CLINICAL PHARMACOKINETICS

ERLI SUSANTI 07 131 062 FAKULTAS FARMASI UNIVERSITAS ANDALAS

Drug Dosing in Special PopulationsHenny 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

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:U Cr xVurine CrCl(ml/min) ! SCr xT

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 patients CrCl: Incomplete urine collection Serum creatinine concentration obtained at incorrect times Collection times errors

Erroneous measured CrCl values

Equation Cockroft and GaultCrCl est CrCl est

140 age BW for males !72 S Cr 0.85 age BW 140 for females ! 72 S Cr

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 JelliffeEss male ! IBW?29.3 0.203 age A Ess female ! IBW?25.1 0.175 age A Ess = the excretion of creatinine IBW = ideal body weight (kg) Age (years)

Adjusting the CrCl from the EssEss corrected ! Ess? 1.035 0.0337 Scrave A 4IBWScr2 Scr1 E ! Ess corrected t E 2 CrCl(ml/min/1.73m ) ! 14.4 Scrave

Equation Salazar and Corcoran (for obese patients)CrCl est(males)

137 age 0.285 Wt Ht 2 ? A 12.1 !51 Scr

CrCl est(females)

? A 146 age 0.287 Wt Ht 2 9.74 !60 Scr

Wt = weight (kg), Ht = height (m) Scr = serum creatinine (mg/dl)

Equation for children and young adultsCrCl est (ml/min/1.73m 2 ) ! 0.45 Ht /S cr ; age0 1year CrCl est (ml/min/1.73m ) ! 0.55 Ht /S cr ; age1 20years2

Ht = height (cm) and Scr (mg/dl)

Equation Traub & Johnson (children 1 18 years)ClCr ml/min/1.73m

2

42 x Height ! S cr

Height in cm Scr in Qmoles/L

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 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

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 DisordersMost lipid soluble drugs are metabolized to some degree by the liver, the mechanism: 1. Phase I : oxidation, hydrolysis and reduction; mediated by the cytochrome P-450 enzyme system, occur in hepatocytes 2. Phase II: conjugation to form glucuronides, acetates, or sulfates; mediated by cytosolic enzymes in hepatocytes

Equation for hepatic drug metabolism

LBF f B CL int CL H ! LBF f B CL int LBF = liver blood flow fB = the fraction of unbound drug in the blood Clint = intrinsic clearance

Two major types of liver diseaseHepatitis - 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 1.

Altered pharmacokinetic parameters1. When hepatocytes are damaged Clint decreases hepatic clearance reduces 2. If the drug has a hepatic first-pass effect BA will increases 3. A simultaneous effect of (1) and (2) results in extremely large increases in Css for orally administered drugs

Altered pharmacokinetic parameters4. LBF decreases depresses hepatic drug clearance even further 5. The liver produces albumin and E-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 t 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 diseaseTest/symptom Total bilirubin (mg/dl) Serum albumin (g/dl) Prothrombin time (seconds prolonged over control) Ascites Hepatic encephalopathy Score 1 point < 2.0 > 3.5 3.0 < 2.8 >6

Absent None

Slight Moderate

Moderate 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 t is difficult to predict in patients with heart failure