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Dosage Regimen

Presented By…Shah Vrushank N.

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Introduction Multiple Dosing Designing of Dosage regimen Concept of Loading Dose. Maintenance Dose. Accumulation Index. References

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Introduction Definition :- Dosage regimen is defined as the Manner in

which a drug is taken. For successful therapy, design of an optimal multiple dosage

regimen is necessary. Multiple dosage regimen:- is defined as the manner in which

the drug is administered in suitable doses by suitable route, with sufficient frequency that insures maintenance of plasma conc. within therapeutic window for entire period of therapy.

In designing a dosage regimen:-• All p’kinetic parameters of the drug remain constant during the

course of therapy once the Dosage regimen is established.• The calculations are based on one- compartment model which

can also applied for two- compartment models. β KE Vd,ss Vd

Definisi: - Dosis regimen didefinisikan sebagai Manner di mana obat diambil.

Untuk terapi sukses, desain dari beberapa regimen dosis optimal diperlukan. Beberapa dosis rejimen: - didefinisikan sebagai cara di mana obat diberikan

dalam dosis yang sesuai dengan rute yang sesuai, dengan frekuensi yang cukup yang menjamin pemeliharaan conc plasma. dalam jendela terapi untuk seluruh masa terapi.

Dalam merancang regimen dosis: - Semua parameter p'kinetic obat tetap konstan selama terapi setelah rejimen

Dosis didirikan. Perhitungan didasarkan pada model satu kompartemen yang juga dapat

diterapkan untuk model dua-kompartemen. β KE     Vd, ss Vd

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In Designing dosage regimen the two major parameters that can be adjusted in developing a dosage regimen are…

1) The Dose size – The qty. of Drug administered.

Greater dose size greater fluctuation btw Cssmax, & Cssmin and greater chance of toxicity

2) The Dosing frequency – The time interval between Doses.

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Design of dosage regimen from plasma concentration :

If the Vd and clearance or half life of the drug is known, then dosage regimen can be design to maintain the drug conc. in the therapeutic range.

Maximum dosing interval which ideally depends upon the therapeutic index and elimination half life of the drug can be expressed as :

max = 2.303 log ( Cupper / Clower ) זז KE

Where KE = 0.693/t1/2

Desain regimen dosis dari konsentrasi plasma

Jika Vd dan pembersihan atau paruh obat diketahui, maka regimen dosis dapat desain untuk menjaga conc obat. dalam kisaran terapeutik.

Interval pemberian dosis maksimum yang idealnya tergantung pada indeks terapeutik dan eliminasi paruh obat dapat dinyatakan sebagai:

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max = 3.32 t1/2 log ( Cupper / Clower ) זז Mostly dosing interval selected is always smaller than זז max

the maximum maintenance dose X0max can be expressed as

X0max = Vd ( Cupper - Clower ) FAfter the convenient dosing interval זז , , smaller thansmaller than זז max has

been selected, maintenance dose is given as :

X0 = Css,av = Xo max

maxmax זזזז

( Cupper / Clower )

2.303 log ( Cupper / Clower )

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Multiple dosing

For chronic diseases, there is necessity of multiple dosing i.e. administration of drugs in number of frequencies.

On continuous steady administration of a drug, plasma concentration will rise fast at first then more slowly and reach a plateau, where:

Rate of administration = Rate of elimination ( steady state is achieved )

Therefore, at steady state:Dose (Rate of Administration) = Clearance x Plasma conc.

OrIf you aim at a target plasma level and you know the clearance,

you can calculate the dose required.`

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Effect of multiple doses

If the plasma concentration prior to next dose is >0 concentration and elimination is of first order, then plasma concentration will increase Increase in elimination rate and eventually steady state.

– For first order elimination kinetic the time to obtain steady state is dependent only of the half time of the drug

– The steady state concentration is determinated by dose (D) and dose frequency

 

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Effects of dose and dose frequencyEffects of dose and dose frequency  

Increase in doseIncrease in dose – Increase in CIncrease in Cmeanmean

– Larger difference between CLarger difference between Cmaxmax and C and Cmin min

– Increased risk for side effects for drugs with small Increased risk for side effects for drugs with small therapeutic windows therapeutic windows

Increase in frequencyIncrease in frequency – Increase in CIncrease in Cmeanmean – Larger inconvenience for patient Larger inconvenience for patient

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Loading Dose

Concept of loading dose 

For drugs with long half-lives, the time to reach steady state might be long. It takes about 5 half- lives to reach steady state.

In a such cases the plateau can be achieved by administering a dose that gives the desired steady- state. Such an initial/ first dose is called as Loading dose.

XXo,o,L =L =CCss,avss,av VVdd

FF

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When Vd is not known then loading dose may be calculated as

The above eq. is applied when Ka >> Ke & drug is distributed rapidly.

But in case of I.V. route the absorption is very fast therefore , absorption phase is neglected then above eq.

XXooLLXX00 (1 –e (1 –e ––

KaKaזז) ) (1 – e (1 – e –Ke –Ke זז

)

11=

XXo,o,LL XX00

=1 – e 1 – e -Ke-Keזז

11= R= Racac

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Maintenance Dose

After the loading dose is given the another dose (I.V) is given to maintain the steady- state drug conc. Or plateau. Such dose is known as maintenance dose.

i.e. maintain the response of drug by replacing drug lost during dosing interval.

Maintenance dose = loading dose x ( 1- e -kז)

Loading dose =maintenance dosemaintenance dose

1 – e 1 – e -K -K זז

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The ratio of loading dose to maintenance dose (X0L/X0) is called as dose ratio

When ז = t1/2 the dose ratio =2.0

When ז > t1/2 the dose ratio < 2.0

when ז < t1/2 the dose ratio >2.0

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Accumulation Index

In case of multiple dosage regimen (drugs are frequently administered) in such a cases the 1st drug conc. remaining in a body after certain time, is added to the next dose, this condition is known as ‘Accumulation’

The accumulation occurs because previous doses has not been removed completely from body.

After some time the rate of absorption is equal to rate of elimination i.e. conc. of drug in plasma approaches to a constant value this condition is called as steady- state, plateau/ infusion equilibrium.

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Consider the Amount of drug in the body-time profile as shown in the Graph.

After admin of first dose X0 = 1X0 At next dosing interval when X = ½ X0, amt of drug

remaining in the body Admin of next i.v. dose raises the body content to X = X0 + 1/2 X0

As the amount of drug in the body rises gradually due to Accumulation, the rate of elimination also rises proportionally until a steady-state or Plateau is reached.

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The maximum & minimum values of X i.e. Xss,max & Xss,min approach respective asymptotes at plateau.

Plateau Xss,min = 1X0 ( amt of drug in body after first dose ) Xss,max = 2X0 ( equals twice the first dose)

Also (Xss,max - Xss,min) = X0

Xss,max / Xss,min = 2

All this applied only when ז = t1/2

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When ז < t1/2 , the degree of Accumulation is greater & vice-versa.

Thus, the extent to which a drug accumulates in the body during multiple dosing, is a function of dosing interval & elimination half life & is independent of dose size.

The extent to which a drug will accumulate with any dosing interval in the patient can be derived from information obtained with a single dose and is given by accumulation index Rac as:

=Rac1

1-e -KE ז

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References

‘Applied Biopharmaceutics & Pharmacokinetics’ by Leon Shargel & Andrew B. C. Yu, 4th Edition

‘Biopharmaceutics & Pharmacokinetics’ A Treatise, D. M. Brahmankar & Sunil B. Jaiswal

‘Clinical Pharmacokinetics, Concepts & Application’, 3rd Edition,

by Malcom Rowland & Thomas N. Tozer, Lea & Febiger www.google.com