Seminar on… Dosage Regimen ByAmruta S. SambarekarDept. Of Pharmaceutics Maratha Mandal’s College of Pharmacy Belgaum.
Table of ContentsPART -IIAdjustment of Dosage in Renal Impairment.Adjustment of Dosage in HepaticImpairment.Individualization.Therapeutic Drug Monitoring.
Adjustment of Dosage in Renal ImpairmentIn patient with renal failure, the half life of the drug isincrease and its clearance drastically decreases if it ispredominantly eliminated by way of excretion.Hence, dosage adjustment should take into account therenal function of the patient and the fraction ofunchanged drug excreted in urine.There are two additional method for dose adjustmentin renal insuffiency if the Vd change is assumed to benegligible.
General Approach… No change in the desired or target plasma concentration. Diminished renal clearance but unchanged non-renal clearance. Unaltered drug protein binding & volume of distribution in the renally impaired patient. Unchanged drug absorption from the GIT.
Three Major Approaches are… Dose adjustment based on Total body clearance. Dose adjustment based on Elimination rate constant or Half life. Dose adjustment in renal failure.
Dose adjustment based on Total body clearance The average drug conc. at steady-state css,av is a function of maintenance dose X0 , the fraction of dose absorbed F, the dosing interval & זclearance Cl T of the drug. Css,av F X0 Cl T ז X0 Css,av F 1 ()ז Cl T ז X X 4
If ClT , X0 & זrepresents the values for the renal failure patient, then the eq. for dose adjustment is given as… X0 X0 Css,av ClT ז ClT ז Rearranging in terms of dose & dose interval to be adjusted, the eq. is… X0 ClT X0 ז ClT ז From the above eq., the regimen can be adjusted by reduction in dosage or increase in dosing interval or a combination of both. 5
Dose adjustment based on Elimination rate constant or Half life The average drug conc. at steady-state css,av is a function of maintenance dose X0 , the fraction of dose absorbed F, the dosing interval & זvolume of distribution vd & t1/2 of the drug. 1.44 F X0 t1/2 Css,av Vdז Where, the coefficient 1.44 is the reciprocal of 0.693. 6
1.44 F X0 Css,av X t1/2 X Vd ז To be kept Assumed increased due Needs normal constant to disease adjustmentIf t1/2 , X0 & זrepresents the values for the renal failurepatient, then the eq. for dose adjustment is given as… t1/2 X0 t1/2 X0 Css,av ז ז
Rearranging in terms of dose & dose interval to be adjusted, the eq. is… X0 t1/2 X0 ז t1/2 ז Because of prolongation of half life of a drug due to reduction in renal function, the time taken to achieve the desired plateau takes longer if the more severe is dysfunction, hence such patient sometimes need loading dose. 8
Diseases are the major source of variation in drug response.Both pharmacokinetic and Pharmacodynamic of many drugsare altered by disease other than the one which is beingtreated.Disease state : Renal dysfunction Uremia
Renal dysfunction :It greatly impair the elimination of drug especially those thatare primarily excreted by the kidney.Causes of renal failure are hypertension, diabetes mellitusUremia :It is characterized by impaired Glomerular filtration andaccumulation of fluid and protein metabolism.In both the cases the half life of the drug are increased as aconsequences drug accumulation and toxicity increases.
Adjustment of Dosage in Hepatic Impairment.The influence of Hepatic disorder on the drugbioavailability & disposition is unpredictablebecause of the multiple effects that liver produces.The altered response to drugs in liver diseasecould be due to decreased metabolizing capacity ofthe hepatocytes, impaired biliary elimination, due tobiliary obstruction (e.g. Rifampicin accumulates inobstruction jaundice)
Impaired Hepatic blood flow leading to an increase in bioavailability caused by a reduction in first pass metabolism (e.g Bioavailabilities of Morphine and Labetalol have been reported to double in patients with Cirrhosis) Decreased protein binding and increased toxicity of drugs highly bound to plasma protein (e.g. Phenytoin, Warfarin) due to impaired albumin production, altered volume of distribution of drugs due to increased extracellular fluid. 10
Oedema in liver disease may be increased by drugs that cause fluid retention (e.g. Acetylsalicylic acid, Ibuprofen, Prednisolone, Dexamethasone). Generally, drug doses should be reduced in patients with hepatic dysfunction since clearance is reduced & bioavailability is increased in such a situation. 11
Renal function determinationGlomerular filtration rate can be determined byfollowing two methods : Insulin clearance Creatinine clearance
For children (1-20 years) : Clcr =0.48 H X [W] 0.7 Scr For Adult (above 20 years) :Males, Clcr = (140 – age) W 72 x ScrFemales, Clcr =(140 – age) W 85 x Scr
A direct method for determining creatinineclearance is :Clcr = Rate of creatinine excretion Serum creatinine in mg %Renal function. RF is calculated by followingequation : RF= Clcr of patient Clcr of a normal person
Dose required by the patient with renal impairment : Normal dose X RFDosing interval : Normal interval/RFDose adjustment in renal failure when drug iseliminated both by renal and non renal mechanism :Normal dose = RF X [ fraction excreted X fraction eliminated] in urine non renally
Conclusion Ideally in planning ‘Dosage regimen’ drug dosage adjustment is important in all critically ill patients with organ failures. In treating such critically ill patients, drug treatment should be so carefully done in order to achieve steady state plasma concentration required within a known and safe effective therapeutic range. 12
Individualization of Therapy Same dose of drug may produce large differences in pharmacologic response in different individuals, this is called as intersubject variability. For the rational drug therapy, requires individualization of dosage regimen. To achieve optimum dosage regimen. 13
Sources of Variability1) Pharmacokinetic Variability : Due to differences in drug conc. at the site of action. Major causes are genetics, disease, age, body wt. & drug-drug interactions.2) Pharmacodynamic Variability : Due to differences in effect produce by a given drug conc.
For individualization of drug therapy, a drug must be available in dosage forms of different dose strengths. Depends on two major factors… i) Therapeutic Index & ii) The degree of intersubject variability. Hence, smaller the therapeutic index & greater the variability, more the no. of dose strengths required.
Steps involved in Individualization of Dosage regimen Estimation of pharmacokinetic parameters in individual patient & determining their deviation from the population values to evaluate the extent of variability. Attributing the variability to some measurable characteristics such as hepatic or renal disease, age, wt. etc. Designing the new dosage regimen from collected data. 16
Dosing of Drug in Obese Patient :IBW (men)=50Kg + 1Kg/2.5 cm above or below150 cm in heightIBW (women)=45Kg +1Kg/2.5 cm above or below 150cm in heightAny person whose body weight is more than 25% above the IBW is considered as obese.
Dosing of drug in Neonates, Infants & ChildrenMosteller’s equation:SA (in m2)=( height X weight )1/2 60Child’s maintenance dose can be calculated from adult dose by using the following equation :Child’s dose= SA of Child in m2 X Adult Dose 1.73 SA (in m2) = Body weight (Kg)0.7
The following relationship can also be written for child’s dose :Child’s dose= [weight of child in Kg] 0.7 X Adult dose 70Dosing of drug in elderly :A general equation that allows calculation of maintenance dose of any age except neonates & infants:Patient’s dose=(weight in Kg)0.7(140- age in years)XAdult Dose 1660
Therapeutic Drug Monitoring Management of drug therapy in individual patient often requires evaluation of the response of the patients to the recommended dosage regimen, known as Therapeutic drug monitoring. Depending on the drug & the disease to be treated, for management of drug therapy in individual patient, we need… 17
I. Monitoring Therapeutic effect : E.g. prevention of an anticipated attack of angina or shortening of duration of pain when attack occurs, through the use of Glyceryl trinitrate.II. Monitoring Pharmacologic actions : E. g. Blood glucose lowering with Insulin.III. Monitoring plasma drug conc. : E.g. Digoxin, Phenytoin etc. 18
Conclusion Successful application of this monitoring therapy requires complete knowledge of pharmacokinetic parameter of the drug, the situation in which this parameters are likely to be altered & the extent to which they could be altered, & a sensitive, specific & accurate analytical method for determination of drug concentration.
References ‘Biopharmaceutics & Pharmacokinetics’, A Treatise, D. M. Brahmankar & Sunil B. Jaiswal, Vallabh Prakashan, Pitampura, Delhi. ‘www.google.com ‘Text Book Of Biopharmaceutics & Pharmacokinetics”, Dr. Shobha Rani R. Hiremath. 20