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3. Clinical Phk-Dosing in special Population & TDM.pptx

This document discusses dosing considerations for various patient populations including infants, children, elderly patients, obese patients, and patients with renal impairment. It notes that infants and children require different dosing than adults due to differences in body composition, organ maturity, and pharmacokinetic parameters. The elderly also have altered pharmacokinetics due to changes in organ function, body composition, and drug absorption, distribution, metabolism, and excretion. Obese patients require dosing based on ideal body weight rather than actual weight. Patients with renal impairment require dose adjustments based on creatinine clearance to maintain therapeutic drug levels. Common methods for estimating creatinine clearance and adjusting doses based on clearance or elimination rate constant are presented.

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1 Application of Pharmacokinetics to Clinical Situations: Dosing in infant, children and elderly
Dosing of Drugs in Infants & Children  Preterm newborn infant,  Newborn infant (0-28 days),  Infant (28 days-23 months),  Young child (2-5 yrs),  Older child (6-11 yrs),  Adolescent (12-18 yrs), & the adult  Unfortunately, the phk & phd of most drugs are not well known in children ˂12 yrs of age.  With age there is differences in PhK due to  The variation in body composition &  the maturity of liver & kidney function 2 Infants & children have different dosing requirements than adults.  Here for convenience, "infants'' are children 0-2 yrs of age.  However, special consideration is necessary for infants ˂ 4 wks,  because their ability to handle drugs often differs from that of more mature infants.
3 Pharmacokinetic in infants  Distribution  many drugs exhibit reduced binding to plasma albumin.  Metabolism  Complete hepatic function is not attained until the 3rd wk.  Oxidative processes are fairly well developed in infants, but there is a deficiency of conjugative enzymes.  Renal excretion  Newborns show only 30–50% of the renal activity of adults
Comparison of Newborn & Adult Renal Clearances 4 Parameters Average Infant Average Adult Body weight kg 3.5kg 70kg Body water Percen t 77% 58% volume 2.7L 41L Inulin clearance Cl  3ml/min 130ml/min k 0.0011 min– 1 0.0032 min– 1 t1/2 630 min 220 min PAH clearance Cl 12 mL/min 650 mL/min k 0.0043 min– 1 0.016 min– 1 t1/2 160min 43min Inulin (*K) PAH (*K)  Infant k(min– 1)= 3/2700 = 0.0011 12/2700 = 0.0043  Adult k(min– 1)= 130/41,000 = 0.0032 650/41000= 0.016
5 Elimination Half-Lives of Drugs in Infants and Adults Drug Half-Life in Neonatesa (hr) Half-Life in Adults (hr) Penicillin G 3.2 0.5 Ampicillin 4 1–1.5 Methicillin 3.3/1.3 0.5 Carbenicillin 5–6 1–1.5 Kanamycin 5–5.7 3–5 Gentamicin 5 2–3 a0–7 days old
Practice Problem 6  The elimination half-life of penicillin G is 0.5 hour in adults and 3.2 hours in neonates (0 to 7 days old). Assuming that the normal adult dose of penicillin G is 4 mg/kg every 4 hours, calculate the dose of penicillin G for an 11-pound infant.  Solution  Therefore, this infant may be given the following dose: Dose = 4mg/kg = 11Lb/2.2Lb/kg = 20 mg every 24 hr  Alternatively, 10 mg every 12 hours would achieve the same C ∞ av.
Dosing of Drugs in the Elderly 7  Defining "elderly'' is difficult.  The geriatric population is often older than 65yrs  "older elderly'' population are often ˃85yrs  Chronologically, the elderly have been classified as  The young old (ages 65–75 years),  the old (ages 75–85 years), and  the old old (age > 85 years)  The aging process is more often associated with physiologic changes during aging rather than
Changes in old age 8 Physiology  Decreased in physiologic function complicates DR  Renal plasma flow, GFR, cardiac output, & breathing capacity can drop from 10% to 30% compared to those at age 30. Pharmacodynamic  Alterations in target drug receptors,  Quantitatively, the number of receptors decline with age  Qualitatively, a change in the affinity for the drug
9 Alterations in drug absorption   in the splanchnic blood flow, altered GI motility,   in gastric pH, and alteration in the GI absorptive surface. Alteration of distribution  Changes in plasma albumin & 1-acid glycoprotein   drug protein binding in the plasma as a result of  in the albumin conc.  Vd may change due to a  in muscle mass and an  in body fat.
10 Alteration of elimination  There is gradual reduction in the kidney size & function.   Renal excretion as a result of  in GFR &/or active secretion.  Both penicillin & kanamycin show  t1/2 in the aged patient   Hepatic drug clearance due to activity of the enzymes Changes in Renal Function with Age  In general GFR decline with age.  GFR decreases at a mean rate of 1%/yr after 40 yrs of age.  Since muscle mass & urinary CrCl decrease at nearly the same rate in the elderly, mean serum conc. may stay relatively constant.  CrCl measured by serum Cr conc. only may yield inaccurate GFR function if urinary CrCl is not measured.
Practice Problems 11 1. An aminoglycoside has a normal t1/2 of 107 min in young adults. In patients 70 to 90 yrs old, its t1/2 is 282 min. The normal dose of the aminoglycoside is 15 mg/kg per day divided into two doses. What is the dose for a 75-year-old patient, assuming that the Vd per body weight is not changed by the patient's age? Solution  The t1/2 in old patient is due to a  in renal function.  There is a good inverse correlation b/n t1/2 & clearance.  To maintain the same average conc. of the aminoglycoside in the elderly as in young adults, the dose may be reduced
12 Therefore, the same dose of the aminoglycoside may be administered every 32 h without affecting the average Css of the aminoglycoside. Keeping the dose constant, DN = Do, where DN is new dose & Do is the old dose
13 2. The clearance (Cl) of lithium was determined to be 41.5 mL/min in a group of patients with an average age of 25 yrs. In a group of elderly patients with an average age of 63 years, the Cl of lithium was 7.7 mL/min. What percentage of the normal dose of lithium should be given to a 65-year-old patient? Solution: The dose should be proportional to clearance; therefore,  The dose of lithium may be reduced to about 20% of the regular dose in the 65-year-old patient without affecting the steady-state blood level.
14 Application of Pharmacokinetics to Clinical Situations: Obese Patient
Dosing of Drugs in the Obese Patient 15  A patient is considered obese if actual body weight exceeds ideal or desirable body weight by 20%.  Obesity often is defined by body mass index (BMI), a value that normalizes body weight based on height.  BMI is expressed as body weight (kg) divided by the square of the person's height (meters) or kg/m2.
Dosing of Drugs in the Obese Patient 16 The obese patient (BMI > 30): total body water vs Vd  has a greater accumulation of fat (Adipose) tissue  Water of fat tissue < muscle tissue. Thus,  Total body water (TBW) of obese pt ˂ TBW of pt of ideal body weight (IBW), which could affect Vd of the drug.  For example, Vd of antipyrine in obese patients is (0.46 L/kg) whereas IBW patients is (0.62 L/kg)  Ideal body weight (IBW) refers to the normal weight for a male or female based on age, height & weight
17 The obese patient (BMI > 30): Body fat vs PhK  There is distributional changes in the drug's phks due to partitioning of the drug b/n lipid & aqueous env’t.  E.g. Very polar Drugs such as digoxin and gentamicin tend to distribute into water rather than into fat tissue.  lipophilic drugs are associated with larger Vd in obese patients compared to hydrophilic drugs Other pharmacokinetic parameters altered  as a result of physiologic alterations, such as  fatty infiltration of the liver affecting biotransformation &  cardiovascular changes that may affect renal blood
18  Dosing by actual body weight may result in overdosing of drugs such as aminoglycosides (eg, gentamicin), which are very polar and are distributed in ECF.  Dosing of these drugs is based on ideal body weight.  Lean body weight (LBW) has been estimated by several empirical equations based on the patient's height and actual (total) body weight.
19 The following equations have been used for estimating lean body weight, particularly for adjustment of dosage in renally impaired patients: Example  Calculate the lean body weight for an adult male patient who is 5 ft 9 in (175.3 cm) tall and weighs 264 lb (120 kg). Solution
Application of Pharmacokinetics to Clinical Situations: Dose adjustment in renal failure
Introduction  Role of kidney  regulating body fluids, electrolyte balance,  removal of metabolic waste, and drug excretion from the body.  Impairment/degeneration of its function affects the phk of drugs.  Some of the causes of its failure include disease, injury, and drug intoxication.
Introduction… Common Assumptions in Dosing Renal-Impaired Patients  CrCL accurately measures the degree of renal impairment  Drug follows dose-independent pharmacokinetics  Nonrenal drug elimination remains constant  Drug absorption remains constant  Drug clearance, Clu, declines linearly with creatinine clearance, ClCr  Unaltered drug protein binding  Target drug concentration remains constant
Introduction… Group Description Estimated CrCl (mL/min) 1 Normal renal function >80 mL/min 2 Mild renal impairment 50–80 mL/min 3 Moderate renal impairment 30–50 mL/min 4 Severe renal impairment <30 mL/min 5 ESRD-end-stage renal disease Requires dialysis Renal Impairment and Creatinine clearance ClCr
Determination of Creatinine clearance  ClCr is most often estimated from the patient's Serum Cr conc, CCr , due to the difficulty of collecting 24 hr urine  The most methods are based on the patient's age, height, weight, and gender. 1. Cockcroft and Gault formula: Adults  For males,  For females, use 85% of the ClCr value obtained in males
Example: What is ClCr for a 25-year-old male patient (5 ft, 4 inches in height & weighs 103 kg) with a CCr of 1 mg/dL? Solution  The patient is obese and the ClCr calculation should be based on ideal body weight.  LBW (males) = 50kg + 2.3kg for each inch over 5 ft = 50kg + 2.3kg x 4 = 59.2kg  Using the Cockcroft and Gault method, the ClCr is
Example:  Bon Josh is a 43 year-old, 50 kg male. The following serum creatinine measurement was returned from the clinical laboratory: SrCr = 1.5 mg/dL.  Estimate Creatinine clearance for B.J.
2. The nomogram method  Siersback-Nielsen et al (1971) estimates ClCr on the basis of  age,  weight, &  Serum CCr
How to use nomogram? Steps  Join the points at age (yrs) & weight with a ruler-let the line intersect line R.  Connect the intersection point at line R with the CCr point, and extend the line to intersect the "clearance line."  The extended line will intersect the clearance line giving the ClCr. Example. What is the ClCr for a 25-year-old male pt with CCr of 1 mg/dL & a body weight of 80 kg?  Solution  join the points at 25 years (male) & 80 kg with a ruler-let the line intersect line R.  Connect the intersection point at line R with the CCr point of 1 mg/dL, and extend the line to intersect the "clearance line."  The extended line will intersect the clearance line at 110 mL/min, giving the ClCr for the patient.
Children  There are a number of methods for calculation of ClCr in children, based on body length and serum creatinine conc.  where ClCr is given in mL/min/1.73 m2.
General Approaches for Dose Adjustment in Renal Disease  Several approaches are available for estimating the appropriate DR. Most of these methods assume that  Plasma [drug]uremic = Plasma [drug] normal renal  Uremic patients are  maintained on the same C∞ av after multiple oral doses or IV bolus injections.  For IV infusions, the same C SS is maintained.
1. Dose Adjustment Based on Drug Clearance A) C∞ av after multiple oral doses or IV bolus injection is  Where ClT is Normal total body Cl is  Therefore, to maintain the same desired C∞ av,  the dose, Do, must be changed to a uremic dose, Du 0 or  the dosage interval, , must be changed to u,  where the superscripts N and u represent normal and uremic conditions, respectively. Total body clearance of the uremic patient is Clu T.
 Rearranging Equation and solving for Du 0.  If  is kept constant, then the uremic dose Du 0 = fraction (Clu T/ClN T) of DN 0 B) For IV infusions the CSS uremic pt = CSS normal renal pt  The rate of infusion, R, must be changed to a new value, Ru, for the uremic patient,
2. Dose Adjustment Based on Changes in the Elimination Rate Constant, K  The overall K for many drugs  in the uremic pt.  A DR may be designed for the uremic patient either  by  Do of the drug and keeping  constant, or  by   and keeping the Do constant.  Assuming the VD is constant, then Du 0 is a fraction (ku/kN) of the DN 0 :
Dose Adjustment Based on K… Nomograms  Are charts used in estimating DR in uremic patients.  Are based on serum Cr conc., patient data (height, weight, age, gender), & the phk of the drug.  Provides an estimate of the ratio of uremic ku to normal (kN) on the basis of creatinine
Dose Adjustment Based on K…  Uremic dose ( is kept constant) can be estimated according to Equation Uremic dose = ku/kN x Normal dose Du 0 = DN 0 (ku/kN) Dosage interval  in Uremia (dose is kept constant) u = ku/kN x N  Where N is the dosage interval in normal renal function.
Practice Problem Lincomycin is given at 500 mg every 6 hours to a 75-kg normal patient.  What doses would be used (a) in complete renal shutdown (ClCr = 0) and (b) when ClCr = 10 mL/min? Solution  To use the nomogram method, follow the steps below:  1. Locate the group to which the drug belongs in the nomogram.  2. Find k u/k N at the point corresponding to the Cl Cr of the patient.  3. Determine ku for the patient.  4. Make the dose adjustment in accordance with pharmacokinetic principles.
41 Application of Pharmacokinetics to Clinical Situations: Therapeutic Drug Monitoring
1. Introduction… 42 What is Therapeutic drug monitoring?  Individualization of dosage by maintaining Cp within a target range  optimize patient management & improve clinical outcomes It involves Measuring [drug] in plasma & interpreting these conc. in terms of relevant clinical parameters. 3/11/2023 TDM
1. Introduction… 43 Why therapeutic drug monitoring?  TDM can guide the clinician to provide effective and safe drug therapy ¡n the individual patient using serum drug concentration Goals of TDM  Ensure that a given drug dosage produces  Maximal therapeutic benefit  Minimal toxic adverse effects  Drug must have an appropriate conc. at site of action that produces benefits 3/11/2023 TDM
1. Introduction… Therapeutic range for commonly monitored drugs 44 Amikacin 20–30 g/mL Carbamazepine 4–12 g/mL Digoxin 1–2 ng/mL Gentamicin 5–10 g/mL Lidocaine 1–5 g/mL Lithium 0.6–1.2 mEq/L Phenytoin 10–20 g/mL Procainamide 4–10 g/mL Quinidine 1–4 g/mL Theophylline 10–20 g/mL Tobramycin 5–10 g/mL Valproic acid 50–100 g/mL 3/11/2023 TDM
3. CRITERIA FOR TDM 45 1. Drugs having narrow therapeutic range 2. Therapeutic effect cannot be readily assessed by clinical observation 3. If a direct relationship exists b/n the drug or drug metabolite levels in plasma & the pharmacological or toxic effects. 4. Large inter-individual variability ¡n plasma conc. 5. Drug follow non-linear Pharmacokinetics 6. Drugs used for treating life threatening 3/11/2023 TDM
Drugs which do not need TDM 46 1. Drugs with wide therapeutic range 2. Pharmacological effects can be clinically quantified/ monitored by clinical end points, e.g., BP, HR, cardiac rhythm, blood sugar, blood cholesterol, etc. 3. Drugs whose serum concentrations do not correlate with therapeutic or toxic effects. 4. Drugs used to treat less complicated or non life threatening diseases 5. Drug following linear kinetics (less complicated Phk) 6. Hit and run drugs e.g. omeprazole 3/11/2023 TDM
4. FUNCTIONS OF A TDM SERVICE 47  Select drug.  Design dosage regimen.  Evaluate patient response.  Determine need for measuring Cp  Assay for [drug] in biological fluids.  Perform phk evaluation of [drug]  Readjust dosage regimen. 3/11/2023 TDM
5. TDM: Common drugs 1. Cardio active drugs:  amiodarone, digoxin, digitoxin, disopyramide, propranolol and quinidine 2. Antibiotics:  gentamycin, amikacin and tobramycin 3. Antidepressants:  lithium and tricyclic antidepressants 4. Antiepileptic drugs:  Phenytoin, Valproic acid phenobarbitone, benzodiazepines, carbamazepine, and ethosuximide 5. Bronchodilators:  theophylline 6. Cancer chemotherapy:  Methotrexate 7. Immunosuppressives:  Cyclosporine 48 3/11/2023 TDM
49 3/11/2023 TDM