Pharmacokinetics of alteplase in the treatment of ischaemic stroke

Abstract

The pharmacokinetic profile of alteplase is almost entirely derived from studies in AMI. Differences in the pathophysiology of AMI and AIS mean it cannot be assumed that the pharmacokinetics of alteplase is similar in these two populations. During AMI, cardiac function and, hence, hepatic perfusion and clearance of alteplase may be impaired. The relatively older population in AIS may have impaired metabolic clearance which may increase plasma concentrations. The concurrent use of medications such as nitrates in the management of elevated blood pressure during AIS thrombolysis is also associated with reduced plasma concentrations of alteplase. Again, differences in clot size and type between AMI and AIS and between subtypes of AIS may influence response to alteplase. There is an inherently higher risk of intracranial haemorrhage in AIS compared to AMI emanating from cerebral infarction and BBB disruption. Accordingly, stroke-specific pharmacokinetics of alteplase and its relationship to efficacy and safety outcomes are required.

Improved Method for the Preparation of a Human Cell-based, Contact Model of the Blood-Brain Barrier

“…This interaction between t-PA and the BBB may contribute to bleeding complications associated with t-PA-induced thrombolysis 4,34,35 and is thus a subject for current research efforts. Our studies in vitro confirmed that t-PA indeed increased the permeability of the intact BBB in a concentration-( Figure 4A) and time-dependent manner (Figure 4B), which were both within a pharmacologically-relevant range 36,37 . Furthermore, dramatic morphological changes of SVG astrocytes could be observed on the porous membranes post exposure to t-PA ( Figure 4C), suggesting that astrocytic responses to t-PA underlie t-PA-induced BBB opening.…”

Coagulation factor XIIIa is inactivated by plasmin

“…20,21 For example, the therapeutic use of plasminogen activators to treat embolic stroke 22 and heart attack 23 may be complicated by the novel discovery of plasmin-mediated inhibition of FXIII-A 2 *. Physiologically, tPA is present in the blood at ;70 pM; however, therapeutic tPA is typically administered either IV, leading to systemic blood concentrations of ;50 nM, 24 or locally into clots from intravascular catheters at ;400 nM. 19 In our experiments, FXIII-A 2 * was degraded during clot formation under thrombolytic conditions, at 50 nM tPA.…”

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

“…As for pharmacokinetics, a dose-dependent effect of alteplase on stroke outcome has been shown in different studies with significant higher rates of ICH rate with doses above 0.95 mg/kg, which has led to a licensed dose for administration of 0.9 mg/kg body weight [16]. The drug is predominantly metabolized by the liver and is eliminated via urine [16], as is ceftriaxone [17]. However, to date no data comparing both pharmacokinetic profiles have been published.…”