INTRODUCTION
Over the past decade, the use of levetiracetam in critical care settings
both in the treatment and prevention of various seizure disorders has
significantly increased [1-2] . This increase is owed in
large part to several studies that have showed it to be a safe,
broad-spectrum and highly effective anti-epileptic drug with minimal
drug interactions and a wide therapeutic index [3-5] . There
is no official requirement for therapeutic drug monitoring and, as such,
no agreed target range for levetiracetam exists. However, a large scale
dose-ranging study conducted among epileptic patients identified a
desired therapeutic target of 12 – 46 mcg/mL at trough level[6] .
Levetiracetam is a small, hydrophilic molecule that is weakly bound to
proteins (<10%) with linear kinetics [5,7-9] . In
a healthy adult, the total clearance of levetiracetam is approximately
4.03L/hr, the half-life is 6 – 8 hours and the volume of distribution
is 0.5 – 0.7L/kg [10] . It is almost exclusively
(>90%) excreted via the kidneys and so dose adjustments
are recommended in patients with impaired renal function[6,8,11,12] . Even mild-to-moderate renal impairment has
been shown to double plasma concentration and significantly increase
drug half-life [13] .
Renal impairment is common in critical care settings with around half of
people admitted to intensive care developing acute kidney injury[14-15] . Continuous renal replacement therapy (CRRT) is
used in severe acute kidney injury to support renal function and
minimise the risk of multi-organ failure and fluid overload.
Additionally, people with end-stage renal disease who require
intermittent haemodialysis often benefit from a temporary transition to
continuous renal replacement therapy in the event of critical illness
due to the enhanced haemodynamic and metabolic control it provides. The
introduction of renal replacement therapy creates challenges for
pharmacological management as pharmacokinetics are altered through both
extrinsic (e.g. filtration mode, filter type, flow rate) and intrinsic
factors (e.g. residual renal function, fluid volume status, protein
binding). For medications that are renally excreted, such as
levetiracetam, the effects on clearance can be significant[16] .
Intermittent haemodialysis (IHD) has already been shown to eliminate
50% of levetiracetam within four hours [13] . As a result,
the current dosing recommendation for patients receiving IHD is a 750mg
loading dose followed by 500 – 1,000mg once daily dosing. However, in
patients on CRRT the current recommended dosing is 250 – 750mg twice
daily without loading – equivalent to a patient with CKD Stage 3b[17] . While there have been a multitude of studies
investigating the pharmacokinetics of levetiracetam in haemodialysis to
support the current dosing recommendation in IHD [18-21] ,
the evidence base for patients undergoing CRRT remains limited. Indeed,
the current dosing recommendations are based on three case reports
alone. In the last few years there has been a renewed focus on
broadening the evidence base [22] .
In this systematic review, we evaluate the latest available evidence on
the pharmacokinetics of levetiracetam in critically ill patients
undergoing CRRT. This review was performed in light of several case
reports and case studies suggesting that the clearance of levetiracetamin vivo may be significantly higher than previously thought –
raising the risk of sub-therapeusis in such patients[22-25] . We undertake a quality assessment of the current
evidence in addition to meta-analysis and computational modelling to
understand the factors that affect clearance and to simulate the effect
of different dosing strategies on plasma concentration.