Factors considered during Designing dosage form

1. Design of
Dosage Regimen
Dr. Ramesh Bhandari
Assistant Professor
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi

2. Difference between dosage
form and dosage regimen
Dosage form: the way in which a therapeutic agent
in taken or administered (tablet, capsule, spray).
Dosage regimen: the schedule of doses per unit of
time ( no. of doses and interval).

3. Introduction
• Dosage regimen design is the selection of drug
dosage, route, and frequency of administration in an
informed manner to achieve therapeutic objectives.
• At the same time, the variability among patients in
pharmacodynamic response demands individualized
dosing to assure maximum efficacy.
• Planning of drug therapy is necessary because the
administration of drugs usually involves risk of
untoward effects.

4. Several Methods Used to Design a Dosage Regimen
1) Individualized Dosage Regimen
2) Dosage Regimens based on Population averages
3) Dosage Regimens based on Partial Pharmacokinetic
parameters
4) Empirical Dosage Regimen
5) Nomogram and Tabulation in Dosage Regimen

5. 1) Individualized Dosage Regimens
Most accurate approach
 Dose calculated based on the pharmacokinetics of the drug
in the individual patient derived from measurement of serum
/ plasma drug levels
Not feasible for calculation of the initial dose, however, once
the patient has been medicated, readjustment of the dose
may be done.
Most dosing program record the patient’s age and weight and
calculate the individual dose based on creatinine clearance
and lean body weight.

6. 2) Dosage regimen based on population
Averages
The method most often used to calculate a dosage
regimen is based on average pharmacokinetic
parameters obtained from clinical studies published in
the drug literature.
There are 2 approaches followed:
a) Fixed model
b)Adaptive model

7. a) Fixed Model
• Assumes that population average pharmacokinetic parameters
may be used directly to calculate a dosage regimen for the
patient, without any alteration.
• The practitioner may use the usual dosage suggested by the
literature and then make a small adjustment of the dosage
based on the patient’s weight and / or age
• Usually, pharmacokinetic parameters such as Ka, F, Vd, k are
assumed remain constant and most often drug is assumed to
follow one compartment open model
• When a multiple dose regimen is designed, multiple dosage
equations based on the principle of superposition are used to
evaluate the dose.

8. b) Adaptive Model
• Attempts to adapt or modify dosage regimen according to the
need of the patient.
• Uses patient variable such as weight, age, sex, body surface
area, and known patient’s pathophysiology such as, renal
disease, as well as known population average pharmacokinetic
parameters of the drug.
• This model generally assumes that pharmacokinetic parameters
such as drug clearance do not change from one dose to the
next.
• However, some adaptive models allow for continuously adaptive
change with time in order to simulate more closely the changing
process of drug disposition in the patient, especially during a
disease state.

9. 3) Dosage regimen based on partial PK
Parameter
• For many drugs, the entire pharmacokinetic profile for the drug is
unknown or unavailable.
• Therefore, the pharmacokineticist needs to make some assumptions in
order to calculate the dosage regimen.
• These assumptions will depend on the safety, efficacy, and therapeutic
range of the drug.
• The use of population pharmacokinetics uses average patient
population characteristics and only a few serum / plasma
concentration from the patient
• Population pharmacokinetic approaches to therapeutic drug monitoring
have increased with the increased availability of computerized data
bases and development of statistical tools for the analysis of
observational data.

10. 4) Empirical Dosage Regimen
• In many cases, physician selects a dosage
regimen of the patient without using any
pharmacokinetic variables.
• The physician makes the decision based on
empirical clinical data, personal experience and
clinical observations.

11. 5) Nomograms andTabulation in Designing
Dosage Regimen
• For ease of calculation of dosage regimens, many
clinicians rely on nomograms to calculate the proper
dosage regimen for their patients.
• The use of nomogram may give a quick dosage regimen
adjustment for patients with characteristics requiring
adjustments such as age, body weight, and physiologic
state.
• In general, nomogram of a drug is based on population
pharmacokinetic data collected and analyzed using a
specific pharmacokinetic model.

12. Nomograms andTabulation in Designing
Dosage Regimen
• A nomogram typically has three scales: two scales represent
known values and one scale is the scale where the result is
read off.
• The known scales are placed on the outside; i.e. the result
scale is in the center.
• Each known value of the calculation is marked on the outer
scales and a line is drawn between each mark.
• Where the line and the inside scale intersects is the result.
• Examples include: height – BMI – weight,
total clearance – maintenance dose – lean body weight, etc.

13. Nomograms andTabulation in Designing
Dosage Regimen
• In order to keep the dosage regimen calculation simple,
complicated equations are often solved and their results
displayed diagrammatically on special scaled axes to produce
a simple dose recommendation based on patient information.
• Some nomograms make use of certain physiologic parameters,
such as serum creatinine concentration, to help modify the
dosage regimen according to renal function.
• For many marketed drugs, the manufacturer provides tabulated
general guidelines for use in establishing a dosage regimen for
patients, including loading and maintenance doses.

14. Examples of drugs for which nomograms are being used
for designing dosage regimen:
• Theophylline
• Aminoglycosides:Tobramycin sulfate
• Warfarin
• Digoxin etc.

15. CONVERSION FROM
INTRAVENOUS INFUSIONTO ORAL
DOSING

16. Importance of IV to PO Conversion
oral formulations are easier to administer, safe, and
achieve desired therapeutic concentrations, thus making
the PO route an ideal choice.
More Comfortable
Cost Effective: reduces hidden expenses
IV therapy restrict the movement and make more
prone to IV related adverse effects.
Furthermore, IV route make portal for bacteria and
fungal infections.

17. Types of IV to PO therapy
Conversion
1) Sequential Therapy
2) Switch Therapy
3) Step-down Therapy

18. 1) SequentialTherapy
It refers to the act of replacing a parenteral version of a
medication with its oral counterpart.
There are many classes of medications that have oral
dosage forms that are therapeutically equivalent to the
parenteral form of the same medication.
E.g. conversion of famotidine 20 mg IV to famotidine
20 mg PO.

19. 2) SwitchTherapy
Used to describe a conversion from an IV medication to
the PO equivalent that may be within the same class and
have the same level of potency, but is a different
compound.
An example is the conversion of IV pantoprazole to
rapidly dissolving lansoprazole tablets omeprazole
capsules.

20. 3) Step-downTherapy
It refers to converting from an injectable medication to
an oral agent in another class or to a different medication
within the same class where the frequency, dose, and the
spectrum of activity (in the case of antibiotics) may not
be exactly the same.
Converting from ampicillin 3 g IV q 6 hr to amoxicillin
875 mg PO q 12 hr is an example of step-down therapy.

21. SELECTION OF PATIENT FOR IVTO
POTHERAPY CONVERSION
I. Intact and functioning of GI tract
II. Improving patient condition
III.Doesn't meet exclusion criteria
IV.Others

22. Pharmacokinetic Consideration
• For oral medications, bioavailability may be less due to
the variability in the rate and extent of dissolution of
the oral form and the total amount that is absorbed into
the systemic circulation.

23. • When intravenous infusion is stopped, the serum drug
concentration decreases according to first-order
elimination kinetics.
• For most oral drug products, the time to reach steady
state depends on the first-order elimination rate
constant for the drug.
• Therefore, if the patient starts the dosage regimen with
the oral drug product at the same time as the intravenous
infusion is stopped, then the exponential decline of
serum levels from the intravenous infusion should be
matched by the exponential increase in serum drug
levels from the oral drug product.

24. • Following two methods may be used to calculate an
appropriate oral dosage regimen for a patient whose
condition has been stabilized by an intravenous drug
infusion.
• Both methods assume that the patient’s plasma drug
concentration is at steady state.

25. METHOD I
C∞
av = SFD0 / k Vd τ
D0 / τ = C∞
av . k Vd / SF
Where, S is the salt form of the drug and D0 / τ is the dosing
rate

26. METHOD II
• This method assumes that the rate of intravenous
infusion (mg/hr) is the same desired rate of oral
dosage.

27. EXAMPLE
• An adult male asthmatic patient (age 55, 78 kg) has been
maintained on an IV infusion of aminophylline at a rate
of 34 mg/hr. The steady state theophylline drug
concentration was 12 µg/mL and total body clearance
was calculated as 3.0 L/hr. Calculate an appropriate oral
dosage regimen of theophylline for this patient.
(Aminophylline is a soluble salt of theophylline and
contains 85% theophylline (S = 0.85). Theophylline is
100% bioavailable (F = 1) after an oral dose.)

28. Solution by Method - I
We know, D0 / τ = C∞
av . k Vd / SF
But, total body clearance (ClT) = kVd
Therefore,
D0 / τ = C∞
av ClT/ SF
• The dose rate (34 mg/hr) was calculated on the basis of aminophylline dosing.
• The patient however will be given theophylline orally, to convert to oral
theophylline S and F should be considered
Oral theophylline dose rate = SFD0 / τ = (0.85) (1) (34) / 1 = 28.9 mg / hr
• Therefore the total daily dose is 28.9 mg/hr x 24 hr or 693.6 mg/day
• Possible theophylline schedules might be 700 mg/day.
• The dose of 350 mg every 12 hours could be given in sustained-release form to
avoid any excessive high drug concentration in the body.

29. Solution by Method - II
Rate of IV infusion is 34 mg/hr and so the daily
dose is 34 mg/hr x 24 = 816 mg/day.
The equivalent dose in terms of theophylline is
816 x 0.85 = 693.6 mg.
Thus the patient should receive approximately
700 mg of theophylline per day or 350 mg every
12 hours.