Design of Dosage form
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The document discusses various methods for designing dosage regimens, including individualized regimens based on pharmacokinetic measurements, population-based regimens, empirical regimens, and regimens based on partial pharmacokinetic data or nomograms. It also covers considerations for converting patients from intravenous to oral drug administration through sequential, switch, or step-down methods based on pharmacokinetic principles and calculations using steady-state drug concentrations and clearance. An example calculation is provided to determine an appropriate oral theophylline dosage based on intravenous aminophylline infusion rates.
Design of 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.