DISCUSSION
Our results demonstrate that the clearance of levetiracetam in
critically ill patients undergoing CRRT is consistently demonstrated in
the literature to be similar to that seen in healthy adult patients.
Both mean total clearance (3.55 L/hr) and elimination half-life (9.41
hrs) were broadly equivalent to that of healthy adults (4.03 L/hr and 6
– 8 hrs respectively). The mean clearance attributable to CRRT was over
50% confirming that CRRT is responsible for the majority of drug
clearance. Moreover, it demonstrates that IHD and CRRT have similar
pharmacokinetic effects in terms of their ability to eliminate
levetiracetam. Taken together, these findings suggest that current
dosing recommendations may pose a risk of sub-therapeutic drug
concentrations.
Our simulation data also raise several concerns over the current UK
dosing recommendations in CRRT, which advise a 250 – 750 mg twice daily
regimen without an initial loading dose [17] . As
demonstrated in Fig. 5 , without a loading dose the majority of
our simulated patients experienced sub-therapeutic drug concentrations
for up (and beyond) 72 hours. This effect was reduced to a limited
extent with higher dosing regimens (750 – 1000 mg) but even at higher
doses, drug concentrations remained sub-therapeutic for the initial 24
hours of treatment. Even the addition of the loading dose recommended
for patients on IHD resulted in the same problem, with the majority of
patients experiencing sub-therapeutic drug concentrations up to 24 – 36
hours into treatment (Fig 4 ). The addition of a standard
loading dose at 60mg/kg resolved this problem and resulted in the
immediate achievement of therapeutic drug concentrations (Fig.
3 ). A significant proportion of patients at this loading dose, however,
had trough concentrations over 80 mcg/mL for the first 24 hours and may
require additional monitoring for potential drug toxicity[41] .
Regular dosing at lower levels (250 – 500mg) was unlikely to achieve
therapeutic levels by steady state (Fig. 3 – 5 ). Even with the
addition of a loading dose, the median drug concentration for patients
receiving these doses remained below 12 mcg/mL at 72 hours. In contrast,
at higher doses (750 – 1000mg) a significant number of patients had
therapeutic drug concentrations at steady. However, without a standard
loading dose of 60mg/kg the time to therapeutic levels (even at higher
doses) was delayed by up to 36 hours.
From a pharmacokinetic perspective, these data suggest that current UK
dosing recommendations in CRRT are likely to result in extended periods
of sub-therapeusis and suggests that patients undergoing CRRT should be
considered for a twice daily dosing of 500 – 1,000 mg in addition to an
initial loading dose of 60mg/kg. A major limitation of this work is the
lack of data on efficacy or the use of the target trough concentration
in the critically ill cohort. However, given the relatively low event
rate of seizures, the relatively low number of patients receiving the
drug whilst also receiving renal replacement therapy and the number
patients receiving this drug for prophylaxis, it is highly unlikely in
our view that a PK-PD trial will be realised.
The specific extrinsic factors related to CRRT, such as effluent flow
rate or dialysate rate, that influence levetiracetam clearance remain
unclear. Few studies investigated the haemofiltration characteristics
that influence clearance with the exception of Kalaria et al. Their
analysis identified effluent flow rate and sieving co-efficient as the
main influences on clearance. Effluent rates in excess of 3.5L/h were
also associated with increased clearance and so higher doses may be
required in these patients.
Similarly, further investigation into the intrinsic patient-specific
factors that affect clearance is also required. While mean clearance was
consistent between studies, there was a wide variation in individual
patient clearance and plasma concentrations which are not easily
explained by effluent rate and sieving co-efficient alone. Six patients
demonstrated trough drug concentrations below the therapeutic target
level but a post-hoc descriptive analysis (Appendix 3 ) found no
obvious explanation. Three of these patients had significant residual
urine output (>300ml per day), while three others had high
effluent rates. However, other patients received similar doses at higher
effluent rates or indeed had higher urine outputs without their plasma
concentrations falling outside of target levels. These data suggest that
there is a high inter-person variability of drug pharmacokinetics and
determining optimum dosing strategies for individuals may require
therapeutic drug monitoring.
Finally, our systematic review illustrates that the availability of
pharmacokinetic data on levetiracetam in CRRT remains limited. Data are
limited to a small number of case reports and two small prospective
studies. There is a lack of consistency between studies, both in terms
of methodology and data reporting, that further limits the overall
evidence base at present. In this paper, we have introduced a novel
quality assessment method that utilises a combination of the QoE
framework, which assesses the strength of pharmacokinetic studies based
on the quality of data and pharmacokinetic modelling provided, and the
ADQI minimum reporting criteria, which was developed to standardise
comparisons between studies that reported on CRRT techniques. Both
methods have been used in similar systematic reviews in this way[42, 43] but never before in combination. By combining
these assessment methods, our quality assessment method allows for equal
consideration of both the pharmacokinetic and haemofiltration data. This
enables an assessment of both the quality of the data itself and the
ability to perform meta-analysis.
Further study is required in order to understand the high inter-person
variability in levetiracetam clearance and the in vivo effects of
different dosing strategies. Such data can be used to develop
pharmacokinetic models that will enable clinicians to determine
patient-specific dosing strategies. Future in vivo studies should
prioritise the collection of standardised data to facilitate
meta-analysis and modelling. Our recommendation is that this should
include the ADQI minimum reporting criteria alongside the following: (1)
IBW; (2) urine output; (3) baseline bloods (albumin, creatinine,
haematocrit, liver function); (4) dosing strategy; (5) a sampling
strategy that at a minimum includes pre-filter, post-filter and effluent
levels; (6) information on whether seizures were controlled or
uncontrolled. Standardisation will enable more robust modelling than is
possible at present.
In addition to in vivo studies, experimental study using
lab-based models that simulate critically ill patients undergoing CRRT
may be valuable. These studies, such as the latest ex-vivo in-vivo study
by Kalaria et al. [44] , would be useful in evaluating the
effects on clearance of different CRRT parameters and levetiracetam
dosing without the potential risk of exposing patients to possible
sub-therapeutic or toxic drug levels.