3 (11-15 days prior to Cycle 3), participants began taking the study drug (either CoQ10 or placebo) and continued taking the study drug through the morning of their Cycle 3 infusion (Day 1 Cycle 3). Participants were then crossed-over to the alternative condition. On the morning of Cycle 3 Day 3, participants began taking the study drug (either CoQ10 or placebo) and continued taking the study drug through the morning of their Cycle 4 infusion (Day 1 Cycle 4). Study drug bottles were collected prior to the infusions and remaining capsules were counted to determine adherence. To ensure that participants understood the dosing schedule and to measure adherence to study drug, participants were provided study drug diaries and signed drug accountability forms when study drug was dispensed and collected. If participants were not ≥80% adherent, they were removed from the study due to non-adherence.

Blood sample collection. Participants remained at CUMC for 8 hours after the infusion and returned to CUMC the following morning for a 24-hours blood draw. A limited sampling strategy was used for pharmacokinetic analysis during Cycles 3 and 4 of doxorubicin/cyclophosphamide therapy and concurrent study drug administration, similar to a previously described limited sampling strategy for doxorubicin metabolism.^19,20 Blood was collected in EDTA tubes prior to the start of the infusion (PK1), at the end of the doxorubicin infusion (PK2), and at 30 minutes (PK3), 1 (PK4), 2 (PK5), 4 (PK6), 6 (PK7), and 24 (PK8) hours after the end of the infusion, Blood was collected in heparinized tubes prior to the start of the infusion and at approximately 24 hours (at the same time as PK8) to assess total antioxidant capacity (TAC) and CoQ10 concentrations (CoQ10 was only assessed at PK1 and PK8). The timing of PK2-8 collections were ±30 minutes of the times stated above. Blood samples were immediately placed on ice after collection and immediately centrifuged at 3000 RPMs for 10 minutes at 4°C. Plasma samples were transferred into cryovials. Cryovials were stored at −20°C for 24 hours if needed prior to being transferred to a −80°C freezer.

Side effect and adverse event evaluation. Side effects and adverse events were measured at each clinical visit using NCI Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Patients on statins, hypoglycemic agents, and insulin were monitored for potential interactions with CoQ10, including lowering of cholesterol/triglycerides, blood glucose, and insulin dose requirements. Safety profiles were assessed by recording the nature, severity, frequency, timing, and duration of any adverse events and their relationship to treatment.

Laboratory Analyses of Blood Sample

The CUMC Core Lab performed laboratory analyses included plasma concentrations of doxorubicin and doxorubicinol measured with high-performance liquid chromatography (HPLC), using methods previously described.²¹ Plasma samples were assessed for TAC using a TAC Assay Kit from MBL International Corporation (Woburn, MA). Blood CoQ10 concentrations were measured by high-performance liquid chromatography with electrochemical detection (HPLC-EQ) by use of a reverse-phase column and isocratic mobile phase, as previously described.²²

Pharmacokinetic Analyses

Non-compartmental pharmacokinetic parameters of doxorubicin and its metabolites were determined using WinNonlin software version 5.2 (Pharsight Corporation, Mountain View, CA, USA). Pharmacokinetic parameters were calculated for each patient and each occasion included area under the serum concentration time curve from t = 0 h until 24 hours (AUC0-24h), the maximum concentration reached (C_max), the time to reach C_max (t_max) and the terminal half-life (t_1/2). These parameters were calculated for the parent compound doxorubicin and for the doxorubicinol metabolites.

Statistical Analyses

We compared the mean age and average daily dietary intakes between study arms using a t-test, and compared the distribution of race, menopausal status, tumor characteristics, chemotherapy regimen and antioxidant use using Fisher’s exact test. Paired t-tests were used to compare the non-compartmental pharmacokinetic parameters of doxorubicin and doxorubicinol during periods with and without CoQ10 administration (treatment effect), and between Cycle 3 and Cycle 4 of doxorubicin infusion (time effect). Treatment effect and time effect were assessed for serum CoQ10 concentration and TAC using paired t-tests. Data analyses, summary statistical tables and concentration versus time curves were generated using R (version 3.3.1, The R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient characteristics

Between December 2010 and August 2012, a total of 6 women were randomized to receive 300 mg/day CoQ10 (n = 3 in Arm A, n = 3 in Arm B) during 1 cycle of doxorubicin. One patient was randomized to receive 600 mg/day CoQ10 but was discontinued due to non-adherence; of note, the patient indicated that the reason for non-adherence was not due to intolerance of the capsules. The study was closed prior to achieving the target 18 patients due to poor accrual. At enrollment, the average age was 57.7 years old (SD = 14.9 years, range = 30-75 years), and 50% were non-Hispanic white, 33.3% were Hispanic and 16.7% were African American. There was no between arm difference in demographic and clinical, and lifestyle factors (Table 1).

Table 1.

Patient Characteristics (n=6).

Patient characteristics	All (n = 6)	Arm A (n = 3)^a	Arm B (n = 3)^a	P-value^b
Mean age, years (SD)	57.7 (14.9)	66 (7.9)	49.3 (16.8)	.22
Race/ethnicity, n (%)
Non-Hispanic White	3 (50%)	2 (67%)	1 (33%)
Non-Hispanic Black	1 (17%)	0 (0%)	1 (33%)	1.00
Hispanic	2 (33%)	1 (33%)	1 (33%)
Stage, n (%)
II	4 (67%)	2 (67%)	2 (67%)	1.00
III	2 (33%)	1 (33%)	1 (33%)
Menopausal status, n (%)
Premenopausal	1 (17%)	0 (0%)	1 (33%)	1.00
Postmenopausal	5 (83%)	3 (100%)	2 (67%)
ER status, n (%)
Positive	3 (50%)	0 (0%)	3 (100%)	.10
Negative	3 (50%)	3 (100%)	0 (0%)
Unknown	0 (0%)	0 (0%)	0 (0%)
PR status, n (%)
Positive	1 (17%)	0 (0%)	1 (33%)	1.00
Negative	5 (83%)	3 (100%)	2 (67%)
Unknown	0 (0%)	0 (0%)	0 (0%)
HER2 status, n (%)
Positive	3 (50%)	1 (33%)	2 (67%)	1.00
Negative	3 (50%)	2 (67%)	1 (33%)
Unknown	0 (0%)	0 (0%)	0 (0%)
Chemotherapy regimen, n (%)
AC × 4 T × 12	3 (50%)	2 (67%)	1 (33%)	1.00
T × 12 AC × 4	3 (50%)	1 (33%)	2 (67%)
Currently using antioxidant, n (%)
No	5 (83%)	2 (67%)	3 (100%)	1.00
Yes	1 (17%)	1 (33%)	0 (0%)
Diet (frequency/day), mean (SD)
Fruit	0.8 (0.7)	1.2 (1.2)	0.6 (0.4)	.59
Fruit juice	1.0 (1.0)	1.0 (1.4)	1.0 (1.0)	1.00
Vegetable	1.7 (1.3)	1.2 (1.6)	2.2 (0.9)	.41
Vegetable juice	0.2 (0.3)	0.4 (0.4)	0.1 (0.2)	.46
Potatoes	0.2 (0.3)	0.0 (0.0)	0.4 (0.3)	.14
Beans	0.4 (0.4)	0.3 (0.2)	0.5 (0.4)	.45
Fiber cereal/dark bread	1.0 (0.6)	0.7 (0.7)	1.4 (0.3)	.21

Arm A: CoQ10 administered in Cycle 3 followed by placebo in Cycle 4; Arm B: Placebo administered in Cycle 3 followed by CoQ10 in Cycle 4.

Means were tested using t-tests and percentages were tested using Fisher’s exact test.

Abbreviations: SD, standard deviation; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; AC, Adriamycin, and cyclophosphamide; T, Taxol.

Safety

No Grade 3 or Grade 4 adverse events were observed; the most common adverse events were Grade 1-2 alopecia (n = 3, 50%), constipation (n = 3, 50%), diarrhea (n = 3, 50%), abnormal ear, nose and throat examination (n = 3, 50.0%), abnormal hemoglobin (n = 3, 50%) and nausea (n = 3, 50%) (Supplemental Table 1). No adverse effects were “definitely related” to CoQ10 treatment; 5 events were considered “possibly related” to CoQ10 treatment. Treatment with CoQ10 did not result in an increased frequency of doxorubicin-induced adverse events, and no participants discontinued the study because of adverse events.

Doxorubicin Pharmacokinetics

Changes in doxorubicin concentrations and its metabolite doxorubicinol were not appreciably different with and without CoQ10 administration (Figure 2). Table 2 summarizes the mean and median non-compartmental pharmacokinetic parameters for doxorubicin and doxorubicinol in patients treated with CoQ10 and placebo, respectively. Mean AUC (0-24h), C_max, T_max and half-life of doxorubicin were generally similar in patients treated with doxorubicin + CoQ10 300 mg/day and patients treated with doxorubicin + placebo. CoQ10 did not change the pharmacokinetic parameters of doxorubicinol or the ratio of doxorubicin AUC (0-24 hours) to doxorubicinol AUC (0-24 hours). Furthermore, there was no statistically significant difference in pharmacokinetic parameters between cycle 3 and 4 of doxorubicin infusion (Supplemental Table 2).

Figure 2.

Mean and 95% confidence intervals are shown for doxorubicin (panels A and B; in panel B, the Y-axis is restricted to 150 ng/mL for comparability, with arrows indicating baseline values beyond the Y-axis) and its metabolite, doxorubicinol (panel C), for the 24 hours following doxorubicin infusion (n = 6).

Table 2.

Pharmacokinetic parameters comparing breast cancer patients undergoing 1 cycle of doxorubicin with CoQ10 and placebo (n = 6).

Pharmacokinetic parameters	Doxorubicin + CoQ10 (300 mg/d)				Doxorubicin + Placebo				Between group difference		P-value^e
Pharmacokinetic parameters	Mean	SD	Median	Range	Mean	SD	Median	Range	Mean	95% CI
Doxorubicin
AUC0_24 (hr*ng/m)^a	1394.5	358.5	1265.5	1034.5, 1983.3	1449.6	472.3	1319.9	1069.2, 2243.5	55.1	−331.9, 442.1	.73
C_max (ng/m)^b	1914.6	990.0	1757.8	894.8, 3435.9	2086.8	1263.9	1858.1	861.1, 4388.3	172.2	−913.3, 1257.7	.70
T_max (hour)^c	0.3	0.0	0.3	0.2, 0.4	0.3	0.1	0.3	0.2, 0.4	0.0	−0.1, 0.1	.88
Half-life (hour)^d	13.7	2.4	13.6	10.7, 17.7	15.4	2.8	15.9	11.9, 19.7	1.7	−0.5, 3.9	.10
Doxorubicinol
AUC0_24 (hr*ng/ml)	443.8	101.9	457.2	274.3, 545.3	466.9	155.7	518.0	223.4, 612.5	23.0	−63.4, 109.5	.52
C_max (ng/ml)	26.0	8.1	28.4	13.2, 33.9	26.6	11.3	27.5	10.5, 39.3	0.6	−3.2, 4.4	.71
T_max (hour)	2.7	2.2	1.8	0.8, 6.4	1.8	1.4	1.3	0.4, 4.5	−0.9	−3.1, 1.3	.35
Half-life (hour)	33.8	23.5	24.3	19.1, 80.7	42.4	33.5	30.5	18.8, 107.8	8.6	−6.6, 23.8	.21
Doxorubicinol/doxorubicin
AUC0_24/AUC0_24	0.3	0.1	0.4	0.2, 0.5	0.3	0.1	0.3	0.2, 0.6	0.0	−0.1, 0.1	.92

AUC0_24 (area under curve) is a measure of the exposure to the drug over the 24 hours after infusion.

C_max is the maximum concentration of drug in the plasma after infusion.

T_max is the time taken to reach the maximum concentration.

Elimination half-life is the time taken for the plasma concentration to fall by half its original value.

P-value was calculated using paired t-test.

Serum Total Antioxidant Capacity (TAC) and CoQ-10 Concentration

Table 3 shows the changes in serum CoQ10 and TAC concentrations after 1 cycle of doxorubicin in patients with and without CoQ10 administration. A statistically significantly greater increase in serum CoQ10 concentration was noted in the patients treated with doxorubicin + CoQ10 compared to patients treated with doxorubicin + placebo (mean ± SD change in serum CoQ10 from baseline: doxorubicin + CoQ10 300 mg/day: 1.6 ± 0.9 µg/ml, doxorubicin + placebo: −0.01 ± 0.3 µg/ml, P = .01). Serum CoQ10 concentrations were not different between Cycle 3 and Cycle 4 (Supplemental Table 3). There was no statistically significant change in TAC between the patients treated with doxorubicin + CoQ10 and doxorubicin + placebo. However, TAC was statistically significantly lower after Cycle 4 of doxorubicin compared to Cycle 3 doxorubicin (mean ± SD TAC: Cycle 3 = 509.7 ± 37.2 nM, Cycle 4 = 482.4 ± 41.4 nM, P = .05; Supplemental Table 3).

Table 3.

Changes in Total Antioxidant Capacity and CoQ10 Concentrations after 1 Cycle of Doxorubicin Infusion (n = 6).

Pharmacokinetic parameters	Baseline				After 1 cycle of doxorubicin				PairedT-testP-value	Changes from baseline				P-value
Pharmacokinetic parameters	Mean	SD	Median	Range	Mean	SD	Median	Range		Mean	SD	Median	Range	P-value
Total antioxidant capacity (nM)	501.3	40.6	495.1	458.8, 568.4					.34					.34
Doxorubicin + CoQ-10					488.3	45.1	507.9	400.5, 519.6		−13.0	56.4	−10.3	−93.8, 54.7
Doxorubicin + Placebo					503.8	37.0	499.1	456.5, 569.2		2.5	60.7	−18.4	−58.3, 103.6
CoQ-10 concentration (µg/ml)	1.0	0.2	1.0	0.8, 1.5					.01					.01
Doxorubicin + CoQ-10					2.6	0.9	2.9	1, 3.4		1.6	0.9	1.9	0, 2.4
Doxorubicin + Placebo					1.0	0.2	1.1	0.6, 1.2		−0.01	0.3	0.1	−0.6, 0.3

Discussion

In this phase I randomized, placebo-controlled, cross-over study, CoQ10 at 300 mg/day was well tolerated and did not change the pharmacokinetics of doxorubicin. No adverse effects were observed. Patients receiving CoQ10 with doxorubicin experienced a statistically significant approximate doubling of serum CoQ10 concentration, or an average increase of 1.6 µg/mL.

Many breast cancer treatments are known to carry a substantial risk of adverse long-term treatment related effects.^7
-10 Antioxidant supplements are an unproven yet widely used approach intended to reduce side effects, used by 45%-80% of breast cancer patients after diagnosis.^16,23
-25 However, antioxidants may counteract the desired effects of cancer treatment²⁶ and moreover their effects on cancer recurrence or mortality are not well understood.^16,27 Few randomized, clinical trials have examined effects of antioxidant supplement intake during breast cancer treatment, which motivated this study.¹⁶ An observational study (SWOG S0221A-ICSC, PI: Ambrosone) examining effects of antioxidant intake on treatment outcomes nested in a therapeutic trial of adjuvant doxorubicin, cyclophosphamide and paclitaxel for breast cancer, recently reported that use of antioxidants, including CoQ10, before and during treatment was associated with an increased risk of recurrence.^28,29 If there is decreased efficacy from doxorubicin when co-administered with CoQ10, based on our findings this does not seem to be related to a change in systemic exposure to doxorubicin or its primary metabolite.

We only tested CoQ10 dosage at 300 mg/d, therefore we cannot report on the pharmacokinetics of higher dose CoQ10 during treatment for breast cancer patients. A daily dose of 300 mg per day for 11 days has been shown to raise plasma CoQ10 concentrations by 300%-400% whereas our study showed less dramatic effects of this dose level on CoQ10 concentrations.³⁰ An NCI-sponsored multi-center trial tested the effects of 300 mg CoQ10 per day on self-reported fatigue over 24 weeks of treatment among women (n = 236) treated with adjuvant chemotherapy.³¹ The study reported significant increase in plasma CoQ10 level in patients receiving CoQ10 supplements but no significant improvement in fatigue. In the current study, we planned to test 3 daily dose levels of CoQ10: 300, 600, and 1200 mg/d. These doses were chosen after reviewing the literature on the use of CoQ10 in oncology, cardiovascular, and neurological patient populations. In oncology clinical studies, daily dosages of CoQ10 for preventing doxorubicin-induced cardiotoxicity ranged from 30 to 120 mg/d.^32
-40 Cardiovascular patient populations typically use doses of CoQ10 ranging from 30 to 300 mg/d,^41,42 intake via dietary supplements is generally considered to be safe at doses up to 1200 mg per day³⁰ and high doses of CoQ10 (up to 3000 mg/d) are being investigated to treat neurodegenerative disorders such as Huntington’s Disease and Parkinson’s Disease.^43
-53 None of the studies provided rationale for doses used, and the studies showed limited effects, if any.

In our study, all patients in both arms had normal level of CoQ10 at baseline (mean = 1.0 μmol/l), within the adult reference interval of 0.5-1.7 μmol/l.^54
-56 The level of CoQ10 was significantly increased by approximately 2-fold after 300 mg/day coenzyme Q10 supplementation. The effect of CoQ10 supplement on serum CoQ10 level was comparable when administered during Cycle 3 and 4 of cancer treatment. The amount of increase was lower to that reported in previous studies of dietary supplementation with 300-900 mg/day CoQ10 and 200 mg/day ubiquinol, in which 3 to 5-fold increases in serum CoQ10 were observed.^30,57
-59 The greater effect of CoQ10 reported in previous studies was likely due to the lower baseline CoQ10 levels (0.5-0.8 μmol/l), higher CoQ10 dosage (up to 900 mg/day) and longer duration of CoQ10 supplementation (4-12 weeks).

The leading mechanistic hypothesis for doxorubicin-induced cardiotoxicity is that doxorubicin differentially increases reactive oxygen species (ROS) within cardiac myocyte mitochondria, as compared to other tissues.^12,60,61 We did not observe statistically significant differences in total antioxidant capacity, a measure of ROS, between groups who did and did not receive CoQ10. We cannot discern if this lack of difference is due to the small sample size and lack of statistical power, if the 300 mg per day dose was too low to reduce oxidative stress, if there is a discrepancy between system and intracellular total antioxidant capacity, or if in fact there is no true difference. In vitro studies have shown that administering CoQ10 either before or during doxorubicin administration can prevent doxorubicin-induced changes including cardiac beat inhibition,⁶² increase in lipid peroxidation as measured by malondialdehyde,⁶³ and reduced cardiac contractile tension.⁶⁴ Animal studies suggest that the impact of doxorubicin on mitochondria is cardioselective, that CoQ10 can prevent doxorubicin-induced mitochondrial damage, and that CoQ10 can prevent the progression of cardiomyopathy induced by doxorubicin.^12,65 Clinical studies of CoQ10 administered before or during doxorubicin treatment have shown that CoQ10 prevented changes in LVEF,³² systolic time intervals (STI),³³ fractional shortening,⁶⁶ intraventricular septal wall thickening,⁶⁶ cardiac output,^34,67 and EKG changes.³⁵ In addition, CoQ10 allowed for increased doses of doxorubicin to be administered.³² However, these studies were small and included patients of mixed tumor types. No studies have focused on early stage breast cancer patients, for whom doxorubicin treatment is standard neoadjuvant and adjuvant therapy.

Strengths and Limitations

Strengths of the study include prospective data collection in a randomized, controlled, cross-over design with a well-defined single pharmacologic agent. However, there are important limitations to consider. The major study limitation is the small sample size, which led to relative imprecision of estimates, and which also made it impossible to exclude safety concerns. The small sample size was due to the difficulty of enrolling participants as the protocol was burdensome to patients due to time, travel and inconvenience. In the adjuvant setting it is challenging to recruit patients to a trial of a dietary supplement as it can be burdensome to follow the study protocol, and dietary supplements are readily available over the counter. Moreover, this trial required patients to enroll prior to their first cycle of chemotherapy, which is often a period of high stress and anxiety for patients. Future trials of this nature should actively employ methods to expand eligibility criteria and reduce participant burden. It is possible that CoQ10 effects may have been difficult to detect in light of natural between-patient and intrapersonal variations of measured parameters. We lacked data on cardiac biomarkers and circulating CoQ10 metabolites, which is another weakness that limited our ability to examine the effects of CoQ10 on level of cardiotoxicity. There are limited data to guide CoQ10 dosing and future studies should assess differences in CoQ10 AUC and pharmacokinetics in order to better guide CoQ10 dosing. Finally, the goal of this trial was to assess changes in doxorubicin pharmacokinetics following CoQ10 administration, but did not assess the pharmacodynamics between CoQ10 and doxorubicin. Pharmacodynamics are of significance because the concern is that CoQ10 may counter the desired therapeutic effect of doxorubicin. Future trials should include pharmacodynamic analyses.

Conclusion

In conclusion, these findings showed that CoQ10 at 300 mg/day was well-tolerated and did not change pharmacokinetics of 1 cycle of doxorubicin in breast cancer patients. However, our results do not warrant clinical recommendation for CoQ10, but indicate that this is a possible area of study. Future studies will need to balance the potential beneficial protective effect against doxorubicin cardiotoxicity in early stage breast cancer patients with the potential risk of use of antioxidants during treatment.

Supplemental Material

sj-docx-1-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Supplemental material, sj-docx-1-ict-10.1177_15347354251388014 for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment by Heather Greenlee, Katherine D. Crew, Matthew Maurer, Kevin Kalinsky, Serge Cremers, Ali Naini, Wei Yann Tsai, Zaixing Shi, Frances Brogan and Dawn L. Hershman in Integrative Cancer Therapies

Supplemental Material

sj-docx-2-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Supplemental material, sj-docx-2-ict-10.1177_15347354251388014 for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment by Heather Greenlee, Katherine D. Crew, Matthew Maurer, Kevin Kalinsky, Serge Cremers, Ali Naini, Wei Yann Tsai, Zaixing Shi, Frances Brogan and Dawn L. Hershman in Integrative Cancer Therapies

Supplemental Material

sj-docx-3-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Supplemental material, sj-docx-3-ict-10.1177_15347354251388014 for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment by Heather Greenlee, Katherine D. Crew, Matthew Maurer, Kevin Kalinsky, Serge Cremers, Ali Naini, Wei Yann Tsai, Zaixing Shi, Frances Brogan and Dawn L. Hershman in Integrative Cancer Therapies

Supplemental Material

sj-docx-4-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Supplemental material, sj-docx-4-ict-10.1177_15347354251388014 for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment by Heather Greenlee, Katherine D. Crew, Matthew Maurer, Kevin Kalinsky, Serge Cremers, Ali Naini, Wei Yann Tsai, Zaixing Shi, Frances Brogan and Dawn L. Hershman in Integrative Cancer Therapies

Footnotes

Acknowledgements

We thank Kirsten Abildskov for her technical work on the Doxorubicin assay and Franco Barsanti for his assistance preparing the IND application. We acknowledge Alan Butcher at Thorne Research (Sandpoint, ID) for coordinating provision of the CoQ10 supplement.

Author Note

The authors confirm that the Principal Investigator for this paper is Heather Greenlee, ND, PhD, MPH, and that as Director of the Breast Medical Oncology Program at Columbia University Irving Medical Center, Dawn Hershman, MD, MS had direct clinical responsibility for patients.

ORCID iDs

Heather Greenlee

Katherine D. Crew

Zaixing Shi

Ethical Considerations

The CUMC Institutional Review Board approved the protocol and informed consent process (initial IRB approval September 2, 2009, CUMC IRB-AAAD8521).

Consent to Participate

All participants provided signed written consent to participate in this research.

Author Contributions

All authors reviewed and approved the final manuscript. Specific contributions are: Greenlee: Designed study, Conducted analyses, Obtained funding, Overall oversight of research. Crew: Designed study, Enrolled participants. Maurer: Designed study, Enrolled participants. Kalinsky: Enrolled participants. Cremers: Designed study, Conducted analyses. Naini: Designed study, Conducted analyses. Tsai: Designed study, Conducted analyses. Shi: Conducted analyses. Brogan: Nil. Hershman: Designed study, Enrolled participants, Obtained funding, Overall oversight of research.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Cancer Institute (K23CA141052 to Dr. Greenlee) and the National Center for Advancing Translational Sciences through grant number UL1TR001873.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Data and analysis code will be made available under reasonable request, and in accordance with limitations of informed consent language, through correspondence with the authors.

References

National Cancer Institute. Cancer Stat Facts: Female Breast Cancer. National Cancer Institute. Accessed July 20, 2018. https://seer.cancer.gov/statfacts/html/breast.html

American Cancer Society. Key Statistics for Breast Cancer. Accessed March 1, 2023. https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html

American Cancer Society. Breast Cancer Facts & Figures 2022-2024. Atlanta: American Cancer Society; 2024.

Giordano

Elias

Gradishar

WJ.

NCCN Guidelines Updates: Breast Cancer. J Natl Compr Canc Netw. 2018;16(5S):605-610.

Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet. 1998;352(9132):930-942.

Henderson

Berry

Demetri

, et al Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003;21(6):976-983.

Romond

Perez

Bryant

, et al Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.

Shan

Lincoff

Young

JB.

Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996;125(1):47-58.

Murtagh

Lyons

O’Connell

, et al Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up. Breast Cancer Res Treat. 2016;156(3):501-506.

10.

Qin

Thompson

Silverman

Predictors of late-onset heart failure in breast cancer patients treated with doxorubicin. J Cancer Surviv. 2015;9(2):252-259.

11.

Ewer

Lenihan

DJ.

Left ventricular ejection fraction and cardiotoxicity: is our ear really to the ground?

J Clin Oncol. 2008;26(8):1201-1203.

12.

Conklin

KA.

Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity. Integr Cancer Ther. 2005;4(2):110-130.

13.

de Baat

Mulder

Armenian

, et al Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines. Cochrane Database Syst Rev. 27 2022;9(9):Cd014638.

14.

Eaton

Skinner

Hale

, et al Plasma coenzyme Q(10) in children and adolescents undergoing doxorubicin therapy. Clin Chim Acta. 2000;302(1-2):1-9.

15.

Karlsson

Folkers

Astrom

. Effect of Adriamycin on heart and skeletal muscle coenzyme Q10 (CoQ10) in man. In: Folkers

Yamamura

, eds. Biomedical and Clinical Aspects of Coenzyme Q. Elsevier/North-Holland Biomedical Press; 1986:241-245.

16.

Greenlee

Hershman

Jacobson

JS.

Use of antioxidant supplements during breast cancer treatment: a comprehensive review. Breast Cancer Res Treat. 2009;115(3):437-452.

17.

Zirpoli

Brennan

Hong

, et al Supplement use during an intergroup clinical trial for breast cancer (S0221). Breast Cancer Res Treat. 2013;137(3):903-913.

18.

Greenlee

Shaw

Lau

Naini

Maurer

Lack of effect of coenzyme q10 on doxorubicin cytotoxicity in breast cancer cell cultures. Integr Cancer Ther. 2012;11(3):243-250.

19.

Joerger

Huitema

Richel

, et al Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG. Clinical Pharmacokinet. 2007;46(12):1051-1068.

20.

Ratain

Robert

van der Vijgh

WJ.

Limited sampling models for doxorubicin pharmacokinetics. J Clin Oncol. 1991;9(5):871-876.

21.

Beijnen

Meenhorst

van Gijn

Fromme

Rosing

Underberg

WJ.

HPLC determination of doxorubicin, doxorubicinol and four aglycone metabolites in plasma of AIDS patients. J Pharm Biomed Anal. 1991;9(10-12):995-1002.

22.

Naini

Lewis

Hirano

DiMauro

Primary coenzyme Q10 deficiency and the brain. BioFactors (Oxford, England). 2003;18(1-4):145-152.

23.

Velicer

Ulrich

CM.

Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol. 2008;26(4):665-673.

24.

Eschiti

VS.

Lesson from comparison of CAM use by women with female-specific cancers to others: it’s time to focus on interaction risks with CAM therapies. Integr Cancer Ther. 2007;6(4):313-344.

25.

Greenlee

Gammon

Abrahamson

, et al Prevalence and predictors of antioxidant supplement use during breast cancer treatment: the Long Island Breast Cancer Study Project. Cancer. 2009;115(14):3271-3282.

26.

D’Andrea

. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin. 2005;55(5):319-321.

27.

Ladas

Jacobson

Kennedy

Teel

Fleischauer

Kelly

KM.

Antioxidants and cancer therapy: a systematic review. J Clin Oncol. 2004;22(3):517-528.

28.

Zirpoli

McCann

Sucheston-Campbell

, et al Supplement Use and Chemotherapy-Induced Peripheral Neuropathy in a Cooperative Group Trial (S0221): the DELCaP Study. J Natl Cancer Inst. 2017;109(12):djx098.

29.

Ambrosone

Zirpoli

Hutson

, et al Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221). J Clin Oncol. 2020;38(8):804-814.

30.

Hathcock

Shao

Risk assessment for coenzyme Q10 (Ubiquinone). Regul Toxicol Pharmacol. 2006;45(3):282-288.

31.

Lesser

Case

Stark

, et al A randomized, double-blind, placebo-controlled study of oral coenzyme Q10 to relieve self-reported treatment-related fatigue in newly diagnosed patients with breast cancer. J Support Oncol. 2013;11(1):31-42.

32.

Judy

Hall

Dugan

Toth

Folkers

. Coenzyme Q10 reduction of Adriamycin cardiotoxicity. In: Folkers

Yamamura

, eds. Biomedical and Clinical Aspects of Coenzyme Q. Elsevier/North-Holland Biomedical Press; 1984:231-241.

33.

Cortes

Gupta

Chou

Amin

Folkers

Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10. Cancer Treat Rep. 1978;62(6):887-891.

34.

Folkers

Baker

Richardson

. Biomedical and clinical research on coenzyme Q10. In: Yamamura

Yamamura

Folkers

Ito

, eds. Biomedical and Clinical Aspects of Coenzyme Q. Elsevier/North-Holland Biomedical Press; 1980:447-454.

35.

Okuma

Ota

. The effect of coenzyme Q10 on ECG changes induced by doxorubicin (Adriamycin). In: Folkers

Yamamura

, eds. Biomedical and Clinical Aspects of Coenzyme Q. Elsevier/North-Holland Biomedical Press; 1986:247-256.

36.

Takimoto

Sakurai

Kodama

, et al [Protective effect of CoQ 10 administration on cardial toxicity in FAC therapy]. Gan To Kagaku Ryoho. 1982;9(1):116-121.

37.

Tsubaki

Horiuchi

Kitani

Investigation of the preventive effect of CoQ10 against the side-effects of anthracycline antineoplastic agents. Gan To Kagaku Ryoho. 1984;1984(11):1420-1427.

38.

Yamamura

. A survey of the therapeutic uses of coenzyme Q. In: Lenaz

, ed. Coenzyme Q: Biochemistry, Bioenergetics and Clinical Applications of Ubiquinone. John Wiley and Sons; 1985:479-505.

39.

Legha

Wang

Mackay

, et al Clinical and pharmacologic investigation of the effects of alpha-tocopherol on adriamycin cardiotoxicity. Ann N Y Acad Sci. 1982 1982;393:411-418.

40.

Akihama

Nakamoto

Shindo

Nakayama

Miura

Protective effects of coenzyme Q10 on the adverse reactions of anthracycline antibiotics: using double blind method - with special reference to hair loss. Gan To Kagaku Ryoho. 1983;10:2125-2129.

41.

Bonakdar

Guarneri

Coenzyme Q10. Am Fam Physician. 2005;72(6):1065-1070.

42.

Pepe

Marasco

Haas

Sheeran

Krum

Rosenfeldt

FL.

Coenzyme Q10 in cardiovascular disease. Mitochondrion. 2007;7:S154-S167.

43.

Musumeci

Naini

Slonim

, et al Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology. 2001;56(7):849-855.

44.

Feigin

Kieburtz

Como

, et al Assessment of coenzyme Q10 tolerability in Huntington’s disease. Mov Disord. 1996;11(3):321-323.

45.

Koroshetz

Jenkins

Rosen

Beal

MF.

Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol. 1997;41(2):160-165.

46.

Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology. 2001;57(3):397-404.

47.

Shults

Beal

Fontaine

Nakano

Haas

RH.

Absorption, tolerability, and effects on mitochondrial activity of oral coenzyme Q10 in parkinsonian patients. Neurology. 1998;50(3):793-795.

48.

Shults

Flint Beal

Song

Fontaine

Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol. 2004;188(2):491-494.

49.

Storch

Jost

Vieregge

, et al Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol. 2007;64(7):938-944.

50.

Lodi

Hart

Rajagopalan

, et al Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with Friedreich’s ataxia. Ann Neurol. 2001;49(5):590-596.

51.

Hart

Lodi

Rajagopalan

, et al Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol. 2005;62(4):621-626.

52.

Shults

Oakes

Kieburtz

, et al Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541-1550.

53.

Thijs

Peeters

Theys

Matthijs

Robberecht

Demographic characteristics and prognosis in a Flemish amyotrophic lateral sclerosis population. Acta Neurol Belg. 2000;100(2):84-90.

54.

Kaikkonen

Tuomainen

Nyyssonen

Salonen

JT.

Coenzyme Q10: absorption, antioxidative properties, determinants, and plasma levels. Free Radic Res. 2002;36(4):389-397.

55.

Molyneux

Florkowski

Lever

George

PM.

Biological variation of coenzyme Q10. Clin Chem. 2005;51(2):455-457.

56.

Molyneux

Young

Florkowski

Lever

George

PM.

Coenzyme Q10: is there a clinical role and a case for measurement?

Clin Biochem Rev. 2008;29(2):71-82.

57.

Ikematsu

Nakamura

Harashima

Fujii

Fukutomi

Safety assessment of coenzyme Q10 (Kaneka Q10) in healthy subjects: a double-blind, randomized, placebo-controlled trial. Regul Toxicol Pharmacol. 2006;44(3):212-218.

58.

Langsjoen

AM.

Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with ubiquinol versus ubiquinone. Clin Pharmacol Drug Dev. 2014;3(1):13-17.

59.

Lee

Tseng

Yen

Lin

PT.

Effects of coenzyme Q10 supplementation (300 mg/day) on antioxidation and anti-inflammation in coronary artery disease patients during statins therapy: a randomized, placebo-controlled trial. Nutr J. 2013;12(1):142.

60.

Shinozawa

Etowo

Araki

Oda

Effect of coenzyme Q10 on the survival time and lipid peroxidation of adriamycin (doxorubicin) treated mice. Acta Med Okayama. 1984;38(1):57-63.

61.

Gille

Nohl

Analyses of the molecular mechanism of adriamycin-induced cardiotoxicity. Free Radic Biol Med. 1997;23(5):775-782.

62.

Kishi

Takahashi

Mayumi

, et al Protective effect of coenzyme Q10 on Adriamycin toxicity in beating heart cells. In: Folkers

Yamamura

, eds. Biomedical and Clinical Aspects of Coenzyme Q. Elsevier/North-Holland Biomedical Press; 1984:181-194.

63.

Takahashi

Mayumi

Kishi

Influence of coenzyme Q10 on doxorubicin uptake and metabolism by mouse myocardial cells in culture. Chem Pharm Bull (Tokyo). 1988;36(4):1514-1518.

64.

Ohhara

Kanaide

Nakamura

A protective effect of coenzyme Q10 on the adriamycin-induced cardiotoxicity in the isolated perfused rat heart. J Mol Cell Cardiol. 1981;13(8):741-752.

65.

Domae

Sawada

Matsuyama

Konishi

Uchino

Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme Q10. Cancer Treat Rep. 1981;65(1-2):79-91.

66.

Iarussi

Auricchio

Agretto

, et al Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. Mol Aspects Med. 1994;15:s207-s212.

67.

Folkers

Baker

Richardson

. New progress on the biomedical and clinical research on coenzyme Q10. In: Folkers

Yamamura

, eds. Biomedical and Clinical Aspects of Coenzyme Q. Elsevier/North-Holland Biomedical Press; 1981:399-412.

Supplementary Material

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Phase I Randomized,Placebo-Controlled,Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Abstract

Aim:

Methods:

Results:

Conclusion:

Trial registration:

Keywords

Introduction

Methods

Participants

Study Drug

Study Design

Laboratory Analyses of Blood Sample

Pharmacokinetic Analyses

Statistical Analyses

Results

Patient characteristics

Safety

Doxorubicin Pharmacokinetics

Serum Total Antioxidant Capacity (TAC) and CoQ-10 Concentration

Discussion

Strengths and Limitations

Conclusion

Supplemental Material

sj-docx-1-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Supplemental Material

sj-docx-2-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Supplemental Material

sj-docx-3-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Supplemental Material

sj-docx-4-ict-10.1177_15347354251388014 – Supplemental material for Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment

Footnotes

Acknowledgements

Author Note

ORCID iDs

Ethical Considerations

Consent to Participate

Author Contributions

Funding

Declaration of Conflicting Interests

Data Availability Statement

References

Supplementary Material