Simultaneous Modeling of Abciximab Plasma Concentrations and ex Vivo Pharmacodynamics in Patients Undergoing Coronary Angioplasty

Abstract

An integrated structural pharmacokinetic/pharmacodynamic (PK/PD) model was developed for the glycoprotein IIb/IIIa antagonist abciximab administered to patients undergoing percutaneous transluminal coronary angioplasty. PK/PD data, in the form of plasma abciximab concentrations and ex vivo platelet aggregation in the presence of 20 M adenosine diphosphate, were obtained from two previously conducted clinical studies. Study 1 consisted of patients who were given abciximab as a single intravenous injection of 0.25 mg/kg (n ϭ 32). Patients in study 2 received an identical bolus dose, followed by a 36-h infusion at 0.125 g/kg/min (n ϭ 15). The PK component of the final model included drug-receptor binding, nonspecific distribution, and linear systemic clearance, whereas the PD module assumed that ex vivo dynamics were controlled by free plasma drug concentration. Mean PK/PD data from both studies were fitted simultaneously using nonlinear regression. PK profiles from both studies show rapidly decreasing plasma abciximab concentrations at early time points, but with extended terminal disposition phases. The maximum effect (E max ϭ 83.6%) was achieved rapidly and gradually returned to baseline values, although inhibition could be measured long after abciximab concentrations dropped below the detection limit. The final model well described the resulting PK/PD profiles and allowed for parameter estimation with relatively small coefficients of variation. Simulations were conducted to assess predicted receptor-occupancy and effects of selected parameters on PK/PD profiles. Models such as the one developed in this study demonstrate how drug binding to pharmacological targets may influence the PK of certain drugs and also provide a suitable paradigm for defining the PK/PD relationships of similar compounds.Activation of the glycoprotein (GP) IIb/IIIa platelet-surface integrin by endogenous agonists (e.g., thrombin, adenosine diphosphate or ADP, and collagen) results in the binding of adhesive proteins such as fibrinogen and von Willebrand factor, thus mediating platelet aggregation (Phillips et al., 1991). Antagonists directed against this receptor represent a family of antiplatelet drugs that are used clinically for the prevention of pathological thromboses (Majerus and Tollefsen, 2001). Abciximab, a monoclonal antibody Fab fragment, was the first approved agent in this class of drugs (Coller, 1997) and has been shown to prevent acute cardiac ischemic complications from percutaneous transluminal coronary angioplasty (PTCA) and atherectomy (EPIC Investigators, 1994). Typical dosing regimens include a weight-normalized i.v. bolus dose of 0.25 mg/kg, followed by an i.v. infusion of 0.125 g/kg/min (up to a maximum of 10 g/min) for 12 to 24 h, depending on the indication. This scheme was designed to achieve and sustain greater than 80% receptor occupancy and less than 20% of baseline ex vivo platelet aggregation (induced by 20 M ADP), which was shown to correspond with the prevention of in vivo thrombus formation in mo...

Application of Target-Mediated Drug Disposition Model to Small Molecule Heat Shock Protein 90 Inhibitors

“…Consistently, we observed that the estimates for volumes of distribution of relatively potent small molecule HSP90 inhibitors were larger than those of less potent inhibitors when structurally similar compounds were compared in our drug discovery program. Since HSP90 is one of the most abundant proteins in unstressed eukaryotic cells, accounting for 1-2% of cytosolic protein (Parsell and Lindquist, 1993;Csermely et al, 1998), it may be possible that the target binding of HSP90 inhibitors affects in vivo PK profiles (e.g., TMDD) as is often observed for biologic drugs (Mager et al, 2003;Mager and Krzyzanski, 2005;Woo et al, 2007;Gibiansky and Gibiansky, 2009). As shown in Fig.…”

“…For HSP90 inhibitors, their bindings to pharmacological target are expected to be as rapid as many other biologics (Mager et al, 2003;Mager and Krzyzanski, 2005;Woo et al, 2007), and R total can be assumed to remain constant because of high HSP90 abundance accounting for 1-2% of the total proteins in normal cells (Parsell and Lindquist, 1993;Csermely et al, 1998). The internalization rate of HSP90 inhibitor-receptor complex can be assumed to be negligible because these inhibitors are considered to bind reversibly to the ATP-binding pocket of HSP90 in the cytosolic fraction without any elimination process through the formation of drug-receptor complex.…”

“…Furthermore, the TMDD model can be simplified to its quasi-equilibrium or rapidbinding form by replacing k on and k off with an equilibrium dissociation constant (K D ), since the in vivo simultaneous estimation of k on and k off often becomes difficult (Wagner, 1971;Mager, 2006;Gibiansky and Gibiansky, 2009;Marathe et al, 2009). A rapid binding approximation of TMDD model was successfully applied to biologic drugs exhibiting nonlinear PK profiles (Mager et al, 2003;Mager and Krzyzanski, 2005;Woo et al, 2007); however, TMDD models to date have rarely been applied to small molecule drugs.…”

Randomized, double‐blind comparison of effects of abiciximab bolus only vs. on‐label regimen on ex vivo inhibition of platelet aggregation in responders to clopidogrel undergoing coronary stenting

“…The cumulative rate of major adverse cardiac events was similarly reduced in the bolus-only arm (2.9%) and bolus + infusion arm (2.4%) as compared with placebo (5.3%) within the first 6 h after intervention [3]. However, higher rates of myocardial infarction and urgent target vessel revascularization were noted thereafter in the bolus arm as compared with bolus + infusion throughout 30 days [3].In the absence of concomitant P2Y 12 inhibition, withholding abciximab post-bolus infusion results in an approximately 30% drop in inhibition of platelet aggregation (IPA) at 6 h [1,4]. …”

“…In the absence of concomitant P2Y 12 inhibition, withholding abciximab post-bolus infusion results in an approximately 30% drop in inhibition of platelet aggregation (IPA) at 6 h [1,4].…”