This post shows how 4 carbidopa/levodopa doses, suitably sized and suitably timed, can have approximately the same pharmacokinetics as Rytary.

rytaryPK.png

Like Sinemet, Rytary (IPX066) contains carbidopa/levodopa at a 1:4 ratio. But whereas normal Sinemet immediately (well, almost) releases all its contents into the stomach, a Rytary capsule contains beads, some of which are immediate release and some of which are delayed release, which are activated at different times.

The situation is explained in a paper by Mittur et al. [1]:
"The formulation contains four components: an IR [immediate release] component, ER [extended release] component 1, ER component 2, and a functional excipient component. The IR component, ER component 1, and ER component 2 contain both levodopa and carbidopa as active ingredients, while the fourth component does not contain levodopa or carbidopa but includes tartaric acid as a functional excipient serving as an acidifying agent designed to facilitate the absorption of levodopa. The four components of the ER carbidopa–levodopa formulation exhibit different individual drug-release characteristics and are designed to deliver the initial increase in levodopa concentrations and provide the sustained plasma profile."

The paper also contains graphs showing levodopa plasma levels against time that follow from the use of both IR C-L and Rytary. It is these graphs that I attempt to approximate. Note that the graph uses two different doses. For C-L the dose is 100mg of levodopa, and for Rytary it is 390mg.

Let's start with the first dose. The graph shows that Rytary gives levodopa plasma levels that plateau, very roughly, between 1 hour and 6 hours after the dose, before falling. The value of CMAX is roughly the same for 390mg of IPX066 as with 100mg of IR C-L. The only part of IPX066 that is in play at this time is the immediate release part, so bead type 1 must carry approximately 100mg levodopa. We use a dose of 100mg IR C-L to match this.

The paper says that the total bioavailability of Rytary is 70% as compared to IR C-L. That means that each capsule contains the equivalent of about 280mg of IR C-L. I assume that the loss of bioavailability comes from the ER components only. Therefore, having used 100mg levodopa on the first dose we are left with 180mg for any further doses.

Rather than use maths to estimate the other doses, I used a program that I posted about on this forum earlier:

Parkinson's Disease Measurement: PwP, surveys, trials, analysis

You input the names of the drugs that you take, their dose, and their time and, using pharmacokinetic parameters, the program, on a minute by minute basis, estimates your levodopa equivalent plasma levels. The program used a TMAX value of 60 minutes and for THALF a value of 81 minutes.

I played "what if" with the program, trying different possibilities. Out of this process came the following regimen that approximates the pharmacokinetics of 390mg of Rytary:

Dose 1: 100mg IR C-L, 0 hours
Dose 2: 60mg IR C-L, 1.5 hours
Dose 3: 60mg IR C-L, 3 hours
Dose 4: 60mg IR C-L, 4.5 hours

The graph is similar to that shown in the paper. The regimen could be optimised further, but it is important to note that we're dealing with estimates. Moreover, there are practical concerns, such as how to get a dose of 60mg, which make it not worth making the regimen even more complicated.

Reference:

[1] "Pharmacokinetics of Rytary®, An Extended-Release Capsule Formulation of Carbidopa–Levodopa"
Aravind Mittur, Suneel Gupta, Nishit B. Modi
Clinical Pharmacokinetics, Feb 2017
Pharmacokinetics of Rytary(R), An Extended-Release Capsule Formulation of Carbidopa–Levodopa | SpringerLink

John