Increased Potency and Decreased Elimination of ...

© 1998 Schattauer Verlag, Stuttgart

Thromb Haemost 1998; 79: 1119–25

Increased Potency and Decreased Elimination of Lamifiban, a GPIIb-IIIa Antagonist, in Patients with Severe Renal Dysfunction Gustav Lehne1, Knut P. Nordal 2, Karsten Midtvedt 2, Timothy Goggin 3, Frank Brosstad 2 From the 1Departments of Clinical Pharmacology, Drug Research Unit, and 2Internal Medicine, The National Hospital, Rikshospitalet, Oslo, Norway; 3 the Department of Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, Switzerland

Summary

Activation of the platelet membrane receptor glycoprotein (GP) IIb-IIIa is essential for thrombus formation. The novel nonpeptide GPIIb-IIIa antagonist, lamifiban, represents a promising approach for antiplatelet therapy in patients with cardiovascular disease. Since renal impairment frequently occurs in these patients, we designed a phase I study to assess the tolerability, pharmacodynamics and pharmacokinetics of lamifiban in patients with renal impairment. Four healthy volunteers (Group 1) with creatinine clearance (CLCR) >75 ml/min, eight patients (Group 2) with mild to moderately impaired renal function (CLCR 30-74 ml/min) and eight patients (Group 3) with severe renal impairment (CLCR 10-29 ml/min) were studied. They received stepwise increased doses of lamifiban intravenously (IV). There was a linear relationship between the systemic clearance of the drug and renal function (R2 = 0.86). The mean plasma concentration required for halfmaximal inhibition of thrombin-receptor agonist peptide (TRAP) induced platelet aggregation (EC50) ex vivo was 21, 28 and 11 ng/ml in Groups 1, 2 and 3. The patients in Group 3 were sensitized to the antiplatelet effect allowing an 18-fold dosage reduction without compromising the pharmacodynamics. In conclusion, the decreased clearance of lamifiban may act in concert with increased potency of the drug in patients with severe renal impairment, and the drug dosage should be reduced accordingly. Introduction

Vascular disease is the major cause of death in the industrialized world, with thrombotic occlusion frequently occurring as the terminal event in the manifestation of a vascular problem (1). The platelet membrane receptor GPIIb-IIIa for the adhesive proteins fibrinogen and von Willebrand factor plays a central role in thrombus formation at sites of vascular damage and high sheer rates as in injured coronary arteries (2-4). Although secondary prevention with acetylsalicylic acid (ASA) and heparin reduces the risk of myocardial infarction, stroke and vascular death (5, 6), vascular thrombi are frequently resistant to the antithrombotic action of conventional therapy with these agents (7-9). More efficacious antithrombotic agents are needed to overcome this clinical problem. GPIIb-IIIa antagonism represents a strategy to counteract platelet aggregation induced by all physiological agonists, and thus prevents the final common pathway of thrombus formation (10). Correspondence to: Dr. Gustav Lehne, Department of Clinical Pharmacology, Rikshospitalet, The National Hospital, N-0027 Oslo, Norway – Tel.: +47 22868529; FAX Number: +47 22111987; E-mail: gustav. [email protected]

GPIIb-IIIa antagonists belong to a class of potential agents including monoclonal antibodies, snake venom polypeptides (disintegrins), and synthetic nonpeptides. The prototype GPIIb-IIIa antagonist is a chimeric Fab fragment of the anti-GPIIb-IIIa monoclonal antibody, c7E3 Fab, which has been demonstrated to reduce by 35% the risk of acute complications associated with high-risk angioplasty compared with ASA and heparin (11). The low molecular weight nonpeptide (0.468 kD) lamifiban (Ro 44-9883) is one of the most potent and selective GPIIbIIIa antagonist yet available (12-15). Recently, a dose-ranging randomized double-blind trial showed that lamifiban administered for 3-5 days reduced the incidence of death and infarction significantly at 30 days in 365 patients with unstable angina (16). Studies in healthy volunteers have shown that lamifiban is not metabolized, but is eliminated almost exclusively by the renal route, with 90% of the drug being recovered unchanged in the urine (Unpublished data on file, F. Hoffmann La Roche Ltd., Basel, Switzerland). Consequently, the elimination of lamifiban will be compromised in patients with impaired renal function as frequently seen with atheromatous vascular disease and end organ kidney damage. Decreased drug elimination may jeopardize the therapy, because blockage of GPIIb-IIIa carries a substantial risk of hemorrhage which is dose-dependent (8, 17). In addition, it is known that patients with uremia have an acquired defect of primary hemostasis (18). Uremic platelets have been shown to have an impaired aggregation response (19, 20), and in end-stage renal disease impaired function of the platelet membrane GPIIb-IIIa has been demonstrated (21). Thus, it is likely that the pharmacodynamic response to lamifiban will change with progressive renal dysfunction. We therefore performed a dose escalating study to evaluate the pharmacokinetics and pharmacodynamics of lamifiban in patients with different degrees of renal impairment in comparison with healthy subjects. Subjects, Materials and Methods Subjects. The study included 4 healthy subjects and 16 patients with a varying degree of renal impairment (Table 1). Screening of subjects was based on medical history, physical examination, electrocardiogram recording and laboratory tests. Renal function was assessed as glomerular filtration rate (GFR) and creatinine clearance (CLCR). The subjects were stratified according to renal function: Group 1 (n = 4) with normal renal function (CLCR >75 ml/min), Group 2 (n = 8) with mild to moderate renal impairment (CLCR 30-74 ml/min), Group 3 (n = 8) with severe renal impairment (CLCR 10-29 ml/min). Study design. The study was carried out in agreement with the Helsinki declaration, and approval was obtained from the Regional Ethics Committee. Groups 1, 2 and 3 received the test drug in sequence, and the drug dose was escalated separately for each group in three steps. Lamifiban was administered intravenously (IV) three times separated by one week washout period. Group 1 received loading doses of 200, 400 and 750 mg IV followed by 4 h infusions of

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Table 1 Anthropometric data of the healthy subjects (Group 1), patients with mild to moderate renal impairment (Group 2) and patients with severe renal impairment (Group 3)

1, 2 and 5 mg/min, respectively. Group 2 was divided into two equal subgroups. Group 2a received loading doses of 40, 200 and 750 mg IV followed by infusions of 0.2, 1.0 and 4.5 mg/min. Based on pharmacodynamic measurements in Group 2a dose adjustments were made, and patients in Group 2b received loading doses of 200, 400 and 750 mg IV followed by infusions of 0.9, 1.8 and 4.5 mg/min. In Group 3, the patients received loading doses of 150, 250 and 500 mg followed by infusions of 0.09, 0.15 and 0.3 mg/min, respectively. Pharmacokinetics. Following each treatment blood samples were drawn at intervals for 28-72 h, and platelet poor plasma was separated and stored in polypropylene tubes at -20° C pending HPLC analysis with electrochemical detection of lamifiban. Briefly, the method employed automated solid phase extraction on C2 columns followed by reversed phase ion pair chromatography. The HPLC equipment consisted of pump (L-600 Merck/Hitachi Darmstadt, Germany and LC-6A Shimadzu Duisburg, Germany), autosampler (Model 232 Gibson/Abimed, Langenfeld, Germany), and electrochemical detector (Coulochem 5100A Bischoff-Analysentechnik, Leonburg, Germany). Separation was achieved with Nucleosil 100 C 18 (5 mm) column and isocratic elution. The mobile phase consisted of 78% v/v 0.05 M phosphoric acid adjusted to pH 2.20 and 22% v/v acetonitrile to which 1.0 g/l sodium dodecylsulphate was added. Only analytical grade chemicals were used. The pharmacokinetic analysis was based on an open one-compartment model using the computer program NONMEM version IV, level 2.0 (Prof. L. Sheiner, University of California, San Francisco, CA). The pharmacokinetic parameters estimated were lamifiban clearance (CL), terminal half-life (t1⁄ b), volume of distribution (Vd) and area 2 under the curve (AUC). Pharmacodynamics. Following each treatment blood samples for ex vivo measurement of platelet aggregation were collected at intervals up to 72 h. Platelet rich plasma (PRP) and platelet poor plasma (PPP) was separated by differential centrifugation of citrated blood. The platelet count in each PRP sample was measured and diluted using the corresponding PPP, to a platelet count of approximately 200 3 109/l. The platelet aggregation test was performed using a four channel PAP-4 Aggregometer (Bio-Data Corporation, Horsham, PA 19040 USA) which was calibrated daily. Blank and reference cuvettes were kept at 37° C. PPP (500 ml) was placed in the blank cuvette and PRP (450 ml) was placed in the reference cuvette. After equilibration for 3 min a bar magnet was introduced into the reference cuvette and set to a speed of 1500 rpm. The baseline was set to 100% transmission with the blank cuvette after the addition of the agonist and to 0% transmission with the reference cuvette. The aggregation was started by adding 50 ml of adenosine diphosphate (ADP, 10 mM) or thrombin-receptor agonist peptide (TRAP, 25 mM). The aggregation reaction was followed for a total of 10 min. Maximum transmission after addition of each agonist (ADPmax and TRAPmax) was determined manually by inspection of the aggregation tracings. In the event of noise in the tracing, measurements were made from the mid-point of deflection of the pen. A modified Ivy bleeding time was measured at the screening visit and three times during each pharmacokinetic profile. A sphygmomanometer cuff was placed around the upper arm of the subject and inflated to a pressure of 40 mmHg. Three punctures were then made on the volar surface of the forearm

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using MonojectTM diabetic gun. Blood from the puncture sites was absorbed to blotting paper every 15 to 20 s without touching the wounds. The bleeding time was measured as the median time to stop blood flowing from the 3 punctures. Bleeding beyond 20 min was stopped by wound compression and the bleeding time was recorded as >20 min. For each subject, the drug effect on ADP and TRAP induced platelet aggregation was determined as the percentage of the baseline values. Because of individual variation in plasma opacity, the PPP of each individual served as his own control. There was no correlation between the baseline aggregation data and renal function (ADP vs. GFR: P = 0.5; ADP vs. CLCR: P = 0.7; TRAP vs. GFR: P = 0.6; TRAP vs. CLCR: P = 0.5). At the highest dose-level t50rec (the time from end of the infusion, to >50% ADP activity) was also calculated. Dose response curves were constructed for individual subjects by plotting the mean effect during infusion at 2 and 4 h against the actual infusion rate on the three occasions. Pharmacodynamic/pharmacokinetic relationship. The relationship of lamifiban concentration (C) and effect (E) on ex vivo platelet aggregation were fit using a sigmoid inhibitory effect model supported by the software WinNonLin (Scientific Consulting Inc., Durham, NC). Due to baseline correction Emax (maximal effect) was fixed to 100. Consequently, the model estimated 2 parameters: the EC50 (the concentration to achieve 50% of the effect) and (the shape parameter). The model is defined by the following equation: E = 100 * [1 - (Cg / (Cg + EC50g)] In the case of ADP-induced platelet aggregation the shape parameter was different from 1, however when the TRAP data were fit the shape parameter was not required since a simple inhibitory effect model gave an excellent fit. This model is defined by the following equation: E = 100 * [1 - (C / C + EC50)] The mean parameter estimates together with their CV% and 95% confidence intervals are reported. A weighting of 1/y2 was used. Tolerability assessment. Routine clinical laboratory tests were determined at screening, at baseline and at discharge from the clinic. In addition, whole blood platelet counts were recorded 2 and 4 h after onset of treatment in case of lamifiban-induced acute thrombocytopenia. Records of adverse events were based on spontaneous reports and intermittent interviews. Blood pressure, pulse rate and body temperature was assessed at intervals and recorded as vital signs. Summary tables of vital signs and clinical laboratory data were prepared by calculating means over time and these were screened for trends. In addition, the magnitude of any changes from baseline data were calculated. Results

The study included 16 patients with variable degree of renal impairment due to various kinds of renal disease, and with considerable concurrent medication (Table 2). Lamifiban was generally well tolerated.

Lehne et al.: Phase I Lamifiban Study in Patients with Renal Dysfunction

Table 2 Individual disease characteristics of patients with different grades of renal impairment

CLCR = creatinin clearance; CsA = cyclosporin A; Tx renis = kidney transplant; ASA = acetylsalicylic acid

Table 3 Infusion rates and antiplatelet effect at steady state (2 and 4 h) in the study groups

Drug-related adverse events occurred in two patients who developed hematomas at the site of a bleeding time incision and at the venipuncture site used for blood sampling, respectively. Thrombocytopenia did not occur during or after any of the treatment courses, and no serious adverse event appeared. There was no change in laboratory values or deviations from baseline observations during the study.

Lamifiban was titrated according to pharmacodynamic measurements. The third titration step aimed at a 60% reduction of TRAP induced platelet aggregation which was obtained with similar infusion rates in Groups 1 and 2 , whereas patients in Group 3 required 18-19-fold reduction in infusion rate to maintain the same effect (P 20 min in all subjects at concentrations in the range of 11-27 ng/ml. For subjects in Groups 1 and 2 the concentration of lamifiban required to achieve similar bleeding time prolongation was 31-44 ng/ml and 28-64 ng/ml, respectively. The bleeding time results are summarized in Fig. 3. The platelet recovery time was estimated using ADP induced platelet aggregation, which was the more sensitive measure of platelet function in this study. The effect of lamifiban was rapidly reversible in subjects with normal renal function, but recovery became progressively slower in patients with mild, moderate and severe renal impairment (Fig. 4). The median time to recover from lamifiban-induced inhibition of ADP-stimulated platelets (ADPt50rec) was 12 h (range: 4-24) in Group 1, 24 h (range: 16-24) in Group 2 and 50 h (range: 24-68) in Group 3. There was a linear correlation between the clearance of lamifiban and GFR on one hand (Fig. 5) and CLCR on the other hand (data not shown). The median of lamifiban clearence was 7.3 l/h (range: 6.8-9.6) in Group 1, 3.7 l/h (range: 2.5-5.0) in Group 2, and 1.4 l/h (range: 0.9-2.4) in Group 3. There was apparently no correlation between the pharmacokinetic parameters of lamifiban and other potential co-variates such as age and body weight, although the study population is too

Fig. 1 Concentration (lamifiban ng/ml) versus effect (% inhibition TRAP-induced platelet aggregation relative to baseline) in each of the treatment groups. Actual values and predicted curves based on a simple inhibitory effect model are shown

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Fig. 2 Combined data of platelet inhibition showing individual dose (actual lamifiban infusion rate mg/min) versus mean effect (% inhibition TRAP-induced platelet aggregation relative to baseline) for all subjects after 2 and 4 h of treatment

Fig. 3 Bleeding time (y-axis) in relation to plasma concentration of lamifiban (x-axis) for healthy volunteers (K), patients with moderate renal impairment (+), and patients with severe renal impairment (p). Note that bleeding time >20 min appeared at lower concentrations in the latter group

Fig. 4 Mean effect (% inhibition ADP-induced platelet aggregation relative to baseline) versus scheduled sampling times (h) in each of the treatment groups. The error bars represent ± one standard deviation

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Fig. 5 Glomerular filtration rate (ml/min) versus clearance of lamifiban (ml/min) showing a linear relationship. The equation of the line resulting from linear least squares regression is shown together with the square of the correlation coefficient

small to draw firm conclusions with respect to co-variation. Therefore renal function, as measured by GFR or CLCR, has a dominant influence on the pharmacokinetics of lamifiban suggesting that dose adjustment based on renal function is necessary.

Discussion

In the present study a bolus dose of 750 mg followed by infusion at 5 mg/min lamifiban was regarded as reference dose for relevant and safe platelet inhibition in healthy volunteers (Group 1). The subsequent dose escalations in Groups 2 and 3 were performed to determine equipotent doses in patients with renal dysfunction. The study, therefore, had an adaptive design, and the required dose adjustments were based on the pharmacodynamic effects measured, provided acceptable tolerability. However, it should be kept in mind that the doses were evaluated by ex vivo tests which do not necessarily parallel in vivo efficacy. The choice of reference dose was supported by the results of a preliminary study in patients with unstable angina (16). On the other hand, the results of the first phase of the multicenter trial of Platelet IIb-IIIa Antagonist for the reduction of Acute Coronary Syndrome events in a Global Organization Network (PARAGON A) (22) lead to the selection of a lower bolus dose (500 mg) followed by a lower infusion rate (1-2 mg/min) in the pivotal study, PARAGON B. Hence, the results of the present study need to be interpreted in light of the lower dose used in PARAGON B. The pharmacokinetics of lamifiban was significantly altered in patients with renal impairment due to reduced systemic clearance of the drug. However, lamifiban CL, t1⁄ b, Vd, and AUC could not be deter2 mined accurately due to interfering peaks probably resulting from concomitant medications and reduced sensitivity of the HPLC assay. Therefore, it was not possible to evaluate the pharmacokinetics of lamifiban using standard non-compartmental methods and a population approach using NONMEM computerized models was used instead. While the EC50 values probably reflect the difference between the groups, the accuracy and the precision may have been affected by the problems encountered in measuring the concentrations of lamifiban. Since lamifiban is excreted unchanged by the renal route, a need for dose adjustments in patients with severe renal impairment was expected. However, the dosage reduction required in this study (on average by a factor of 18) to obtain the same pharmacodynamic effect in patients

with severe renal impairment (CLCR or GFR reduced on average by a factor of 7; see Table 1) cannot be explained entirely by changes in the pharmacokinetics of the drug. In the present study bleeding time was included as in vivo measure of platelet inhibition. The normal range for bleeding time using the Monoject diabetic gun, has not been formally established. However, since each individual served as his own control, the increased bleeding duration revealed by this method, was considered relevant and thus reflected the influence of lamifiban on platelet function. The Monoject method was preferred to the conventional determination of bleeding time according to Ivy due to the great number of tests (n = 16) being performed in each individual. The scarring of the skin which is frequently seen with the Ivy method, was considered undesirable in this study. Impaired function of platelet membrane GPIIb-IIIa has been demonstrated in end stage renal disease (21) and it is possible, that patients with severe renal impairment, but not yet in end stage renal disease, manifest such a dysfunction. However, uremic platelets may also exhibit a reduction in several of the biochemical responses necessary for aggregation, including reduction of platelet granular content of ADP and serotonin (23, 24), reduced platelet thromboxane production (20, 25), and rise in cytoplasmic free calcium and cAMP levels (26, 27). The results of the present study suggest that lamifiban has a lower EC50 for both ADP and TRAP induced platelet aggregation ex vivo in patients with CLCR in the range 10-30 ml/min. In addition, the concentrations required to attain bleeding times >20 min in vivo were also lower in these patients. The higher sensitivity to the pharmacodynamic effect of lamifiban in these patients may be explained by altered binding to the platelet GPIIb-IIIa, which is likely to be true for other GPIIb-IIIa antagonists as well. Whether this also reflects impaired function of GPIIbIIIa, warrants further study. The difference in EC50, which was observed in all groups, comparing TRAP and ADP, may be explained by the fact that TRAP, a strong agonist, stimulates the platelets to a much greater extent than ADP, causing activation of more GPIIb-IIIa receptors. Because of the resulting increase in the number of receptors on the cell surface, a higher concentration of lamifiban is required to inhibit the response to TRAP. Interestingly, the increase in the bleeding time to values >20 min appeared at concentrations in the range of the EC50 for TRAP, whereas the bleeding times were comparable to baseline values at the EC50 for ADP. We chose to estimate recovery by ADP stimulation as there is still a measurable effect with ADP when there is no 1123


measurable effect with TRAP, which is the more powerful agonist of platelet aggregation. The sustained platelet recovery time in patients with severely impaired renal function is an important finding considering the clinical use of lamifiban. Recovery as defined in this study, was 4-fold extended in these patients compared to subjects with moderate or no renal impairment. The delay in platelet recovery is a serious threat to the patient if a major bleeding should occur, and strategies for assisted clearence of lamifiban by hemodialysis or charcoal hemofiltration should be addressed in further studies with this drug. However, the problem of sustained platelet inhibition may be expected only in patients with severe renal impairment (CLCR 30 ml/min, but patients with lower CLCR required substantial reduction in the infusion rate of lamifiban. By dose adjustments according to renal function treatment with lamifiban should be safe even in the case of renal dysfunction. Lamifiban was generally well tolerated in this study. However, our patients were carefully screened to avoid bleeding diathesis, and the study situation was not comparable to that of a therapeutic approach including heparin and ASA in acute cardiac events. Previously, a few cases of severe thrombocytopenia have been reported with GPIIb-IIIa antagonists even at low dosages (28). In our study no incident of thrombocytopenia occurred, but the study population was to small to discover rare adverse events. Considering the results of this study, some open questions do, however, remain to be addressed. A means to speed up the recovery following cessation of a lamifiban infusion in patients with severely impaired renal function would greatly enhance the safe use of the drug in such patients. Studies in patients with end stage renal disease that requires dialysis will show whether lamifiban is easily removed from circulation by hemodialysis. Therefore a study of lamifiban administration to patients prior to, during and after hemodialysis, seems warranted. The introduction of the GPIIb/IIIa antagonists has opened a new therapeutic era in the management of cardiovascular disease because these agents are far more potent platelet inhibitors than the conventional antithrombotics (29). In particular, the nonpeptide lamifiban represents a promising therapeutic approach being highly potent and selective with respect to GPIIIb/IIa antagonism. We demonstrated a complete inhibition of platelet aggregation at tolerable plasma concentrations of lamifiban. However, the changes in pharmacokinetics and pharmacodynamics that we also demonstrated in patients with severe renal impairment, requires circumspection in drug dosing. Because lamifiban has increased potency and decreased clearance in patients with severe renal impairment, the drug dosage should be reduced accordingly. Acknowledgements The authors are grateful to Karen Johanne Beckstrøm, Reidun Hauge, May Ellen Lauritsen and Stine Bjørnsen for excellent technical assistance, and to Anne Beate Hvinden for accommodating patient care. References 1. Stein B, Fuster V, Halperin JL, Chesebro JH. Antithrombotic therapy in cardiac disease. An emerging approach based on pathogenesis and risk. Circulation 1989; 80: 1501-13.

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PARAGON investigators. Delaying and preventing ischemic events in patients with acute coronary syndromes using the platelet glycoprotein IIb/IIIa inhibitor lamifiban. J Am Coll Cardiol 1997; 29: 409A. 23. Eknoyan G, Brown CH. Biochemical abnormalities of platelets in renal failure. Evidence for decreased platelet serotonin, adenosine diphosphate and Mg-dependent adenosine triphosphatase. Am J Nephrol 1981; 1: 17-23. 24. Di Minno G, Martinez J, McKean ML, De La Rosa J, Burke JF, Murphy S. Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med 1985; 79: 552-9. 25. Smith MC, Dunn MJ. Impaired platelet thromboxane production in renal failure. Nephron 1981; 29: 133-7. 26. Ware JA, Clark BA, Smith M, Salzman EW. Abnormalities of cytoplasmic Ca2+ in platelets from patients with uremia. Blood 1989; 73: 172-6.

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Received July 28, 1997 Accepted after resubmission February 11, 1998

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