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Dear Pharmacokinetists,
Can anyone knows how to calculate Loading dose and Maintenance dose
for the designing of Controlled Release Dosage forms.
Kindly reply.
Yours Sincerely
A. M. Deshmukh
E. Mail : abhijitd_2000.at.rediffmail.com
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Dear Mr. Deshmukh,
One general method (one compartment drug) is as follows:
LD = Io/ke, where LD is the loading dose (mg) , Io = the dosage form
zero order
release rate (mg/hr) and ke is the overall elimination rate constant of the
drug.
LD is also equal to Cpss* Vd where Cpss is the steady state target
conc., and Vd
is volume of distribution of the drug.
Hope this helps.
Sri
Srikumaran Melethil, Ph.D.
Professor of Pharmaceutics and Medicine
University of Missouri-KC
203 B Katz Hall, School of Pharmacy
5005 Rockhill Road
Kansas City, MO 64110
816-235-1794 (voice); 816-235-5190 (fax)
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I would like to hear some additional discussion on the topic of how
absorption is quantified. I have seen pk models that included an absorption
constant for the modeled drug but I have no idea where such constants can be
obtained other than to try to feather them out of clinical data. Is there any
data base of "absorption" constants and what factors would need to be
considered to use them?
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In the Land of OZ (not far from where I live -- "this ain't Kansas") it
seems easier to say:
LD= TC * Vd
MDR= TC * CL
LD=Loading Dose
TC=Target Conc (not necessarily SS)
MDR=Maintenance Dose Rate
CL=Clearance
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Dr.Deshmukh,
Formulas for calculating oral loading doses and maintenance
doses are available in references such as Winter's Basic Clinical
Pharmacokinetics.
I) Loading dose
Loading doses are usually calculated using the estimated
volume of distribution based on the patient's weight and the
literature value for the drug.
Loading dose= Cp x Vd/[FS)
Cp= plasma concentration desired (literature based)
Vd= volume of distribution
F= fraction of drug absorbed
S= fraction of drug salt form which is active drug
A good example is digoxin, in which the literature-based values
for Vd and Cl are relatively complicated.
a) Digoxin pharmacokinetic parameters
Cp 0.8-2ug/L
F 0.7 for Tablets
S 1.0
Vd (L) 3.8(Wt in Kg)+ 3.1(CrCl as ml/min)
Cl (ml/min) 0.8ml/kg/min(Wt in Kg)+ CrCl(ml/min)
Cl CHF (ml/min) 0.33ml/kg/min(Wt in Kg) + 0.9(CrCl)
T1/2 2 days
b) Loading dose Calculation
A 70kg, 68 inch, 70 year old male with a serum creatinine of
1.4mg/dl being treated for CHF;
Cp 1.5ug/L
F 0.7
S 1.0
IBW 50kg + 2.3kg(8)= 68.4 kg
CrCl (140-age)(IBW)/Secr(72)= 47.5 ml/min
Vd= 3.8(70kg) + 3.1(47.5)= 413.25 liters
Cl CHF 0.33(70) + 0.9(47.5)= 65.85 ml/min
Loading dose= Vd(Cp)/FS= (413.25L)(1.5ug/L)/(.7)(1)=885.54 ug~= .75mg
= three 0.25mg tablets
b) Maintenance dose calculation
Maintenance dose= (Cl)(Css ave)(Tau)/SF
Cl= Clearance = 65.85ml/min= 3.951 liters/hour
Css ave= 1.5ug/ml
Tau= 24 hours
S= 1
F= 0.7
Maintenance dose= (3.951 L/hr)(1.5ug/L)(24hrs)/(1)(0.7)=203.194 ug
= 0.203 mg ~= 0.25mg
The same equations can be used for sustained release, but the
choice of Tau will depend on the sustained release properties of
the dosage form. For example, if the medication is slowly released
over 12 hours (eg Theodur), then the choice of Tau would be 12 hours
and this would determine the maintenance dose according to the above
equation.
Considerations of the drugs Cpss max and Cpss min can also be
used in determining the maintenance dose and Tau:
Cpss max= (F)(S)(Dose)/(Vd)(1-e-KTau)
Cpss min= Cpss max(e-KTau)
Tau= (1/K)(ln (Cpss max/Cpss min)
With a sustained release form, there would be less fluctuation
in the Cpss max and Cpss min for a given Tau, allowing longer Tau's.
More complicated models would include the first order oral absorption
model, but this might not be as useful clinically.
Mike Leibold, PharmD, RPh
ML11439.-a-.goodnet.com
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Vahn:
It's an old reference now but one of the origins of an absorption
constant came from the Glasgow, Scotland, group interested in
gastric emptying. They derived an absorption constant for
acetominophen from a correlation of the t and Cmax, ie: the slope
of the rise to tmax. (Clements JA et al 1978, Kinetics of
acetominophen absorption and gastric emptying in man. Clin
Pharmac Ther, 24, 420-431). If it would be of interest and when I
get my hands on a copy I can send you some info on the equation
they derived.
Andrew Sutton.
Andrew Sutton MD
Guildford Clinical Pharmacology
ASutton.-a-.gcpl.co.uk
+44 (0) 1483 406886
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Dear Drs. Deshmukh and Liebold:
About digoxin and its PK parameters, it is useful to consider
the work of Reuning, Sams, and Notari, who showed that the inotropic
effect of digoxin does not correlate with events in the central or
serum compartment, but rather with those in the peripheral, nonserum
compartment. (Reuning, Sams, and Notari, Role of pharmacokinetics in
drug dosage adjustment. Pharmacologic effects, kinetics, and apparent
volume of distribution of digoxin. J. Clin. Pharmacol. 13: 128-41,
1973).
This model has been very useful to us in planning,
monitoring, and adjusting digoxin dosage regimens for many years, to
achieve clinically selected target goals in the peripheral, not
central, compartment, adjusted to a patient's age, gender, weight,
and renal function. The USC*PACK programs have used a slightly
modified version of this model to analyze digoxin behavior in
patients, and to develop dosage regimens to achieve selected target
goals not only in the serum compartment, but especially in the
peripheral compartment. We think their model is really useful
clinically. This was discussed in an article in Therapeutic Drug
Monitoring, 15: 380-393, 1993.
Such a model lets you see the important exchanges between
serum and nonserum compartments, and gives, I think, a much richer
clinical insight into what is going on with patients, not just in a
steady state situation, but in unstable and rapidly changing
patients, where you need to capture the dynamic behavior of the drug,
select a target therapeutic goal chosen for that patient according to
his/her needs for the drug, and clamp the patient there by developing
a dosage regimen specifically designed to do the job. Many
cardiologists feel strongly that monitoring serum levels is not
useful, and I think they are right, because only the raw data are
usually considered, models of only one compartment are used, and
dosage regimens are often developed only for steady state
situations, which are not useful for many patients.
Please consider this really super model of Reuning and
colleagues when using digoxin. It is really super!
Best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.at.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
******
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Dear Dr.Deshmukh,
you can find the calculation of loading dose and
maintainance dose in Remington's text book of pharmaceutical
sciences. in that the author has given a detailed description of
how to calculate the loading dose and maintainance dose in two cases
ie 1)if the release from the maintainance dose portion starts after
a stipulated time and 2) if the release from the maintainance portion
starts immediately after giving the formulation.
you just go through the reference.
B.Ravi Kanth
Dept. of Drug Metabolism and Pharmacokinetics
Dr.Reddy's Research foundation
Hyderabad
bravikanth.at.hotmail.com
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)