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PHARMACOKINETICS |
Simulation of Exposure
From Sanofi Aventis, Science & Medical Affairs, Bridgewater, New Jersey (Dr Paccaly, Dr Rohatagi, Dr Liu, Dr Shukla, Dr Jensen), and Frankfurt, Germany (Dr Frick, Dr Rosenburg, Dr Hinder). Shashank Rohatagi is currently at Sankyo Pharma Development, Clinical Pharmacology and Pharmacokinetics, Edison, New Jersey. Umesh Shukla is currently at Johnson & Johnson, Experimental Medicine, Pharmaceutical Research & Development, Raritan, New Jersey. Anne Paccaly and Shashank Rohatagi are fellows of ACCP (FCP).
Address for reprints: Anne Paccaly, PharmD, Sanofi Aventis, 1041 Route 202-206, PO Box 6800, Mail Stop M303A, Bridgewater, NJ 08807-0800.
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ABSTRACT |
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 TOP ABSTRACT OBJECTIVESMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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studies. Otamixaban exhibited in healthy subjects several interesting pharmacokinetic features in view of its potential therapeutic use in coronary thrombosis: a rapid plasma distribution and elimination, a well-described dose-exposure relationship, a low intersubject variability in plasma exposure, and a mixed renal and biliary excretion with constant renal clearance.
Key Words: FXa inhibitor • otamixaban • pharmacokinetics • model
Specific FXa inhibitors act either indirectly through antithrombin III inhibition (eg, fondaparinux) or directly (eg, DX-9065a and otamixaban). The essential role of FXa in the thrombin generation process being well established, there is an urgent need to develop new anti-FXa agents and evaluate their therapeutic effect in antithrombotic therapy.4,5
Otamixaban {2-(R)-(3-carbamoylimidoylbenzyl)-3-(R)-[4-(1-oxypyridin-4-yl) benzoylamino]-butyric acid methyl ester, hydrochloride salt} is a direct potent and selective inhibitor of FXa. The antithrombotic efficacy of otamixaban has been tested in vitro (coagulation tests, FXa activity assays) and in several in vivo models of thrombosis in rat and dog.6,7 Otamixaban inhibited FXa in human plasma with a Ki of 0.52 nM (0.25 ng/mL) and doubled activated partial thromboplastin time (aPTT) in man at 2.5 times lower concentrations as compared to dog.6,7 Otamixaban minimally binds to human plasma proteins (<25% binding) and has limited affinity for red blood cells (blood/plasma ratio = 0.6-0.8). The preclinical pharmacokinetics of otamixaban is characterized by a fast systemic clearance (T
= 0.5-1.5 hours), despite a total clearance below the liver blood flow, and by a volume of distribution at steady state (Vdss) slightly exceeding the volume of total body water. Otamixaban is excreted unchanged in urine and undergoes biliary excretion followed by metabolism, likely gastrointestinal and essentially results in the formation of the reduced N-oxide (MA). MA possesses similar anti-FXa activity as the parent drug (unpublished data).
The anti-FXa activity of otamixaban is expressed by a prolongation of clotting times, that is, aPTT, prothrombin time (PT), Heptest clotting time, and Russell's Viper Venom induced clotting time. These changes in clotting times relate directly to the circulating otamixaban plasma concentrations.8
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OBJECTIVES |
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TOPABSTRACTOBJECTIVESMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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MATERIALS AND METHODS |
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TOPABSTRACTOBJECTIVESMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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70 L/h) or the maximal life span approach (Cl 14 L/h).6,9 The starting dose was defined at one tenth of this active dose, while dose escalation was supported by on-site coagulation measurements, that is, aPTT, PT, and template bleeding time. Doses for the bolus plus 6-hour infusions and for the 24-hour infusions were defined from the 6-hour infusion data using modeling and simulation.
Clinical Study Design
The 2 clinical phase 1 studies were placebo-controlled (double-blind treated vs placebo) and randomized designs, using sequential parallel groups of healthy male volunteers (8 subjects/group, 6 active and 2 placebo). Both studies were conducted at the same study center (Association de Recherche Thérapeutique, Lyon, France), in accordance with the ethical principles set forth in the Declaration of Helsinki and in compliance with local regulations. The protocols were reviewed and approved by the Comité Consultatif pour la Protection des Personnes dans la Recherche Biomédicale de Lyon B. Prior to any study procedure, subjects provided written informed consent after having received verbal and written information on the procedure and possible hazards and risks of the studies. Subjects (18-45 years old) satisfied the specified inclusion/exclusion criteria of phase 1 clinical studies.
Study 1 was composed of eight 6-hour infusions (1.7, 6.7, 27, 53, 80, 107, 142, 183 µg/kg/h) and 2 intravenous bolus plus 6-hour infusions (30 µg/kg + 60 µg/kg/h, 120 µg/kg + 140 µg/kg/h). Study 2 was composed of four 24-hour infusions (53, 83, 107, 142 µg/kg/h). Blood samples were collected at predose and at defined sampling times from the start of infusions (T0) until 12 hours (6-hour infusions, n = 13), 16 hours (bolus-plus-6-hour infusions, n = 17), or 48 hours (24-hour infusions, n = 23) post-T0.
Bioanalytical Methods
Otamixaban and MA (when applicable) were analyzed in blood, plasma, and urine using a validated LC/MS/MS method. Solid-phase extraction of 0.1 mL of sample occurred in the presence of an internal standard (otamixaban-D6) using a 96-well C8 (Octyl) standard density extraction disk plate. High-performance liquid chromatography separation was carried out on a BDS Hypersil C8 column (50 x 4.6 mm, 5 µm) under isocratic conditions (0.2 mL/min) using acetonitrile/10 nM acetic acid containing 1% formic acid (80/20, v/v). Mass spectrometry detection occurred on a tandem mass spectrometer operating in multireaction monitoring mode, with the mass transitions 447 m/z
198 m/z (otamixaban and MA) and 453 m/z198 m/z (D6-otamixaban), respectively. A weighted (1/X2) linear regression algorithm was applied using the peak area ratios of the analyte to the internal standard. The calibrations ranged from the lower limit of quantitation and were 1.0 to 500 ng/mL (otamixaban and MA in plasma and blood, otamixaban in blood) and 10 to 1000 ng/mL (otamixaban and MA in urine). Higher concentrations of otamixaban (up to 1000 ng/mL in plasma and 75000 ng/mL in urine) were measured upon appropriate dilution of the samples. The assay performances were satisfactory throughout the assay period. Accuracy, defined as the percentage difference between the nominal and mean measured calibration standard concentrations, was between –4.7% and 13.1% for study 1 and between –0.99% and 0.95% for study 2. Precision, defined by the coefficient of variation (CV%) of the quality controls, was between 2.9% and 10.3% for study 1 and between 2.2% and 5.74% for study 2. Sample integrity until analysis was ensured by appropriate stability testing of the 2 analytes in the biological matrices.
Data Analysis
Plasma Data
Pharmacokinetic analysis and modeling and simulation were conducted with WinNonlin software version 3.3 (Pharsight Corporation, Mountain View, Calif), using Windows NT. The following pharmacokinetic parameters obtained by noncompartmental analysis were presented per dose groups (n = 6) with descriptive statistics (geometric mean ± SD, or geometric mean [CV%]):
) by adding Clast/Ke; ) using 0.693/Ke, with Ke being the apparent terminal elimination rate constant; , where D is the dose; and The 2- and 3-compartment modeling, using naïve pooled data per dose group, generated a single set of pharmacokinetic parameters for each dose group and for the complete data set, provided dose proportionality was verified or non–dose proportionality was accounted for. This analysis was referred to as "global analysis." The models for this global data analysis consisted of a series of differential equations per dose group that described the amount of drug in each compartment and resulted in the estimation of the drug concentration in the central compartment. Goodness of fit was estimated based on diagnostic criteria, that is, Akaike information criterion, Schwartz Bayesian criterion, and weighted residual sum of squares (WRSS) and by visual observation of the graphical presentations for curve fitting of predicted versus observed concentrations and residual values as a function of the observed concentrations and time. If both the 2- and 3-compartment models satisfied the criteria mentioned above, then the final selection was performed using the Fisher test, following the equation FFisher = |(WRSS1 – WRSS2)/(df1 – df2)|/(WRSS2/df2), where WRSS is the weighted residual sum of squares, df is the degrees of freedom in each model (df = Nobs – Nparam), and FFisher is read in the table (0.05%) at the row and the column corresponding to (df1 – df2) and df2, respectively.10
Urine Data
Otamixaban and MA excreted in urine (Ae0-t) were expressed as amount (micrograms) and as percentage of the dose. The renal clearance (Clr) was estimated from the cumulative renal excretion (Ae0-t) and the corresponding observed plasma exposure (AUC0-t), based on the equation Clr = Ae0-t/AUC0-t.
Dose-Exposure Relationship
The dose-exposure relationship was investigated over an infusion rate range of 27 to 183 µg/kg/h. The following individual pharmacokinetic parameters determined by noncompartmental analysis were considered for dose proportionality: end-of-infusion concentration (Ceoi), dose-normalized area under the plasma concentration-time profile (AUC/D), systemic plasma clearance (Cl), and renal clearance (Clr). These parameters were graphically represented as a function of the infusion rate. Dose proportionality is observed when Ceoi increases proportionately with increasing dose and when AUC0-/D, Cl, and Clr remain unchanged with increasing dose.
Dose Prediction and Simulation of Exposure
Dose optimization for bolus plus 3-hour-infusion doses of otamixaban was performed using modeling and simulation to reach a target Ceoi of 75, 150, 300, 450, and 600 ng/mL. In addition, the "dip" in plasma concentrations occurring at 15 to 30 minutes post-T0 was maintained close to Ceoi, that is, greater than 80% of the Ceoi values, by adjustment of the bolus dose.
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RESULTS |
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TOPABSTRACTOBJECTIVESMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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General Considerations for the Pharmacokinetic Analysis
In an effort to best describe the fate of otamixaban in plasma in these first studies in man, blood sample collection times were optimized as the studies progressed, resulting in the addition of later time points after the end of infusion in the bolus plus 6-hour-infusion and in the 24-hour-infusion dose groups. Considering the multiexponential decline of the drug plasma concentrations over time, time-dependent pharmacokinetic parameters, such as the apparent terminal elimination rate constant (Ke) and volume of distribution at steady state and at the terminal elimination phase (Vdss and Vz) depend on the methodology applied. Therefore, these parameters cannot be compared across all dose groups within a study and across studies.
Otamixaban in Blood
Otamixaban blood concentrations (n = 585) and corresponding plasma concentrations correlated closely with maximal values of 424 ng/mL in blood and 633 ng/mL in plasma(Figure 1).
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Otamixaban plasma exposure increased with the dose. Plasma exposure (Ceoi and AUC0-) showed a low intersubject variability with CV% of 9% and 36%, respectively. The observed AUC0-t accounted for 95% to 97% of the AUC0-. The mean (CV%) total plasma Cl ranged from 20 (21) to 42 (17) L/h in the 6-hour infusion study and from 29 (32) to 36 (25) L/h in the 24-hour infusion study and tended to decrease as the infusion rate increased. Vdss values ranged from 35 (16) to 90 (25) L in the 6-hour infusion study and from 136 (81) to 202 (43) L in the 24-hour infusion study. Vdss values tended to decrease as the infusion rate increased. The apparent terminal elimination half-life (T
z), although highly dependent on the sampling times considered for its estimation, remained essentially unchanged across the dose groups with similar sampling times, that is, around 2 to 3 hours, 3 to 4 hours, and 10 to 16 hours, for the sampling times until 6, 10, or 24 hours post-Teoi, respectively. The constancy of T disregarding the duration of infusion was indicated by the parallel course on the log concentration time (not shown).
Dose proportionality of otamixaban plasma exposure (Ceoi) and elimination (Cl) over infusion rates ranging from 27 to 183 µg/kg/h are represented in Figures 3 and 4, respectively. Individual Ceoi values increased slightly more than proportionately and AUC0-/D increased as the infusion rate increased, while it expected to remain constant (figure not shown). The individual otamixaban plasma clearance values decreased significantly (Pslope <.001) as the infusion rate increased.
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The global 2- and 3-compartment analyses accounted for the 30% decrease in plasma clearance (Cl) and volume of distribution (V) as a function of the infusion rate (27 to 183 µg/kg/h). This was achieved by replacing in the equations for the infusions the volume of the central compartment (V) by an equation of the type V = A + B*INF, where INF is the infusion rate and A and B (negative value) are estimated by the model. This adjustment for V also adjusted for Cl. No correction was made for the bolus dose, and the usual term V was kept in these equations.
The pharmacokinetic parameters for the pooled data 2- and 3-compartment model analysis with their diagnostic criteria are presented in Table I, and the observed versus predicted plasma concentrations are presented in Figure 5 (Figures 5a and 5b for the 2- and 3-compartment models, respectively). Both models provided a good estimation of the parameters V, A, B, Cl, and T, as indicated by the less than 20% CV values on these parameter estimates. However, K13 and K31 were less accurately estimated, with CV values of 34% and 89%, respectively. As the Fisher test did not reveal superiority of the 3-compartment model, the less complex 2-compartment model was retained based on the principle of parsimony.
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The pharmacokinetics of otamixaban was characterized by high transfer rate constants and a rapid elimination from the plasma compartment, expressed in a short disappearance half-life from the central compartment. The parameter V decreased from 19 to 14 L with increasing infusion rates and was 11 L for the bolus doses, while Cl decreased from 31 to 22 L/h with increasing infusion rates and was 17 L/h for the bolus doses.
Otamixaban in Urine
More than 97% of the total renal excretion of otamixaban occurred within 24 hours post-Teoi. The renal excretion accounted for 13% to 32% of the total dose administered. The renal clearance remained constant over the dose range, with values (X [CV%]) between 6 (25) and 7 (15) L/h after the 6-hour infusions and between 4 (16) and 6 (15) L/h after the 24-hour infusions.
Metabolite in Plasma and Urine
The metabolite MA was present in very low concentrations in plasma (Ceoi and AUC0-t <2%) and in urine (Ae0-t 1%), as compared to otamixaban.
Dose Prediction and Simulation of Exposure
The optimized combinations of bolus plus 3-hour-infusion doses to reach a target Ceoi of 75, 150, 300, 450, and 600 ng/mL are presented in Table II. Special emphasis was put on keeping the gap that appeared about 15 to 30 minutes post-T0 above 80% of the Ceoi value. This was achieved by slightly increasing the bolus dose.
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DISCUSSION |
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TOPABSTRACTOBJECTIVESMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Otamixaban concentrations in blood and plasma highly correlated (r2 = 0.9741), with a blood/plasma ratio (slope) of 0.66, in agreement with in vitro findings (0.76-0.60). As MA represented less than 2% of the parent compound in plasma, its contribution to any pharmacological effect is negligible. The most notable feature in the plasma concentration-time profiles of otamixaban is the rapid disappearance of the drug from plasma as soon as the administration is stopped (50% in the first 0.5 hours), despite an expected effective half-life of about 2 to 3 hours. Therefore, otamixaban plasma concentrations should fall by half within 30 minutes upon cessation of the infusion in the event of any unforeseen bleeding or adverse response during therapy.
Otamixaban pharmacokinetics in man was in agreement with animal data (not published). The total plasma clearance of otamixaban was below the hepatic plasma flow (48 L/h) in man. The volume of distribution at steady state (Vdss), close to or exceeding the volume of total body water in man (42 L), was in agreement with the high water solubility and the low plasma protein binding of the drug. The renal clearance (6-7 L/h) of otamixaban accounted for 13% to 32% of the total clearance of the drug and remained below the glomerular filtration rate in man (7.5 L/h).
The more than dose-proportional increase in plasma exposure (Ceoi) of otamixaban, with a simultaneous decrease (30%) in Cl and V resulting in no change in T, merits further consideration. With respect to the clearance, otamixaban in man is excreted unchanged in urine (25% of the dose) and in bile (75% of the dose). The biliary excretion is followed by metabolism, likely gastrointestinal, and results in the fecal excretion of only metabolites. This biliary excretion and/or metabolism of otamixaban might be saturating at higher doses, resulting in higher plasma exposure. In the presence of an unchanged Clr, the renal excretion (percentage of dose) therefore increased with the dose.
With respect to distribution, otamixaban preferably distributes into the total body water and poorly binds to plasma proteins. Among potential explanations for the nondose proportionality, saturation of red blood cell distribution was considered and ruled out based on the linear relationship between plasma and blood otamixaban concentrations. Nevertheless, a change in volume of distribution is the most straightforward underlying mechanism for the non-dose-proportional exposure of otamixaban. A possible saturation of the biliary excretion and/or subsequent metabolism could be regarded as a shift in distribution from a peripheral compartment (bile) in favor of the central compartment (plasma). In this case, the not-affected renal clearance of otamixaban from the central compartment would result in a higher percentage of the dose excreted, as noticed.
The naive pool data analysis accurately described the non-dose-proportional plasma exposure of otamixaban in a single set of pharmacokinetic parameters over the dose range of 27 to 183 µg/kg/h. The main pharmacokinetic parameters from the 2- and 3-compartment model analysis were very similar to those from the noncompartmental analysis. Cl values ranged from 22 to 31 L/h, and V values ranged from 14 to 19 L, while the elimination half-life (0.45 hours) from the central compartment (plasma) coincided with the observed time (0.5 hours) requested to halve plasma concentrations as the infusion was stopped. This 2-compartment model was used to optimize combinations of bolus and 3-hour infusion doses, which immediately generated the target Ceoi and/or mimicked steady-state otamixaban plasma concentrations. The slight dip in plasma concentrations at 15 to 30 minutes post-T0 was maintained above 80% of the Ceoi value by adjusting the bolus dose.11
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ACKNOWLEDGEMENTS |
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TOPABSTRACTOBJECTIVESMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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1. Bertrand ME, Simoons ML, Fox KA, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2002;23: 1809-1840.
2. Wykrzykowska JJ, Kathiresan S, Jang IK. Clinician update: direct thrombin inhibitors in acute coronary syndromes. J Thromb Thrombolysis. 2003;15: 47-57.[CrossRef][ISI][Medline] [Order article via Infotrieve]
3. Dyke CK, Becker RC, Kleiman NS, et al. First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation. Circulation. 2002;105: 2385-2391.
4. Samama MM, Gerotziafas GT. Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux). Thromb Res. 2003;109: 1-11.[CrossRef][ISI][Medline] [Order article via Infotrieve]
5. Kaiser B. DX-9065a Daiichi. Curr Opin Investig Drugs. 2003;4: 1105-1112.[Medline] [Order article via Infotrieve]
6. Chu V, Brown K, Colussi D, et al. Pharmacological characterization of a novel factor Xa inhibitor, FXV673. Thromb Res. 2001;103: 309-324.[CrossRef][ISI][Medline] [Order article via Infotrieve]
7. Rebello SS, Bentley RG, Morgan SR, et al. Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis. Br J Pharmacol. 2001;133: 1190-1198.[CrossRef][Medline] [Order article via Infotrieve]
8. Paccaly A, Ozoux M-L, Chu V, et al. Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor. Thromb Haemost. In press.
9. Mahmood I, Balian JD. Interspecies scaling: predicting clearance of drugs in humans. Three different approaches. Xenobiotica. 1996;26: 887-895.[ISI][Medline] [Order article via Infotrieve]
10. Gabrielsson J, Weiner D. Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications. 2nd ed. Stockholm, Sweden: Apotekarsocieteten; 1997.
11. Paccaly A, Rohatagi S. Prospective dose prediction for FXa inhibitor otamixaban (OTAM) using PK/PD simulations accounting for non-dose proportional plasma exposure. Clin Pharmacol Ther. 2005;77: 40.
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