Drug Dosing in Special Populations Prof. Henny Lucida, PhD, Apt

Patient conditions that may altered the dosing of most drugs: Renal or hepatic disease, may decrease the elimination or metabolism of the majority of drugs and change the clearance Dialysis procedures, conducted using artificial kidneys in patients with renal failure, removes some medications from the body although the pharmacokinetic of other drugs are not changed

Heart failure, results in low cardiac output, which decreases blood flow to eliminating organs Obesity, adds excessive adipose tissue to the body, which may change the way that drugs distribute in the body and alter the VD

Common causes of kidney failure Pyelonephritis Inflammation and deterioration of the pyelonephrons due to infection, antigens or other idiopathic causes Hypertension Chronic overloading of the kidney with fluid and electrolytes may lead to kidney insufficiency Diabetes mellitus The disturbance of sugar metabolism and acid-base balance may lead to or predispose a patient to degenerative renal disease Nephrotoxic drugs/metals Certain drugs taken chronically may cause irreversible kidney damage (the aminoglycosides, phenacetin , heavy metals such as mercury, lead Hypovolemia Any condition that causes a reduction in renal blood flow will eventually lead to renal ischemia and damage Neophroallergens Certain compounds may produce an immune type of sensitivity reaction with nephritic syndrome. (quartan malaria nephrotoxic serum)

Renal Disease Glomerular filtration is the primary elimination route for many medications The most common method of estimating glomerular filtration for the purpose of drug dosing is to measure /estimate Creatinine Clearance (CrCl)

Equations: UCr = the urine creatinine concentration (mg/dl) Vurine = the volume of urine collected (ml) SCr = the serum creatinine collected at the midpointof the urine collection (mg/dl) T = the time of urine collection (minute)

Problems of routine measurement of patient’s CrCl: Incomplete urine collection Serum creatinine concentration obtained at incorrect times Collection times errors Erroneous measured CrCl values

Equation Cockroft and Gault CrCl est = estimated creatinine clearance (ml/min) Age in years BW = body weight (kg) Scr = serum creatinine (mg/dl)

This equation should be used only in patients: Age > 18 y With the weight of 30% of IBW IBW males (kg) = 50 + 2.3 (Ht – 60) IBW females (kg) = 45 + 2.3 (Ht – 60) Ht: height in inches If Scr values were not stable the Cockroft and Gault equation cannot be used

Equation Jelliffe and Jelliffe Ess = the excretion of creatinine IBW = ideal body weight (kg) Age (years)

Adjusting the CrCl from the Ess

Equation Salazar and Corcoran (for obese patients) Wt = weight (kg), Ht = height (m) Scr = serum creatinine (mg/dl)

Equation for children and young adults Ht = height (cm) and Scr (mg/dl)

Equation Traub & Johnson (children 1 – 18 years) Height in cm Scr in mmoles/L

Renal impairment based on ClCr Group Description Estimated ClCr (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 End Stage Renal Disease Required dialysis

Estimation of drug dosing using CrCl renal clearance of drug is smaller in patients with reduced GFR All drug excreting by tubular secretion and reabsorption decline in parallel with glomerular filtration When CrCl is <50 – 60 ml/min, a possible modest decrease in drug doses When CrCl is <25 – 30 ml/min, a moderate decrease in drug doses When CrCl is <15 ml/min, a substantial decrease in drug doses

Modifying Doses for patients with renal impairment It is possible to decrease the drug dose and retain the usual dosage interval,or Retain the usual dose and increase the dosage interval, or Both decrease the dosage and prolong the dosage interval The choice was made depend on the route of drug administration, the dosage forms available

For drugs with narrow therapeutic index Measured or estimated CrCl may be used to estimate pharmacokinetic parameters for a patient based on prior studies conducted in other patients with renal dysfunction Estimated pharmacokinetic parameters are then used in pharmacokinetic dosing equation to compute initial dose

Problem OI is a 65 yo, 170 kg (5’5”) female with Class III heart failure. Her current serum creatinine is 4.7 mg/dl and is stable. A digoxin dose of 125 mg/d given as tablets was prescribed and expected to achieve Css equal to 1 ng/ml. After 3 weeks of therapy, the Css was measured and equalled 2.5 ng/ml. Calculate a new digoxin dose that will provide a Css of 1.2 ng/ml

Solution Estimate CrCl. This patient has a stable Scr and is obese [IBWfemales (kg) = 45 + 2.3 (Ht – 60) = 45 + 2.3 (65” – 60) = 57 kg]. The Salazar and Corcoran eq. can be used to estimate CrCl (Ht is converted from inches to meters(65 in x 2.54 m/in)/(100cm/m) = 1.65 m

This patient has poor renal function, but can be expected to be at Css with regard to digoxin serum conc after 3 weeks of treatment. 2. Compute drug clearance (digoxin conc in ng/ml = mg/L) 3. Compute new dose to achieve desired serum conc (use the Cssave eq):

60 mg/d or 120 mg every other day 60 mg/d or 120 mg every other day. This would be rounded to digoxin tablets 125 mg every other day. The new suggested dose is 125 mg every other day given as digoxin tablets, to be started at the next scheduled dosing time. Since the dosing interval is being changed, a day should be skipped before the next dose is given.

Renal dysfunction Urinary excretion of drugs decreased due to a decrease in renal function (exp: cephalosporine) drug accumulation (exp: amikacin in patient with 17% renal function) Drug accumulation depends on frequency of adm and t½ elimination. If t½ increase tss increase, then dosage must be reduced

Renal dysfunction : estimation of renal function CLCr (d) = creatinine clearance in the patient with renal dysfunction CLCr (t) = creatinine clearance in the typical 55 year-old and 70 kg patient RF = renal function

Renal dysfunction: dosage regimen adjustment Maintenance dose: (*) Adjusment may be made by reducing the frequency of administration, or reducing the MD or both.

Exp: adjustment of dose of amikacin sulfate Usual dose regimen: 7.5 mg/kgBW im every 12 hrs The dose for 23 year-old, 68 kg patient with CLCr 13 mL/min would be: CLCr expected for typical patient = 77 mL/min RF (d) = 13/77 = 0.17 Using equation (*), MD amikacin has to be reduced by a factor of 6 (or 1/0.17)

Exp: adjustment of dose of amikacin sulfate Thus, the maintenance regimen could be: Dosing interval become 6 x longer, regimen: 500 mg (7.5 mg/kg x 68 kg) every 72 hrs MD may be reduced by a factor of 6 regimen: 83 mg every 12 hrs Both dosing interval and MD may be adjusted to reduce average dosing 6x regimen: 167 mg every 24 hrs

Confirmation by TDM t½ amikacin in typical patient = 2 hr t½ amikacin in (d) patient = 12 hr TDM results in: Regimen with 72 hrs interval showed >>> fluctuations Changing MD reduced fluctuation but inconvenience of frequent im injection Change interval & MD, reduced fluctuation and inconvenience : the most appropriate Loading dose: same usual LD for amikacin suggested

Welling and Craig Method  

Giusti-Hayton Method  

General guidelines for dosage adjustment in (d) patient As long as fraction of drug unbound eliminated by renal route (fe) is 0.30 or less and metabolites are inactive no change in a regimen is called for based on RF Regardless of the contribution of the renal route if RF is 0.70 x typical value no change is needed If RF approach zero fe(t) approach 1 CLt reduced dosing rate must be drastically reduced.

Hepatic Disorders Most lipid soluble drugs are metabolized to some degree by the liver, the mechanism: Phase I : oxidation, hydrolysis and reduction; mediated by the cytochrome P-450 enzyme system, occur in hepatocytes Phase II: conjugation to form glucuronides, acetates, or sulfates; mediated by cytosolic enzymes in hepatocytes

Equation for hepatic drug metabolism LBF = liver blood flow fB = the fraction of unbound drug in the blood Clint = intrinsic clearance

Two major types of liver disease Hepatitis - Patients with hepatitis inflammation of the liver decreased ability of hepatocytes or die - Acute hepatitis: mild, transient decreases in drug metabolism required no or minor changes in drug dosing - Chronic hepatitis: irreversible hepatocytes damage required drug dosage changes. Patients with long term hepatocytes damage can progress to hepatic cirrhosis 2. Cirrhosis; a permanent lost of functional hepatocytes. Drug dosage schedules usually need to be modified

Altered pharmacokinetic parameters When hepatocytes are damaged Clint decreases hepatic clearance reduces If the drug has a hepatic first-pass effect BA will increases A simultaneous effect of (1) and (2) results in extremely large increases in Css for orally administered drugs

Altered pharmacokinetic parameters 4. LBF decreases depresses hepatic drug clearance even further 5. The liver produces albumin and a-1-acid glycoprotein in the blood. The production of these proteins decline in patient with cirrhosis free fraction of drugs in the blood. 6. Since clearance decreases and VD usually increases the t½ almost always increases.

Measurement of liver function No single laboratory test to assess the liver function (not like CLCrest to measure renal function) The most common way to estimate the ability of the liver to metabolize the drug is to determine the Child-Pugh score for a patient

The Child-Pugh score Consists of 5 laboratory test or clinical symptoms, ie: - serum albumin - total bilirubin - prothrombin time - ascites - hepatic encephalopathy

Table: Child-Pugh scores for patients with liver disease Test/symptom Score 1 point Score 2 points Score 3 points Total bilirubin (mg/dl) < 2.0 2.0 – 3.0 >3.0 Serum albumin (g/dl) > 3.5 2.8 – 3.5 < 2.8 Prothrombin time (seconds prolonged over control) < 4 4 – 6 > 6 Ascites Absent Slight Moderate Hepatic encephalopathy None Severe

Each of the symptom is given a score of 1 (normal) to 3 (severely abnormal), and the scores for the five areas are summed. The Child-Pugh score for a patient with normal liver function is 5, whereas for abnormal (hepatic damage) is 15

Dosage adjusment A Child-Pugh score of 8 – 9 : a moderate decrease (+ 25%) in initial daily drug dose for agents that are primarily (> 60%) metabolized hepatically A Child-Pugh score of > 10 : a significant decrease in initial daily dose (+ 50%) is required for drugs that are mostly liver metabolized It is possible to decrease the dose while retaining the normal dosage interval, retain the usual dose and prolong the dosage interval, or modify both the dose and dosage interval

Heart Failure Is accompanied by a decrease in cardiac output results in lower liver and renal blood flow Decreased drug bioavailability has been reported, due to collection of edema fluid in the GI tract difficult absorption and decreased blood flow to GI tract VD of some drugs decreases, the alteration in t½ is difficult to predict in patients with heart failure