Acta Oncologica 28 (1989) Fasc. 5

FROM THE DEPARTMENTS OF SURGERY AND ANAESTHESIA, UNIVERSITY HOSPITAL, UMEA, AND KARO- LINSKA PHARMACY, STOCKHOLM, SWEDEN.

PHARMACOKINETICS AND CENTRAL HAEMODYNAMIC EFFECTS OF DOXORUBICIN AND 4’EPI-DOXORUBICIN IN THE PIG

M. ANDERSON, L. DOMELLOF, S. EKSBORG, S. HAGGMARK, G. JOHANSSON, S. REIZ and A. HERSLOF

Abstract The relationship between the cardiotoxicity and the haemody-

namicsi pharmacokinetics of clinical concentrations of doxorubi- cin and 4‘epi-doxorubicin was studied. Twelve pigs were ran- domized to receive i.v. infusions of either drug of 50 mg/mz over 3.0 min. Aortic, pulmonary arterial, coronary sinus and central venous plasma concentrations of the agents were determined until 180 min after the infusion. The V5 ECG, left ventricular dP/dT, aortic, pulmonary arterial and right atrial pressures were recorded continuously, cardiac output and coronary sinus blood flow were recorded intermittently. No haemodynamic changes were recorded after administration of either drug. Pharmacoki- netic data indicated myocardial extraction, followed by myocar- dial release of both drugs. This release was higher after adminis- tration of 4’epi-doxorubicin than after doxorubicin, within the range 2 4 min and 2 0 4 0 min after the infusion. The tendency of greater myocardial release of 4’epi-doxorubicin may explain its lower cardiotoxicity.

Key words: Doxorubicin. 4’epi-doxorubicin, haemodynamics, pharmacokinetics, cardiotoxicity, pig.

Doxorubicin is an effective antineoplastic anthracycline antibiotic (1). Recently, a new anthracycline analogue, 4’epi-doxorubicin, has been clinically tested. This drug seems to have the same efficacy as doxorubicin in the treatment of solid and haematologic malignancies ( 2 4 ) . Both drugs are associated with acute and cumulative car- diac toxicity (3, 5, 6). Acute effects include ECG altera- tions and arrhythmias (3, 7). Cumulative toxicity may cause congestive heart failure (68 ) . Several studies indi- cate that the cardiotoxicity related to the new compound appears at a higher cumulative dose compared to doxoru- bicin (3, 4, 9). The aim of the present study was to evaluate the relationship between the pharmacokinetics of the 2 drugs and their acute effects on systemic, pulmonary and coronary haemodynamics and on myocardial oxygen- ation.

Material and Methods

Twelve chloralose-anaesthetized pigs weighing 47-53 (average 49) kg were used for the study. After induction of anaesthesia with 900 mg i.v. pentobarbital, a tracheosto- my was performed and the animals were attached to a volume cycled ventilator. Ventilation was maintained by oxygen enriched air (fraction of inspired oxygen=30 %). Anaesthesia was maintained by continuous i.v. chloralose infusion at 40 mglkglh. End-tidal carbon dioxide tension was kept around 4.0 kPa. During the 5-h preparation and study period, the animals received approximately 2 000 ml normal saline i.v. Catheters were placed under fluoro- scopic guidance in the thoracic aorta via the femoral artery, in the pulmonary artery, in the coronary sinus and in the caval vein via the external jugular vein. Pressure transducers (Siemens-Elema 746/5 1) were placed at mid- chest level and calibrated by water standards. In addition, a pressure transduce tipped catheter (PC 471, Millar In- struments) was placed in the left ventricle. The V5 ECG, left ventricular dP/dT, aortic, pulmonary arterial and right atrial pressures were recorded continuously during the study period on a Mingograph 82 recorder. Cardiac output and coronary venous blood flow were determined by the bolus and retrograde continuous thermodilution tech- niques respectively (10, 11) .

The animals were randomized to receive doxorubicin or 4‘epi-doxorubicin at a dose of 50 mg/m2 (BSA), adminis- tered i.v. over 3.0 min. Blood was sampled from the aorta, coronary sinus, pulmonary artery and caval vein for plasma drug concentration determination before and 10 s , 1 , 5 , 15, 30,45,60,90, 120, 150, and 180 min after the end of the drug infusion. Blood samples (5-7 ml) were collected in glass test tubes (Vacutainer), containing 250

Accepted for publication 21 September 1988.

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M. ANDERSSON ET AL.

201 20 x 101 _J

A 2 i \

a a r z w U z 0 U

a I m U 2 5 0.OOl-l 1 9 , I , I , I 1 , , . I . I , I

0 20 4 0 60 80 100 120 140 160 180

20 2 101

cs

M I N

0.005 u 0.002 m

2 0 . 0 0 1 0 2 0 4 0 60 80 l o o 120 1110 1 6 0 181 M I N

Fig. 1. Plasma concentration time curves in aortic (A), pulmo- nary arterial (PA), coronary sinus (CS) and caval vein (CV) plasma. O=determined plasma concentrations. The solid lines

IU of heparin (freeze-dried). The blaod samples were centrifuged for 10 min to separate the plasma fraction. The plasma was removed and transferred to a glass test tube and stored at -80°C until analysis. The exact times of blood sampling were recorded and used for the pharma- cokinetic calculations. The blood sampling procedure did, as a role, not exceed 5 s.

Haemodynamic measurements were obtained in associ- ation with the blood samples except at 10 s. Blood was sampled from the aorta, coronary sinus and pulmonary artery, for measurement of oxygen contents, before and 5 , 15, 30 and 60 min after the anthracycline infusion.

Analytical procedure. Plasma concentrations of doxo- rubicin, 4'epi-doxorubicin and their active metabolites doxorubicinol and 4'epi-doxorubicinol were determined by an analytical method based on liquid-liquid extraction (1 ml plasma samples) with a subsequent separation by reversed phase liquid chromatography with photometric detection at 500 nm. The method used is based on a procedure for the determination of doxorubicin and doxo- rubicinol(l2) with a slight modification of the composition of the mobile phase (13). All plasma concentration data used for the pharmacokinetic evaluation are mean values of at least duplicate analyses.

Pharmacokinetic evaluation. All pharmacokinetic par- ameters were determined from post infusion data by a non-linear estimation program using a Gauss-Newton- Hartly algorithm with initial estimates obtained from a

PA

;;;; \ = 0 .05 . 0.02- 0.01: -

0.005- 0 . 0 0 2 - 0 . 0 0 1 i , I

0 20 4'0 6'0 80 I b O 150 1 4 0 160 193 M I N

0 . 5

cv

0 . 0 0 2 j i r . U O I '0 2'0 Irb 6'0 8'0 160 i i 0 140 1 6 0 1h M I N

show plasma concentrations calculated from equation 1 by means of estimated pharmacokinetic constants. Data from animal No. 12.

stripping procedure (14). The reciprocal plasma concen- trations were used as weights in the iterative procedure. The areas under the plasma concentration time curves from start of the infusions to infinite time (AUC) were obtained by numeric integration of the equations, describ- ing the plasma concentration time curves.

The plasma drug concentration, C, after administration, can be expressed as:

C = Axe-at+Bxe-Bt+Cxe-yt (equation 1)

where t is the time from the end of the injection and A, B, C, a, p and y are constants.

The myocardial uptakeirelease of the anthracyclines (in percentage) is calculated according to the equation:

% = (CA-CCS) x 1oO/cA (equation 2)

where CA and CCS are the plasma concentrations (pg/ml) in the aortic and in the coronary sinus plasma samples respectively, calculated from the determined pharmacoki- netic constants by the use of equation 1. By this calcula- tion technique, the influence of minor differences in the sampling times is minimized.

Statistical procedures. The choice of numbers of expo- nential terms in the equations describing the pharmacoki- netics of doxorubicin and epirubicin was based on the F ratio test (15). The goodness of fit was further established by a plot of Rankits versus residuals (16). Medians and

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PHARMACOKINETICS OF DOXORUBICIN AND EPIDOXORUBICIN 711

Table 1

Pharmacokinetic parameters after 3 min i .v. infusions of I’epi-doxorubicin

Animal No. Dose“ Ab B b Cb ac p’ Y‘ AUCd cmaxc

site Sampling x10’ x102 xi01 xi03

2A 2PA 2 cs 2 cv 3 A 3 PA 3 cs 3 cv 7 A 7 PA 7 cs 7 cv 9 A 9 PA 9 cs 9 cv 10 A 10 PA 10 cs 10 cv 13 A 13 PA 13 CS 13 CV

70 3.23 70 3.10 70 3.20 70 2.86 67 1.60 67 3.49 67 3.17 67 3.11 65 2.59 65 12.57 65 2.38 65 4.23 65 1.56 65 3.33 65 4.30 65 2.23 70 2.91 10 2.72 70 3.75 70 6.33 65 3.23 65 2.91 65 5.99 65 2.70

11.81 0.87 0.31 6.29

16.54 0.91 7.82 8.94

31.23 32.14 29.00 29.18 35.63 29.55

1.19 29.44 21.92 25.91 18.97 22.28 18.24 32.11

1.24 30.56

3.30 1.27 2.81 7.03 0.94 6.12 2.49 0.51

2.03 0.51 0.26 2.47 2.83 0.84 2.30 7.25 3.37 1.13 2.86 9.25 2.70 0.46 0.83 7.16 3.78 0.64 2.52 6.61 2.94 0.64 2.50 7.95 3.26 1.29 2.66 6.55 2.69 2.55 2.12 5.84 4.48 0.95 2.57 6.31 3.06 1.71 2.81 6.29 3.25 1.65 2.93 6.90 3.28 1.02 2.67 1.10 2.02 0.38 0.50 0.66 3.63 1 S O 2.74 8.73 3.61 1.09 2.79 6.22 3.90 1.10 3.10 6.94

2.60 6.14 4.67 0.84 4.30 1.61 2.61 7.31 3.53 0.58 2.42 5.73 4.31 1.27 2.71 7.53 3.34 0.42 0.64 3.66 3.97 1.02 2.75 6.07

11.43 11.02 15.16 10.04 10.84 12.49 13.80 12.12 18.71 21.35 20.88 17.73 17.81 18.94 44.18 16.39 16.31 16.47 19.36 18.16 19.31 19.63 25.40 20.31

4.44 3.21 3.25 3.52 3.29 3.61 3.99 4.03 5.74

15.81 5.32 7.18 5.16 6.32 4.44 5.21 5.14 5.35 5.70 8.60 5.09 6.17 6.15 5.79

mg, pgxml-I, min-l pgxrninxml-‘ and pg/ml. Abbreviations: A=aorta, PA=pulmonary artery, CS=coronary sinus and CV=caval vein.

confidence intervals were calculated by the Wilcoxon- Tukey method, the population symmetry established by the Gupta symmetry test. The Wilcoxon matched-pairs signed-ranks test was used for the comparison of 2 related samples. Two independent samples were compared with the Mann-Whitney U-test. A p-value equal to or less than 0.05 was considered statistically signifcant. All pharma- cokinetic data are presented as medians with 93.6 % confi- dence intervals.

Results

Pharmacokinetics The plasma concentration time curves of doxorubicin

and 4’epi-doxorubicin from all sampling sites were most adequately described by an open 3-compartment model (Fig. 1). The pharmacokinetic constants, determined from post injection data and their medians with 93.6% confi- dence interval are presented in Tables 1-3. The deter- mined constants fitted closely to the experimental data. Concentrations of doxorubicinol and 4’epi-doxorubicinol were below detection limits (2 ng/ml) in all samples. Only significant differences in values of AUC, half-lifes (t112 a, B and y), maximal plasma concentration (C,=), and myo- cardial extraction are commented below.

AUC. Coronary sinus AUCs were higher than aortic AUCs after administration of both drugs ( ~ ~ 0 . 0 2 ) . Aortic AUCs after administration of doxorubicin were higher than the corresponding AUCs after 4’epi-doxorubicin (p=0.055). Caval vein AUCs after doxorubicin were high- er than after 4’epi-doxorubicin ( ~ ~ 0 . 0 5 ) .

t l ~ Coronary sinus t112 a, p and y were higher than the corresponding t l /2 values from the aorta after administra- tion of 4’epi-doxorubicin (p<0.05). Coronary sinus 4’epi- doxorubicin t1/2 as were higher than the coronary sinus doxorubicin tl/2 as (p<O.Ol), and the aortic tl/2 /?s were higher after doxorubicin than after 4‘epi-doxorubicin infu- sion (pc0.01).

C,,,& The C,,, values in aortic plasma were higher after doxorubicin than after administration of 4’epi-doxorubicin (p<O.OS).

Myocardial uptakelrelease. There were considerable in- terindividual variations in myocardial drug uptakehelease during the period 0-30 min after the infusion. Almost all coronary sinus drug concentrations of both drugs were higher than the corresponding aortic values after 30 min. The calculated myocardial extractions are illustrated in Figs 2 and 3. A significantly higher myocardial drug re- lease of 4’epi-doxorubicin was observed within the range 2 4 min and 2040 min (pS0.05).

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Table 2

Pharrnacokinetic parameters after 3 min i.u. infusions of doxorubicin

Animal No. Dose" Ab B b Cb a' B' Y' AUCd Cmax.

site Sampling x1ol XI02 xiol x103

4 A 4 PA 4 cs 4 cv 5 A 5 PA 5 cs 5 cv 6 A 6 PA 6 CS 6 CV 8 A 8 PA 8 cs 8 cv 11 A 11 PA 11 cs 11 cv 12 A 12 PA 12 cs 12 cv

64 64 64 64 65 65 65 65 65 65 65 65 70 70 70 70 65 65 65 65 70 70 70 70

3.07 3.47 3.45 2.88 4.59 4.08 2.89 1.85 3.23 3.55 3.41 2.07 4.05 3.30 3.51 2.60 4.45 3.69 3.74 5.54 4.97 4.82 3.27 7.98

28.97 24.44 28.37 30.69 19.91 16.20 16.12 23.74 27.15 24.26 20.61 24.58 28.97

1.03 27.94 32.54 5.17

23.70 28.53 29. I3 22.89 24.87 22.17 15.88

3.46 3.12 3.56 3.49 2.95 2.77 3.32 3.47 3.03 3.66 3.33 3.08 3.72 2.94 4.23 4.03 2. I5 3.41 4.08 3.18 3.55 2.99 2.88 2.67

2.05 0.96 2.06 I .83 2.25 1.03 1.17 2.81 4.43 1.27 1.03 1 .oo 2.28 0.25 1.83 1.44 0.30 1.51 1.59 5.44 1.02 1.08 0.89 1.29

1.88 1.96 I .95 2.12 2.09 1.85 1.88 2.20 2.05 2.01 1.93 2.00 2.12 0.66 2.13 2.19 0.83 1.68 1.62 1.67 1.58 1.53 1.44 1.32

7.90 7.31 5.96 8.01 7.08 7.47 5.66 8.29 6.97 8.89 6.65 6.65 6.12 4.04 4.99 6.24 2.46 6.45 3.88 4.87 7. I5 6.88 2.82 4.58

21.31 20.38 22.23 20.42 15.74 16.45 16.92 15.61 18.32 18.95 19.02 19.02 21.50 21.84 23.52 23.13 29.70 21.88 30.52 24.96 24.31 25.03 29.32 24.05

mg, pgxml-', min-l, pgxminxml-', pg/ml. Abbreviations as in Table 1.

Table 3

Pharmacokinetic parameters after infusions of 4'epi-doxorubicin and doxorubicin (median k93.6 % confidence interual; n=6)

Aorta

Aorta

Pulm. artery

Pulm. artery

Coron. sinus

Coron. sinus

Caval vein

Caval vein

4'epi-d.

dox.

4'epi-d.

dox.

4'epi-d.

dox.

4'epi-d.

dox.

15.4 (11.1-19.0)

21.4 ( I7 .0-27.0)

(1 1.8-20.5)

20.7

20.3

16.5

(17.7-27.0)

(14.5-34.8)

23.5 (1 8 .o-29.9)

16.2 (11.1-19.2)

21.5 (17.3-24.5)

15.1 (3.9-5.5)

6.3 (5.5-7.1)

5.8 (3.4-1 1.1)

5.9 (4.6-6.7)

4.9 (3 3-5.9)

5.9 (5.0-6.5)

5.6 (3.8-7.9)

6.4 (4.4-9.0)

0.6 (0.5-0.9)

0.4 (0.23-1.5)

0.8 (0.4-1.5)

0.6 (3.5-8.9)

(0.8-1.7)

0.5 (0.4-0.7)

0.6 (0.4-1.0)

0.4 (0.2-0.6)

1.3

2.5 (2.4-2.7)

3.8 (3.3-8.7)

4.8 (2.4-15.2)

4.0 (3.5-8.9)

8.3 (2.7-14.1)

3.8 (3.4-4.5)

3.0 (2.5-3.7)

3.7 (3.14.8)

103.5 (86.5-1 16.0)

97.0 (88.0-376.0)

100.0 (87.5-116.0)

89.5 (72.5-154.5)

177.0 (1O9.wA4.5)

121 .o (104.0-155.0)

97.0 (83.0-112.0)

96.5 (83.54 3 1 .O)

6.01 5.94 6.32 5.98 6.61 5.73 4.53 4.26 5.97 6.01 5.51 4.56 6.99 3.43 6.35 5.89 4.99 6.09 6.64 8.48 7.30 7.33 5.52 9.59

a pgxminxrnl-I, bg/m/ml, min. Abbreviations: dox. =doxorubicin, 4'epi-d=4'epi-doxorubicin

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PHARMACOKINETICS OF DOXORUBICIN AND EPIDOXORUBICIN

100 90 80

70

60 50

713

~

~

- ~

~

-

60 50

Myocordial extraction

%

- -

30 1-

I -90 1 Fig. 2. Myocardial extraction of doxorubicin and 4‘epi-doxorubi- cin, calculated for each min from the end up to 40 min after the infusion. Data are calculated from equations 1 and 2. Solid lines represent medians, shaded area represents 93.6 % confidence interval of doxorubicin extraction, lined area represents 93.6% confidence interval of 4’epi-doxorubicin extraction.

Fig. 3. Myocardial extraction of doxorubicin and 4’epi-doxorubi- cin, calculated at every 10 min from the end up to 180 min after the infusion. Data are calculated from equations 1 and 2. Solid lines represent medians, shaded area represents 93.6 % confi- dence interval of doxorubicin extraction, lined area represents 93.6 % confidence interval of 4’epi-doxorubicin extraction.

Haemodynamics Neither doxorubicin nor 4’epi-doxorubicin produced

any significant changes in systemic, central or coronary haemodynamic or any metabolic variables (data not shown). No ECG changes were recorded.

Discussion

The acute cardiotoxic effects of doxorubicin and 4’epi- doxorubicin most commonly include non-specific ST-T wave changes, sinus tachycardia, low voltage of the QRS complex and different types of arrhythmias. These changes which have been noted during andlor after i.v. drug infusion appear to be reversible and do not seem to predict later chronic toxicity (7). The chronic cardiotoxic effects of anthracyclines may be lethal. These include ventricular dysfunction on the basis of myopathy (17). Several hypotheses have been proposed regarding the pathogenesis of anthracycline-induced cardiomyopathy. These include effects on nucleic acid synthesis, calcium overload, free radical formation and release of vasoactive substances (17). The pig was chosen as experimental ani- mal due to its cardiovascular similarities to humans (18). In addition, chronic anthracycline cardiotoxicity similar to that in the beagle dog has been described in the minia- ture swine (19).

Acute haemodynamic effects after administration of i.v. doxorubicin (1-4 mg/kg) in the dog, have earlier been reported (20, 21). These effects include decreases in indi-

ces of myocardial contractility and increases in heart rate, coronary blood flow and systemic vascular resistance. The noted changes are similar to effects produced by histamine (20). In the present study, no signifcant haemo- dynamic changes were observed. This discrepancy be- tween the present and earlier studies may be explained by species differences. It has previously been noted that anthracycline-induced acute cardiotoxicity varies be- tween different animal species (6). However, the studies performed in dogs were performed in an open-chest model with the pericardium widely opened. The fact that a more physiological closed-chest model, and that a slightly lower dose was used in the present study, makes direct compari- sons difficult. In the present study myocardial oxygen- ation was unaffected by both drugs. This is to be expect- ed, considering the fact that the clinical reports of cardio- toxicity lack direct evidence of myocardial ischemia.

No pharmacokinetic data analysing myocardial extrac- tion of anthracyclines have, to our knowledge, been pre- viously published. The data in the present study strongly suggest an early myocardial uptake of both drugs, mainly during drug-infusion. The differences between coronary sinus and aortic plasma drug concentrations, and the high- er coronary sinus AUCs as compared to the aortic AUCs, indicate myocardial release of both drugs during the stud- ied post-injection period. The fact that t1/2 a, /3 and y were higher in the coronary sinus than in the aorta after infu- sion of 4’epi-doxorubicin, further indicates myocardial release of that drug. The same t1/2 differences were not

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found after infusion of doxorubicin, which, together with the lower doxorubicin myocardial arterio-venous drug concentration differences, may indicate a less pronounced myocardial release of doxorubicin than of 4'epi-doxoru- bicin.

The myocardial extraction (Figs 2 and 3) show that this is a process with great interindividual variations. The myocardial release appears to be lower for doxorubicin than for 4'epi-doxorubicin. The release of both drugs tends not to decrease during the 3-h study period. The accuracy of this technique for data calculation is support- ed by the very close agreement between the found and calculated concentration data, estimated by the pharma- cokinetic model, cf. Fig. 1.

It has been proposed that pulmonary drug clearance occurs for several drugs, mostly as the lungs receive the whole cardiac output. In the present study, no differences could be found between pulmonary arterial and aortic anthracycline concentrations, which argues against pul- monary drug extraction.

The pharmacokinetics in man have been studied after simultaneous administration of doxorubicin and 4'epi- doxorubicin intravenously and intra-arterially (22, 23). These studies show consistently higher doxorubicin plas- ma concentrations, higher doxorubicin AUCs and Cmaxs as compared t o 4'epi-doxorubicin. Comparable data in the present experimental study show higher aortic Cmaxs and caval venous AUC values after infusion of doxorubicin than after 4'epi-doxorubicin. It has been shown that acute pathologic changes in human myocardium, measured by endomyocardial biopsies 4 and 24 h after the first doxoru- bicin administration are similar to chronic changes. This observation suggests that repeated myocardial insults may lead to impaired heart function (24). If so, it is reasonable to believe that both acute and chronic anthracycline car- diotoxicity is related to myocardial drug extraction. The present pharmacokinetic data suggest a rapid myocardial uptake of both drugs followed by a prolonged release from the myocardium. The greater myocardial release of 4'epi- doxorubicin may explain its lesser cadiotoxicity.

A C K N O W L E D G E M E N T S We wish to thank Ms Anita Westman for excellent technical

assistance. This work w a s financially supported by Farmitalia Carlo Erba AB, Taby, Sweden.

Request for reprints: Dr Magnus Andersson, Department of Surgery, Orebro Medical Center Hospital, S-70185 Orebro, Swe- den.

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