Question: Perampanel is an oral antiseizure medication that may occasionally be used for refractory status epilepticus. It has a half-life of 105 hours. Different sources recommend three different regimens for its dosing:
- (a) 18-24 mg load followed by 12 mg/day.(33830480)
- (b) 32 mg load followed by 12 mg/day.(31565443)
- (c) 36 mg on day #1, 24 mg on day #2, then 12 mg/day subsequently.(35605086)
We don't have enough clinical data to tell which regimen works best. Which of these regimens makes the most sense based on pharmacokinetics?
Let's start with three basic pharmacokinetic equations:
We want to solve for the loading dose, in terms of stuff we know. The first step is rearranging Equation #3 to yield the the volume of distribution (Equation #4 below). This can then be substituted into Equation #1, thereby eliminating the volume of distribution:
The next step is rearranging Equation #2 to yield the concentration (Equation #6 below). The target concentration and the steady state concentration should be the same. This concentration can then be substituted into Equation #5, to yield our final equation for the loading dose (#7 below).
This final equation is pretty useful, because it allows us to estimate the loading dose of any medication based solely on the maintenance dose, dosing interval, and half-life (information which is readily available).
In the case of perampanel, if we use a daily dose of 12 mg, dosing interval of 24 hours, and half-life of 105 hours this yields a loading dose of 75 mg! That's a really big dose, and perhaps too large of a dose to be given safely all at once (or perhaps not, I'm not sure). But this implies that among the various published dosing schemes, the 36 mg – 24 mg loading scheme (choice c above) is the most pharmacokinetically sensible approach.
This math emphasizes that an aggressive loading dose is required to reach therapeutic concentrations rapidly. For an intubated patient in refractory status epilepticus, we don't have two weeks to wait while the drug level achieves a therapeutic level!
To check our work, there is another, entirely different approach to calculating the loading dose. A loading dose should ideally achieve the same concentration as an infinite series of preceding maintenance doses (as would occur for a patient in steady state). Thus, the loading dose can be calculated as an infinite sum using the following equation:
This is easily calculated using a spreadsheet on Microsoft Excel, and it yields nearly the same answer:
The two methods don't yield precisely the same answer because Equation #2 approximates the steady-state drug concentration as fixed over time (whereas in reality it will fluctuate somewhat). Alternatively, the infinite sum (Equation #8) requires no approximations, making it the exact answer. In clinical practice, the difference is irrelevant (75 vs. 82 mg).
So that's it. One of my pet peeves is mismatch between loading doses and maintenance doses (e.g., dosing dexamethasone, a drug with a biological half-life measured in days, as 4 mg IV q6 without a loading dose 😤). Maybe these equations can get us a baby step closer to mathematically coherent dosing regimens.
Addendum! A pharmacist on twitter (@phil_c89) alerted me to a faster way to do this using the formula below. The formula below is based on the use of the accumulation index:
In this case, applying the formula yields a value of 82 mg – which matches the infinite-sum strategy precisely. This is equivalent to calculating the infinite sum, but it's much easier:
More on pharmacokinetics from the deranged physiology blog:
- Pulmcrit wee: The cutoff razor - April 15, 2024
- PulmCrit Blogitorial – Use of ECGs for management of (sub)massive PE - March 24, 2024
- PulmCrit Wee: Propofol induced eyelid opening apraxia – the struggle is real - March 20, 2024