Multiple Dosing Lecture

Question 1

If someone has a chronic disease its not going to be a single dose administration, normally you need the patient to receive several doses. For example if patient is suffering from an infection then normally they need to take multiple dose of the antibiotic if the patient is taking high blood pressure medication normally they are going to take multiple doses for several years its not just one single dose…we need to know what happens if patient is taking multiple doses

Question 2

When we have several doses we need to know how much means the dose 400mg, 100mg and the frequency that is the interval…between each and every dose there is an interval and this interval is normally fixed so there are times when we need to adjust the interval dose

Question 3

This tower interval is a fixed time so by now you learned in IV infusion we need 4 half lives to reach to steady state

Question 4

In order to achieve steady state it takes _______half lives

Answer 4

4 half lives

Question 5

From this plot your going to do something important; the accumulation of the drug from the first dose up to the steady state we are going to have a less fluctuating concentration or no fluctuating concentration in regards to the Cmax and Cmean meaning Cp trough basically its not indefinite means that at some point its not going to accumulate anymore its going to be constant…if you don’t have this principle accumulation is going to cause toxicity eventually…just imagine that accumulation doesn’t stop at this point and it goes up and up so definitely we are going to reach some sort of toxicity or toxic concentration at some point

Question 6

At steady state that is the maximum accumulation your going to have.Then after that if you keep the dose and interval of the drug consistent your going to have same peak and trough concentration during the therapy.

Question 7

A narrow therapeutic index not fluctuating over this minimum effective concentration and minimum toxic concentration and that can be achieved by knowing the principle of __________

Answer 7

superposition

Question 8

In chronic diseases we should apply in multiple dosing but in regards to your interval how we should determine the next dose time in other words what is important in identifying the best interval basically timing

Question 9

With a single IV bolus dose your going to give the entire dose to pt so Cmax occurs at t time zero and then we have a curvature here which is a typical first order elimination pattern and the drug is going to be eliminated from the body

Question 10

Now 2 scenarios, in scenario 1 we wait very long in regards to the half life in comparison w/ the half life…we wait a long time until the concentration is almost negligible in the plasma and then we are going to give the second dose in other words we are going to wait long enough until drug is clinically is cleared from the body as you can see no accumulation occurs there is no accumulation…the drug is going to be washed out of the body and then your going to give the second dose

Question 11

Each and every one of these doses are going to act like singularities…they are going to act like they are separate doses and they are not going to affect…there is no impact on accumulation of the drug..is this desirable or not? It is not acceptable because there is no accumulation now lets move on to the second scenario. In the second scenario compared to the half life we are going to reduce the interval time now when you actually give the first dose and the second dose. Second dose is going to build up on the concentration leftover from the first dose and third dose and fourth dose etc. its going to accumulate until it reaches a steady state. After steady state the Cmaximum and the Cminimum and obviously the concentration in between are going to be the same

Question 12

We need to adjust the interval compared to the half life to make sure we have accumulation.

Question 13

Degree of accumulation:Short half-life

Short half-life case (with respect to the dosing interval)

No accumulation, the body manages to eliminate all drug before next dose

Question 14

so this is not acceptable no accumulation happens this is NOT GOOD! Versus the second scenario which we have the accumulation and this is acceptable because at some point we are going to reach to steady state and we can actually keep the concentration of the Cmax and Cmean within the therapeutic index and that’s perfect so we are going to achieve the therapeutic goal of this medication

Question 15

Csteady state average…Caverage is not a mathematical mean of the Cmax and Ctrough
Caverage has its own definition…you look at slide 25 or 26 your going to see the way we have to calculate the Css average but we are actually going to calculate the Caverage a lot…this is probably the most important parameters that in practice and in clinic and in drug development that you use but keep in mind Caverage and Csteady state average is not the mathematical means of the Cmax and Cmean there are certain ways we can do the calculation I will mention this and I’m going to repeat it several times because in the past we had students in the exam when I asked them to calculate the Caverage they simply add the Cmax and Cmeans and then gave me the average that’s very wrong…conceptually wrong

Question 16

Caverage is not normally what we understand from an average that we actually add 2 values and then take the average that’s not the case here…same thing that I mentioned for IV infusion that the input and output are the same so at steady state also the rate of drug input and the rate of drug elimination are the same that’s why no more accumulation happens

Question 17

Always remember __________means input simple….input and output are the same

Answer 17

steady state

Question 18

If 50mg goes into the body…50 mg comes out of the body and that is the simple concept of the steady state…our assumption is one compartment so we are going to use the principle of one compartment and our model is open model means that we have an elimination system that eliminates the drug from the body. So again as I mentioned drug accumulation is not forever and normally after 4 half lives

Question 19

_________half lives its going to take to reach to steady state

Answer 19

4 half lives

Question 20

From now on when you see multiple dosing I want you to calculate time to reach to steady state then your going to compare it with the dosing time and then your going to figure out whether we are in steady state or not. If you are in steady state we are going to use the equation for steady state