Pharmacokinetics and safety of binodenoson after intravenous dose escalation in healthy volunteers

Pharmacokinetics and safety of binodenoson after intravenous dose escalation in healthy volunteers Richard J. Barrett, PhD,a Michael J. Lamson, PhD,a James Johnson, PhD,a and William B. Smith, MD, FACCb Background. Binodenoson, a highly selective agonist of the adenosine A2A receptor, is being developed as a short-acting coronary vasodilator as an adjunct to radiotracers for use in myocardial stress imaging. This study was designed to assess the single-dose pharmacokinetics, safety, and tolerability of intravenous binodenoson. Methods and Results. This was a single-center, open-label, nonrandomized, dose-escalation study in 24 healthy volunteers. Each subject received 3 successive intravenous doses of binodenoson (0.1, 0.2, 0.4, 0.6, 1, 2, 3, 4, 5, and 6 ␮g/kg), each infused over a period of 10 minutes and separated by washout periods of at least 120 minutes. Generally, binodenoson was well tolerated. There were no serious adverse events. However, there was a dose-related increase in adverse events (eg, headache, nausea, vasodilation, chest pain), consistent with the pharmacology of the drug. Binodenoson exhibited linear pharmacokinetics as indicated by a doseproportional increase in peak concentration (Cmax) and area under the concentration-time curve (AUC). Systemic clearance was independent of dose but was correlated with body weight. The mean terminal half-life of binodenoson across all doses was 10 ⴞ 4 minutes. Conclusions. Overall, binodenoson was well tolerated and exhibited linear pharmacokinetics when administered intravenously over a 60-fold dose range from 0.1 to 6 ␮g/kg. (J Nucl Cardiol 2005;12:166-71.) Key Words: Binodenoson • A2A-receptor agonist • pharmacokinetics • safety Several million myocardial perfusion imaging (MPI) procedures with a radiopharmaceutical are performed annually in the United States to detect coronary artery disease (CAD). The growth and popularity of MPI have been driven by consistent findings that this noninvasive procedure is a powerful prognostic indicator of cardiac outcomes in patients with varying risk of CAD, as well as an aid in the medical management of CAD.1-3 The presence of ischemia on an exercise-rest MPI is associated with an adverse cardiac outcome; conversely, a normal MPI scan is associated with a very low (⬍1% per year) risk of cardiac death or nonfatal myocardial infarction.1 Pharmacologic stress agents are frequently used to produce coronary vasodilation in patients who cannot exercise adequately to produce a diagnostic exercise stress MPI study.4-9 These agents dilate the coronary vasculature by activating adenosine A2A receptors either directly (adenosine) or indirectly (dipyridamole). In addition, they also nonselectively activate the remaining adenosine-receptor

subtypes (A1, A2B, and A3), which are often associated with undesirable pharmacologic effects including dyspnea, shortness of breath, flushing, chest pain, and second- or third-degree atrioventricular block. Binodenoson, 2-[(cyclohexylmethylene)hydrazino] adenosine (MRE0470), is being developed as a short-acting coronary vasodilator, administered intravenously, as an adjunct to radiotracers in myocardial stress imaging techniques to detect the presence and severity of CAD in patients unable to exercise.10-12 The compound is a highly selective agonist at the adenosine A2A receptor and also has weaker affinity for adenosine A1-, A2B-, and A3-receptor subtypes compared with adenosine. The objectives of this study were to evaluate the pharmacokinetics, safety, and tolerability of binodenoson after intravenous dose escalation in healthy volunteers. METHODS Subjects

From King Pharmaceuticals Research & Development, Inc, Cary, NC, and New Orleans Center for Clinical Research, New Orleans, La. Reprint requests: Richard J. Barrett, PhD, King Pharmaceuticals Research & Development, Inc, 400 CentreGreen Way, Cary, NC 27513. 1071-3581/$30.00 Copyright © 2005 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2004.12.294 166

This study was conducted at the New Orleans Center for Clinical Research, New Orleans, La, in accordance with US Good Clinical Practice guidelines. Subjects were required to be in generally good health as determined by physical examination and laboratory testing, as well as assessment of vital signs. Exclusion criteria included testing positive on drug screening (drugs of abuse); ingesting caffeine, alcohol, or medication

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within 24 hours of study entry; or receiving an investigational drug with 30 days of study entry. Women of childbearing potential and men whose female partners were not using an acceptable contraceptive method were excluded. Other exclusion criteria included subjects with known postural hypotension, resting supine systolic blood pressure of 90 mm Hg or lower, diastolic blood pressure of 60 mm Hg or lower, and heart rate of 90 beats/min or greater; history of human immunodeficiency virus infection; positive test result for hepatitis B surface antigen or hepatitis C antibody; and any clinically relevant condition that could potentially confound the analysis or present a safety risk.

Study Methods The study was designed as a single-center, open-label, nonrandomized, intravenous dose-escalation study in 4 cohorts (n ⫽ 6 each) of healthy volunteers. The protocol was approved by the institutional review board; all subjects gave written informed consent. Subjects from each cohort were to receive 3 rising doses of binodenoson administered via intravenous infusion over a period of 10 minutes, at a rate not to exceed 6 ␮g · kg⫺1 · min⫺1. Although the successive doses of binodenoson were administered on the same study day, the washout period between doses was at least 2 hours. Subjects in cohort 1 received consecutive binodenoson doses of 0.1, 0.2, and 0.4 ␮g/kg; cohort 2 received 0.6, 1, and 2 ␮g/kg; cohort 3 received 2, 3, and 4 ␮g/kg; and cohort 4 received 4, 5, and 6 ␮g/kg. Serial vital sign monitoring of heart rate, supine systolic blood pressure, and diastolic blood pressure was done at screening and during each dosing phase within 10 minutes before infusion, at 2, 4, 6, 8, and 10 minutes during infusion, and at 2, 5, 7.5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes after infusion. A 12-lead electrocardiogram (ECG) was obtained at screening and the end of the study. The ECG was monitored via telemetry during the treatment phase, including during the infusions. Monitoring was initiated within 1 hour before dosing and continued until 24 hours after completion of the last dose. A total of 40 to 42 blood samples were collected during the treatment phase for quantitation of binodenoson in plasma. Before dosing, a polyethylene catheter was inserted into a vein of the forearm contralateral to the infusion site. Blood samples (5 mL) were drawn into prechilled Vacutainer tubes (BD, Franklin Lakes, NJ) just before infusion (⫺1 minute), at the midpoint (5 minutes) and end (10 minutes) of infusion, and at 2, 5, 7.5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes after the end of infusion. Plasma was separated from cellular material by centrifugation under refrigeration (4°C) at 4000 rpm for 10 minutes and then stored in cryotubes at ⫺80°C until analyzed. The total amount of blood taken during the intensive sampling period was approximately 200 mL. Plasma concentrations of binodenoson were determined by a validated high-performance liquid chromatography–mass spectrometry (LC/MS/MS) assay at Phoenix International, Inc (Montreal, Quebec, Canada). The LC/MS/MS assay had a lower limit of quantitation of 0.201 ng/mL. Pharmacokinetic parameters were derived for each subject’s plasma binodenoson concentration-time profile for each

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binodenoson infusion by use of noncompartmental methods with the statistical software program SAS (SAS Institute, Cary, NC). The peak concentration (Cmax) and corresponding time to Cmax (tmax) were derived by observation. The terminal half-life (t1/2) was calculated from (ln2)/␭z, where ␭z, the elimination rate constant, was determined by log-linear regression of the terminal phase of the binodenoson concentration-time profile. The area under the curve (AUC0-t) was calculated by the linear trapezoidal rule from time 0 to the last quantifiable concentration (Clast). The area up to infinity (AUC0-⬁) was estimated by summation of AUC0-t ⫹ Clast/␭z. Systemic clearance (CL) of binodenoson was derived from the ratio of binodenoson dose and AUC0-⬁, and volume of distribution (Vz) was derived from the ratio of CL and ␭z. Summary statistics for pharmacokinetic parameters were tabulated. Linear regression analysis was used to evaluate the relationship between AUC and dose. The safety analysis focused on vital signs, physical examination findings, clinical laboratory values, ECGs, and adverse events (AEs). AEs and serious AEs were defined according to US Food and Drug Administration regulations.13 AEs recorded were those reported spontaneously by volunteers or in response to nonleading questions or those recognized by investigators. Safety data were tabulated by cohort and/or dose. The maximal effect of binodenoson dose on vital signs (systolic blood pressure, diastolic blood pressure, heart rate) was analyzed by comparing the predose mean value with the maximally changed value recorded during each 10-minute infusion period or during the 120-minute postinfusion period. A 2-tailed, paired Student t test was used to determine whether the change was significantly different from 0 (␣ ⫽ .05).

RESULTS Subjects A total of 24 healthy adult volunteers (17 men and 7 women) participated in the study. The mean values for age and weight over all cohorts ranged from 29 to 39 years and 70.8 to 83.3 kg, respectively. For the study group as a whole, the mean age was 35 ⫾ 9 years and the mean body weight was 75.6 ⫾ 12.0 kg. Of the subjects, 15 of 24 (63%) were white, 8 were black, and 1 was Hispanic. All enrolled subjects met the study inclusion and exclusion criteria, and no concomitant medications were used during the study. Pharmacokinetics The pharmacokinetics of binodenoson is presented in Table 1. Peak concentrations (Cmax) were generally achieved by the end of the dosing infusion period (Figure 1). Thereafter binodenoson concentrations declined in a biphasic manner. Area under the curve as calculated by the trapezoidal rule (AUC0-t) generally represented greater than 80% of the total AUC0-⬁. Binodenoson AUC increased proportionally with dose (Figure 2). Binode-

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Table 1. Binodenoson pharmacokinetic parameters

Dose of Binodenoson (␮g/kg)

N Cmax (ng/ml) Tmax (min) AUClast (ng · min/ml) AUC0-⬁ (ng · min/ml) t1/2 (min) CL (mL · min⫺1 · kg⫺1) Vz (L/kg)

0.4

0.6

1

2

6 0.9 (0.2) 10 9.0 (2.6) 12.4 (2.6) 8.8 (8.7) 33.4 (6.7) 0.39 (0.3)

6 1.1 (0.1) 7.5 12.5 (5.3) 21.2 (3.6) 11.7 (6.3) 28.8 (4.4) 0.46 (0.2)

6 2.1 (0.5) 10 24.9 (7.4) 27.9 (8.2) 7.4 (1.8) 38.3 (10) 0.40 (0.2)

10 3.9 (0.9) 10 51.3 (10) 55.7 (9.7) 10.0 (2.3) 33.0 (12) 0.48 (0.2)

3

4

6 11 6.2 (0.8) 8.7 (3.9) 9.5 10 78.7 (7.2) 116 (40) 85.4 (7.6) 122 (40) 12.8 (3.8) 13.0 (3.1) 35.4 (3.3) 39.8 (27) 0.65 (0.2) 0.69 (0.3)

6

8

6 12.5 (2.7) 9 133 (15) 139 (15) 14.9 (3.3) 33.9 (7.9) 0.70 (0.1)

4 12.1 (4.3) 10.5 156 (44) 163 (44) 12.3 (2.2) 39.5 (14) 0.68 (0.7)

Data are given as mean (SD). 8

6

150 AUC0- t (ng min/ml)

Concentration (ng/mL)

200

4

100

2

50 0 0

10

20

30

40

0

Time (minutes) 0

Figure 1. Mean (⫾ SD) concentrations of binodenoson after administration of 3 ␮g/kg over a period of 10 minutes.

noson Cmax also increased with dose but was subject to change resulting from slight variations in the duration of infusion. The apparent volume of distribution indicates that binodenoson distributes into extracellular fluid spaces. The mean values for apparent elimination half-life of binodenoson ranged from 7.4 minutes (at 1 ␮g/kg) to 14.9 minutes (6 ␮g/kg), with a slight tendency toward higher values with increasing dose. However, because the plasma concentrations for the lowest dose level (0.4 ␮g/kg) were only marginally higher than the assay lower limit of quantitation, the plasma concentrations could be determined for a longer period of time at the higher dose levels. On average (harmonic mean), the terminal half-life of binodenoson across all doses was 10 ⫾ 4 minutes. There was no detectable difference (analysis of variance) among the dose levels with respect to binodenoson systemic clearance. The mean systemic clearance of binodenoson across all dose levels was 34.4 ⫾

100

200 300 Total Dose (mcg)

400

500

Figure 2. Relationship between binodenoson AUC0-t and total dose (in micrograms).

7.5 mL · min⫺1 · kg⫺1. However, systemic clearance correlated with subject body weight as shown in Figure 3. A linear mixed-effect model (S-Plus, Insightful Corp., Seattle, Wash), with subject used as a random-effects variable and body weight as a regressor term, established the following relationship between binodenoson clearance (CL) and body weight (BW): CL ⫽ ⫺0.19 ⫹ 0.039 · BW (P ⫽ .004). Safety AEs. Generally, binodenoson was well tolerated. There were no serious AEs and no clinically significant ECG changes. The incidence of AEs was dose-related, and 21 of 24 volunteers (83%) reported at least 1 AE (Figure 4). Nearly all AEs (99%) were judged by the investigator to be related to administration of binodenoson and were of mild (82%) or moderate (17%) severity.

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8

6-␮g/kg dose. The mean maximal increases in systolic and diastolic blood pressure were statistically significant at the 2- and 4-␮g/kg dose levels, respectively (P ⬍ .05). Binodenoson doses of 0.1 ␮g/kg or greater were associated with increases in heart rate (Figure 5). Maximum increases in heart rate ranged from 29 beats/min at the 1-␮g/kg dose to 66.3 beats/min at the 6-␮g/kg dose. The changes at doses of 0.4 ␮g/kg and at doses of 1 ␮g/kg or greater were statistically significant (P ⬍ .001).

CL ~ -0.19 + 0.039 (BW) p=0.004

CL (L/min)

6

4

2

DISCUSSION

0 40

50

60

70

80

90

100

Body Weight (kg)

Figure 3. Relationship between binodenoson systemic clearance and body weight. 14 12

No. of AEs per Subject

169

10 8 6 4 2 0 0.1

0.2

0.4

0.6

1

2

3

4

5

6

Dose (ug/kg)

Figure 4. Number of AEs per subject.

Most AEs (75%) began during drug infusions and resolved spontaneously within 30 minutes of onset. None required clinical or pharmacologic intervention to reverse the action of the drug. The most frequently reported AEs were headache and vasodilation. There was a significant increase in frequency of AEs related to binodenoson at doses of 2 ␮g/kg or greater as compared with doses of 1 ␮g/kg or lower, particularly with respect to headache (60% vs 7%), nausea/vomiting (49% vs 0%), vasodilation (54% vs 14%), dizziness (24% vs 0%), and paresthesia (19% vs 3%). Vital signs. The maximal effects of binodenoson on blood pressure were variable at doses of 1 ␮g/kg or lower. Mean systolic pressure increased consistently at doses of 1 ␮g/kg or greater, and both mean systolic pressure and mean diastolic pressure were increased at doses of 2 ␮g/kg or greater. The mean maximal increase in systolic blood pressure from baseline ranged from 8.8 mm Hg at the 1-␮g/kg dose to 27.9 mm Hg at the

Intravenous binodenoson is being developed as a short-acting coronary vasodilator as an adjunct to radiotracers for use in myocardial stress imaging. This study represents the first time a selective adenosine A2Areceptor agonist had been administered to human beings and was conducted to determine the safety and pharmacokinetics of a wide range of doses. The most prevalent AEs—vasodilation, headache, dizziness, nausea, chest pain, abdominal pain, and paresthesia—were consistent with the pharmacologic properties of the drug. The incidence of AEs was strongly associated with dose and exposure, with a marked increase in the incidence and frequency of the more unpleasant AEs such as chest pain, abdominal pain, dizziness, nausea, and vomiting at doses of 4 ␮g/kg and higher. However, there were no serious AEs, and most AEs began during the infusion period, were mild or moderate in severity, and resolved within 30 minutes of onset. In animals, binodenoson produced dose-related hypotension and reflex tachycardia.14 In this study, peripheral vasodilatory responses were suggested by the occurrence of tingling, flushing, headache, fullness, and warmth. Despite the apparent peripheral vasodilation, changes in blood pressure were variable at lower doses, resulting in unchanged mean values, and both systolic blood pressure and diastolic blood pressure increased slightly at doses greater than 1 ␮g/kg. Dose-related increases in heart rate at doses of 1 ␮g/kg or greater suggest that binodenoson increases heart rate independently of changes in blood pressure, and it is uncertain whether the positive chronotropic responses may have obscured drug-induced systemic hypotension. Binodenoson is the first adenosine A2A-receptor–selective agonist to be administered to human beings, and this independent increase in heart rate represents a novel finding. Binodenoson did not increase the rate in isolated and denervated atrial preparations and has no affinity for ␤-adrenergic or muscarinic receptors that might explain such a response.14 There is preclinical evidence that activation of adenosine A2A receptors enhances norepinephrine release from sympathetic efferent nerve terminals, but such

Mean (+ SD) Maximal HR Change

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Barrett et al Pharmacokinetics and safety of binodenoson

80 70

* p < 0.05, ** p < 0.01, *** p < 0.001

60

**

***

3.0

4.0

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***

***

5.0

6.0

5.0

6.0

***

Heart Rate

50 40

***

30

**

20 10 0 0.1

0.2

0.4

0.6

1.0

2.0

Mean (+ SD) Maximal Change

50 40

Diastolic Blood Pressure Systolic Blood Pressure

30

** *

*

20 10 0 -10 -20 0.1

0.2

0.4

0.6

1.0

2.0

3.0

4.0

Dose (µg/kg)

Figure 5. Mean (SD) maximal changes in heart rate and systolic and diastolic blood pressure.

6

30 Seconds 3 Minutes 10 Minutes

Concentration (ng/mL)

5

4

3

2

1

0 0

5

10

15

20

25

infusion. Systemic clearance of binodenoson was independent of dose and indicative of rapid removal from the systemic circulation. Although no metabolism studies have been conducted in human beings, in vitro studies with hepatocytes and microsomes suggest low metabolic activity and no significant inhibition of cytochrome P450 enzymes. The relationship between binodenoson clearance and body weight provides a rational basis for establishing the dose of binodenoson based on body weight to minimize pharmacokinetic variability. In this first–in– human beings study, binodenoson was infused over a period of 10 minutes. The resulting pharmacokinetic data suggested that shorter infusions and bolus doses might provide pharmacodynamic responses consistent with pharmacologic stress imaging. In a recent dose-ranging study, the safety and efficacy of intravenous binodenoson were assessed by use of 30-second bolus infusions of 0.5 ␮g/kg (n ⫽ 58), 1.0 ␮g/kg (n ⫽ 60), and 1.5 ␮g/kg (n ⫽ 53) compared with a 3-minute infusion of 1.5 ␮g/kg of binodenoson (n ⫽ 55) and a standard dose of intravenous adenosine (n ⫽ 226).16 In terms of the severity and incidence of side effects and relationship to dose, the results of the phase II study were consistent with those of our study. More importantly, however, the results of the phase II study also suggest that 1.5 ␮g/kg of binodenoson may be administered as a bolus dose, obviating the need for an infusion pump. The simulated binodenoson concentrations after a 1.5-␮g/kg dose administered over a period of 30 seconds, 3 minutes, and 10 minutes are shown in Figure 6. Additional studies are underway in target patient populations to evaluate the efficacy and safety of 1.5 ␮g/kg of binodenoson for use as a coronary vasodilator as an adjunct to radiotracers in myocardial stress imaging.

30

Time (minutes)

Conclusion Figure 6. Simulated binodenoson concentrations in the systemic circulation after administration of 1.5 ␮g/kg over periods of 10 minutes, 3 minutes, and 30 seconds.

a mechanism has not been defined in human beings.15 The vasodilator pharmacologic stress agents adenosine and dipyridamole produce modest increases in heart rate, and it is likely that this effect enhances their direct coronary vasodilatory responses by increasing myocardial oxygen demand. The same is expected to be true of binodenoson. The pharmacokinetics of binodenoson were characterized by dose linearity with respect to exposure parameters (Cmax and AUC) and rapid disappearance (t1/2 ⫽ 10 minutes) from the systemic circulation after cessation of

Intravenous binodenoson was well tolerated when administered at doses ranging from 0.4 ␮g/kg to 6 ␮g/kg, with pharmacologic effects generally consistent with the pharmacologic properties of A2A-receptor activation. Binodenoson pharmacokinetic/pharmacodynamic properties were characterized by dose linearity, short duration of action, and rapid removal from the systemic circulation, which are desirable characteristics for this class of drugs.

Acknowledgment R.J.B., M.J.L., and J.J. are employees of King Pharmacenticals, Research and Development, Inc.

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