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PHARMACOKINETICS |
From Depomed, Inc, Menlo Park, California (Dr Gordi); CVT, Inc, Palo Alto, California (Dr Blackburn); and Portola Pharmaceuticals, Inc (Dr Lieu).
Address for correspondence: Toufigh Gordi, PhD, Depomed, Inc, 1360 O'Brien Dr, Menlo Park, CA 94025; e-mail: tgordi{at}yahoo.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: A2A adenosine receptor agonist • regadenoson • renal impairment • CVT-3146
Coronary vasodilation with intravenous adenosine and dipyridamole is widely used in cardiac stress testing or MPI, especially in those patients who cannot adequately exercise. Both agents induce coronary vasodilation via direct activation of A2A adenosine receptors on the arteriolar smooth muscle cells. However, they also activate A1, A2B, and A3 adenosine receptors and are therefore less than ideal as the nonselective activation of these other subreceptors is associated with undesirable side effects.1,2 Side effects such as flushing, lightheadedness, and dizziness are frequently believed to be A2A and possibly A2B adenosine receptor mediated3,4; first- and second-degree atrioventricular (AV) block are possibly adenosine A1 receptor mediated5,6; and bronchoconstriction in patients with bronchospastic lung disease is believed to be adenosine A2B receptor mediated.3,7
Regadenoson (CVT-3146) is a novel, selective A2A adenosine receptor agonist being developed as an adjunctive pharmacological stress agent in MPI. Regadenoson has been well tolerated in healthy volunteers in doses up to 10 µg/kg in the standing and 20 µg/kg in the supine position.8,9 Renal elimination accounts for on average 57% of the total clearance of regadenoson. Thus, renal function may have an impact on the clearance of regadenoson, potentially resulting in a longer duration of side effects in patients with decreased renal function. Pharmacological stress MPI studies are often indicated in older CAD patients who cannot exercise adequately, many of whom have other comorbidities such as renal insufficiency. Furthermore, a decrease in renal function due to age is expected in this generally older population. Frequently, risk factors that are associated with an increased incidence of coronary artery disease (such as diabetes) may also be associated with renal insufficiency. It has been previously demonstrated that regadenoson follows a 3-compartment behavior after an intravenous bolus dose and that it increases heart rate in a concentration-dependent manner.8,9 The heart rate effect is indicated to be caused by a direct stimulation of the sympathetic nervous system rather than an indirect response to a decrease in arterial blood pressure.10 A reduction in renal clearance of regadenoson is likely to prolong the terminal elimination half-life but not the early concentration time-course that is dominated by distribution processes. The duration of heart rate increase is of clinical importance as it may determine the time period during which a patient has to be under surveillance in connection with an MPI study. It is therefore of importance to characterize the entire concentration-time profiles of regadenoson in subjects with decreased renal functions and the associated changes in hemodynamics.
The aims of this study were to investigate the impact of renal function over a wide range of creatinine clearance (CLCR) values on the pharmacokinetics of regadenoson, the possible influence of patient factors on the pharmacokinetic parameters, and the relationship between regadenoson plasma concentrations and changes in blood pressure and heart rate. Furthermore, the safety and tolerability of regadenoson in patients with decreased renal function was assessed by adverse event rates and electrocardiogram (ECG) parameters.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetic Sampling
Blood samples were collected from each subject's right hand via a cannula or by repeated venous punctures at the following time points: predose and 5, 15, 30, and 45 minutes and 1, 2, 4, 6, 8, 12, 24, and 36 hours postdose. At each time point, 5 mL blood was collected into heparin lithium tubes; blood samples were centrifuged at 3000 rpm for 10 minutes, and the plasma was stored in polypropylene tubes at approximately -20°C until analysis.
All urine was collected at the following time intervals: 0 to 6, 6 to 12, 12 to 24, and 24 to 36 hours postadministration. Urine volumes were recorded, and a 20-mL aliquot was stored frozen at below -20°C until analysis.
Bioanalytical Assay
Concentrations of CVT-3146 in human plasma were determined using a validated high-performance liquid chromatography/tandem mass spectrometric assay (LC/MS/MS) following solid-phase extraction. An aliquot of plasma (0.5 mL) spiked with a deuterated (d3) analog of CVT-3146 (internal standard, 1.5 ng) was extracted using reversed-phase (C18) solid-phase extraction. High-performance liquid chromatography was performed on a Higgins C18 Clipeus column (3 x 50 mm) and a Keystone Hypersil BDS C-18 guard column (20 x 2 mm) using a Waters Alliance 2690 delivery system (Milford, Mass). The mobile phase consisted of water containing 0.1% formic acid (pH 3.0) and methanol containing 0.1% formic acid (50:50 v/v) eluted isocratically at a flow rate of 0.2 mL/min. The effluent was directed into a Micromass Quattro Ultima mass spectrometer (Beverly, Mass) operated in positive ionization and multiple-reaction monitoring (MRM) modes, monitoring the transition of m/z 391.2 
259.0 for CVT-3146 and 394.2 262.0 for the internal standard. Quantification of CVT-3146 was achieved by an internal standard method. The quantification limit was 40 pg/mL using 0.5 mL plasma. The dynamic range of quantification was 0.0400 to 40.0 ng/mL.
Quality control samples, prepared by spiking CVT-3146 at low (0.100 ng/mL), medium (1.50 ng/mL), and high (36.0 ng/mL) concentrations into plasma from untreated subjects, were apportioned into aliquots and stored in a freezer set to maintain -20°C with the study samples. At least 2 quality control (QC) samples at each of the 3 concentrations were analyzed for CVT-3146 with the unknowns each day to monitor the performance of the method. Dilution QCs (180 ng/mL), representing a 1:5 dilution, were also included in runs with unknown samples that were diluted prior to analysis. Accuracy, as measured by percent relative error, ranged between -5.56% and 6.00%. Precision, as measured by coefficient of variation (%CV), ranged from 2.23% to 8.09% across all concentrations.
Noncompartmental Pharmacokinetic Analysis
Individual plasma concentration versus time data were used in a noncompartmental analysis of the data (WinNonlin Version 4.1, Pharsight Corp, Mountain View, California). Various pharmacokinetic (PK) parameters, including clearance, volume of distribution, and terminal half-life, were estimated. Fraction regadenoson excreted unchanged in urine was estimated as the ratio of regadenoson amounts in urine (Ae) over administered dose:
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Compartmental Pharmacokinetic Analysis
To characterize the pharmacokinetics of regadenoson, evaluate the relationship between regadenoson concentrations and changes in hemodynamic parameters, and investigate the possible influence of patient factors on the parameters determining the concentration-time profiles, a compartmental approach was used. A pooled data set of regadenoson plasma concentration and accumulated amounts of the compound in urine over each time period was used for the modeling purpose, using a mixed-effect modeling approach (NON-MEM, Version V, Globomax, Hanover, Maryland). Plasma and urine data from all individuals were fitted simultaneously, using the first-order conditional estimation with interaction option (FOCE INTERACTION) in NONMEM. Discriminations between hierarchical models were based on the objective function value (OFV) provided by NONMEM at a significance level of .001, equal to a decrease of 10.8 in the OFV, graphical analysis of residuals, and predictions in model diagnostics using Xpose Version 3.1.12 Influence of CLCR, body weight, body mass index, sex, and age was assessed by regressing individual PK parameters versus the covariate.
During the model-building procedure, several structural pharmacokinetic models were tested. These included, among others, a 2-compartment model and a 3-compartment model with or without CLCR being incorporated as a covariate of the renal clearance. CLCR was found to correlate with regadenoson's renal clearance (CLR) and was subsequently incorporated in the PK model. A 3-compartment model was chosen as the final model, describing the time course of regadenoson plasma concentrations. An additional compartment was added to the model, representing the drug amounts excreted in urine (Figure 1):
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denotes the changes of the regadenoson amounts in the specified compartment, with 1 referring to the central (plasma), 2 and 3 representing the peripheral, and 4 referring to the urine compartments. CL is the sum of renal (CLR) and nonrenal clearance (CLNR) from the central compartment. The typical value of CLR was defined as
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where SLP is the slope factor. Intercompartmental clearances were denoted CLD2 and CLD3. VC, V2, and V3 represent the volume of distribution of the corresponding compartments. Sex was found to be a significant covariate of V3 and its effect was expressed as
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Thus, the typical value of V3 (TVV3) was expressed as the estimated population value of V3 in male subjects (V3,male) minus a gender effect parameter (GE) times SEXF, where SEXF was set equal to 0 for male and 1 for female subjects.
An exponential variance model was used to describe the interindividual variability in CL and V3. The final model included proportional residual error models for both plasma and urine data. Fraction of regadenoson excreted unchanged in urine was estimated as the ratio of renal clearance over total clearance:
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To evaluate the predictive power of the model, simulations (n = 1000) of plasma concentration versus time were made corresponding to each study subject using estimated model parameters and each individual's creatinine clearance value and sex. The simulation results were used to construct a regadenoson plasma concentration-time curve covering the 5th to 95th percentiles of the simulated data. Actual observations were then superimposed on the graph.13
Safety Measurements and Analysis
Electrocardiograms were recorded at predose and at 2, 15, and 60 minutes after drug administration. Vital signs, including heart rate (HR), were monitored prior to and at 2, 5, and 15 minutes and 1, 2 to 3, 6 to 8, 12, and 24 hours after regadenoson injection. Clinical laboratory analyses (hematology, chemistry, and coagulation) were conducted on samples collected at screening, on day -1, and at 24 hours postdose. Baseline assessment included a complete physical exam, vital signs (blood pressure and pulse) in standing and supine positions, ECG, and laboratory values. Adverse events or serious adverse events were collected. All dosed subjects were included in the safety analyses.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Compartmental Analysis
Regadenoson plasma concentrations fell rapidly after the bolus dose (Figure 3). Table III shows typical parameter values of the model. Total clearance, as predicted by a nonrenal part and a renal part linearly related to CLCR, showed close agreement with the estimates of the noncompartmental analysis. Individual plasma concentration-time profiles were well described by the proposed 3-compartment PK model (Figure 4). This was also evident by the graph of the mean and 5th to 95th percentiles of the simulated concentrations for each subject, which captured most of the observed data within its boundaries. Figure 5 shows 4 representative graphs for male and female subjects with different creatinine clearance values.
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The effect of body weight, body mass index (BMI), and age on clearance of regadenoson was assessed. None of these covariates was found to be correlated with clearance (Figure 6). The volume of distribution estimates for the 3 compartments were all unaffected by creatinine clearance.
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Heart rate increased in all 4 treatment groups within 30 seconds postdose, with the largest mean increase in the group with creatinine clearance values above 80 mL/min (+30 bpm) and the smallest in the group with the lowest creatinine clearance values (+18 bpm). Heart rate returned to within 10 bpm above baseline within 15 minutes in all but 10 subjects, of whom 4 had a creatinine clearance 
80 mL/min, 3 had a creatinine clearance lower than 80 but higher than 50 mL/min, 2 had a creatinine clearance lower than 50 but higher than 30 mL/min, and 1 had a creatinine clearance lower than 30 mL/min. Heart rate returned to less than 10 bpm above baseline within 60 minutes in all but 2 subjects (1 with creatinine clearance above 80 mL/min and 1 between 30 and 49 mL/min, respectively). Within 150 minutes, all subjects had a heart rate less than 10 bpm above baseline.
Safety Analysis
The type and frequency of the most common adverse events are shown in Table IV. There were no clear differences in pattern or incidences in the studied group.
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In parallel with the increase in heart rate, the PR and QT intervals shortened, whereas the QRS interval remained unchanged. Mean QTc interval values, calculated using the Fridericia correction formula, showed transient increases at 2 minutes postdose, amounting to 4 to 23 ms across groups, that resolved by the 15-minute time point.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The pharmacokinetics of regadenoson in subjects with different creatinine clearance values was initially investigated using a noncompartmental (NCA) approach. The NCA results were subsequently used as guidance in developing a population compartmental model, which characterized the regadenoson concentration-time profiles successfully. Parameter estimates provided by both methods showed close agreement. Collection of urine for a period of 36 hours enabled the estimation of the renal clearance of regadenoson and its change across subjects with different creatinine clearance values. Information on the amount of regadenoson excreted unchanged in urine was incorporated in the population model, where the simultaneous use of urine and plasma data enabled the estimation of the renal clearance of the compound.
Renal function, represented by creatinine clearance, had a pronounced effect on the renal clearance of regadenoson and thereby its total clearance values (Figure 2). This resulted in prolonged elimination half-lives and decreased fraction of regadenoson excreted in urine with decreasing creatinine clearance (Figure 3). However, the plasma concentration-time profiles in early stages were not significantly different between subjects, evident by similar maximum observed concentrations as well as lack of influence of creatinine clearance on the different volume of distribution estimates of the compartmental model. As regadenoson is being developed as a single bolus injection, the prolonged elimination half-life, evident only at low concentrations compared to Cmax, is not deemed to be of any clinical significance because there is no risk for accumulation, which would be the case in repeated dosing.
Although the subjects were stratified based on a categorical description of their renal function, the individual CLCR values rather than the impairment category were used for the compartmental PK modeling. In a previous report, a 3-compartment model was fitted to regadenoson plasma concentrations in healthy volunteers receiving escalating doses of regadenoson, whereas a fourth compartment represented the total amount of the drug excreted in urine.9 The same structural model best described the present data with the model parameters similar to those of the healthy volunteers. As an example, substituting the CLCR in the model with the average value for those with a creatinine clearance above 80 mL/min (mean = 97 mL/min) results in a renal clearance of 19.4 L/h, which is similar to the previous estimate of 22 L/h in healthy volunteers.
Sex was found to be a statistically significant covariate for the volume of the third compartment of the model, and its inclusion in the structural model resulted in a significantly better fit, evident as a significant drop in the OFV and a decrease in the interindividual variability associated with this parameter. However, the effect does not seem to have any clinical impact as there were no apparent differences between male and female subjects with regard to the observed Cmax values, effects on heart rate, or the frequency or severity of adverse events.
There were no differences in the pattern or incidence of adverse events among the groups. Furthermore, there was clear effect of regadenoson on systolic or diastolic blood pressure in this study. Interestingly, there appears to be an inverse relationship between heart rate increase and the severity of renal impairment, especially for those with the lowest creatinine clearance. Regadenoson caused less HR acceleration in these subjects (+18 bpm) than in those with a creatinine clearance above 80 mL/min (+30 bpm). Even with this small sample size, we have observed that the incidence of tachycardia in the former subjects was less than in the latter (Table IV). The tachycardia induced by regadenoson is likely secondary to norepinephrine release through direct stimulation of the sympathetic nervous system.10 Thus, it is possible that renally impaired subjects, especially those who are severely diseased, cannot achieve a similar sympathoexcitation as normal subjects. Additional observations from phase III trials may shed more light on this phenomenon. Thus, regadenoson appears to be safe in renally impaired subjects.
The transient change in the QTc interval is consistent with the well-characterized QT/RR interval hysteresis, where, after a rapid change in heart rate, the QT interval adaptation lags behind the change in heart rate for up to several minutes.14 If the heart rate is rapidly increased, this hysteresis results in an increased value of QTc until the QT interval is fully adapted to the new heart rate.
In conclusion, regadenoson plasma concentrations in subjects with different renal functions were described by a 3-compartment PK model. There were no differences in the maximum concentrations, number, or severity of adverse events among the groups, although the elimination half-life of regadenoson was prolonged with decreasing renal function. Heart rate, which is increased by regadenoson, returned to within 10 bpm above baseline values within 2.5 hours in all subjects. Results from the present study do not indicate that dose adjustments will be necessary when using regadenoson for MPI in subjects with impaired renal function.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Belardinelli L, Shryock JC, Snowdy S, et al. The A2A adenosine receptor mediates coronary vasodilation. J Pharmacol Exp Ther. 1998;284: 1066-1073.
2. Shryock JC, Snowdy S, Baraldi PG, et al. A2A-adenosine receptor reserve for coronary vasodilation. Circulation. 1998; 98: 711-718.
3. Feoktistov I, Biaggioni I. Adenosine A2B receptors. Am Soc Pharmacol Exp Ther. 1997;49: 381-402.
4. Belardinelli L, Linden Y, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis. 1989;32: 73?97.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Olsson RA, Pearson JD. Cardiovascular purinoreceptors. Physiol Rev. 1990;70: 761-845.
6. Shryock JC, Belardinelli L. Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. Am J Cardiol. 1997;79: 2-10.[Web of Science][Medline] [Order article via Infotrieve]
7. Baraldi PG, Cacciari B, Romagnoli R, et al. A3 adenosine receptor ligands: history and perspectives. Med Res Rev. 2000;20: 103-128.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Abdallah H, Jerling M, Cannon RO, et al. A randomised, placebo-controlled, crossover, ascending dose tolerance and pharmacokinetic study of CVT-3146, a novel agent for potential use in myocardial perfusion imaging. Poster presented at the ASCPT annual conference; March 25, 2003; Miami Beach, Fla.
9. Gordi T, Frohna P, Sun H-L, Wolff A, Belardinelli L, Lieu H. A population pharmacokinetic/pharmacodynamic analysis of regadenoson, an A2A adenosine receptor agonist, in healthy male subjects. Accepted for publication in Clin Pharmacokinet.
10. Dhalla AK, Wong MY, Wang WQ, Biaggioni I, Belardinelli L. Tachycardia caused by A2A adenosine receptor agonists is mediated by direct sympathoexcitation in awake rats. J Pharmacol Exp Ther. 2006;316: 695-702.
11. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16: 31-41.[Web of Science][Medline] [Order article via Infotrieve]
12. Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comp Meth Prog Biomed. 1999;58: 51-64.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Holford N. The visual predictive check—superiority to standard diagnostic (Rorschach) plots [abstract 738]. Available at: www.page-meeting.org/?abstract=738.
14. Lau CP, Freedman AR, Fleming S, Malik M, Camm AJ, Ward DE. Hysteresis of the ventricular paced QT interval in response to abrupt changes in pacing rate. Cardiovasc Res. 1988;22: 67-72.[Web of Science][Medline]
[Order article via Infotrieve]
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