Rational use of Drug Concentration

Clinicians who consider using drug drug concentration monitoring

• Is the patient already responding appropriately to the drug therapy?

• Is the patient having any toxicity from the drug therapy?

• Is the efficacy and toxicity of this drug better predicted by measuring drug conc or evaluating the clinical response?

• Will obtaining a drug conc change the clinical mgt of the patient

Is therapy appropriate?

Is a less toxic alternative Available?

Re-evaluate therapy

NO Yes

Is immediate effectRequires/ expected?

Use less toxic agent that does not require drug conc monitoring

YesNO

Dosing estimations shouldLean towards a higher dose

Rather than lower doseStart w/ a low dose

And slowly titrateupward

NOYes

Are drug conc measurements predictiveOf drug efficacy or toxicity?

Can the efficacy or toxicity be measured by immediate

Clinical endpoints?

Yes NO

Drug concentration monitoring likely only to Be beneficial for

verifying adherence

Drug concMonitoring indicated

Yes NO

Drug conc monitoring

Probably unnecessary

Evaluating need for drug conc measurement

• Aminoglycoside Nephrotoxicity

• Valproic acid ( infrequent seizures) ( Migraine Headache

prophylaxis)

D R U G S E L E C T I O N

Appropriateness of selected drugs

Desired outcome in specific patient

Evaluating need for drug conc measurement

E F F I C I A C Y I S S U E S

Drug Concentration measurement is USEFUL in research since this will be predictive of therapeutic or toxic effects.

Evaluating need for drug conc measurement

T O X I C I T Y I S S U E S

TOXICITY

DRUG

Dose must be empirically decreased

DRUG CONCENTRATION

MEASUREMENT

Evaluating need for drug conc measurement

A D E H E R E N C E I S S U E S

Drug Concentration may be useful tool, along with evaluation of pharmacy records or medication administration records.

Approaches to Dosing with Limited Need for Drug

Concentration Measurements

IMMEDIATE EFFECT REQUIRED OR EXPECTED

The initial dosage selected for the life threatening infection does not have to be the dosage used for continued therapy.

Dosage Adjustment can be guided by drug concentration measurements, when appropriate based on all other considerations.

Approaches to Dosing with Limited Need for Drug

Concentration Measurements

IMMEDIATE EFFECT NOT REQUIRED OR EXPECTED

Titrating the dose up Titrating the dose down

A strategy of using ¼ to ½ the usual starting dose could minimize side effects by identifying the lowest effective dose.

Theophylline

Start with 100 mg SR 2x/ day per week

Incr 200 mg 2x/day

Incr 300 mg 2x/ day

Begin therapy with the product monograph recommended dose, assess response, gradually reduce the dose accrdg to the response of the px

Disadvantages

Incr frequency

Compromise adherence

Incr cost of therapy

Drug Concentration monitoring should be considered as a tool to supplement clinical assessment if patient response.

However, appropriate drug selection and

proper initial dosage selection, along with the clinical monitoring are the most crucial components of pharmacotherapy.

Medication Dosing in Overweight

and Obese Patients

Obesity is a major public health issue that presents a number of challenges is the difficulty of designing medication dosing regimens that take into account the body composition alterations and disease states associated with excess weight.

Overweight and Obesity are most commonly defined by body mass index calculations.

Adult subjects with a value of 25.0 to 29.9 are considered overweight, with a

value of 30.0 and above are considered obese.

Adult subjects with BMI values above 40 are termed extremely obese.

Product information from the pharmaceutical industry lacks details regarding dosing in obese patients.

Studies have been conducted in patients with varying degrees of obesity for Limited Medications ONLY.

BODY MASS INDEX (BMI)ABW (kg) / Height (m)2 kg/m2 Adult 13 ABW (kg) / Height (m)2 percentile Child

2

-adjust by growth charts for age and sex

BODY SURFACE AREA (BSA)ABW (kg) 0.625 / Height (m)0.725 m2 Adult 14

SQRT (Height (cm) X ABW (kg)/ 3600 m2 child/ Adult 15

ABW (kg) 0.5378 X Height (cm) 0.3964 m2 infant/ child 16

X 0.024265 / Adult

BODY SIZE DESCRIPTIONS

BODY SIZE DESCRIPTIONS

Lean Body Mass Descriptions

IDEAL BODY WEIGHT (IBW)

BODY SIZE DESCRIPTIONS

Lean Body Mass Descriptions

FAT FREE MASS (FFM)

BODY SIZE DESCRIPTIONS

Adjusted Body Weight Descriptors

ADJUSTED BODY WEIGHT

PREDICTED NORMAL WEIGHT

Obtaining an Accurate Weight

Clinicians should have access to an ABW measurement.

Weighing devices must be calibrated

Body Composition Changes Associated with Obesity

Subjects body composition must be considered when dosing medications

X

Y

Z

Weigh 100 kg, 20 liters of excess body fluid

Weigh 100 kg, 20 liters of excess body fat

Weigh 100 kg is a body builder with very low percentage of body fat

Factors affecting volume of distribution

The primary factors affecting Vol of Distribution of a medication into fat and fat-free mass are the relative size of the compartments and binding competition bet fat, blood and other lean tissues.

Factors affecting Clearance

Use of Actual Body Weight for Dosing

Size Descriptors.

Recommendations for Dosing Medications in Obese Patients

Evaluate the clinical investigations involving the medication to determine the degree of obesity in the patients under study and the weight descriptors used for dosing, which is usually ABW in studies leading to medication approval.

Determine if the patient under consideration appears to fit the pxs in the study.

STEP 2STEP 1If the patient does not fit the profile of the patients in the clinical investigations, search the literature for pharmacokinetic studies involving the medication in obese patients. Assess whether the pharmacokinetic parameters of the medication appear to increase proportionally w/ the increasing wt suggesting that ABW is appropriate.

STEP 3 STEP 4If the px does not fit the profile of the px in the clinical investigations and if no pharmacokinetic studies involving the specific medication in obese pxs are available, evaluate the literature for dosing studies in obese pxs with medications that have similar physiochemical and pharmacokinetic parameters.

Assess the benefits and risks of using ABW for dosing using step 4a for weight based dosing or 4b for non-weight based dosing.

STEP 4a

STEP 4b

If weight based dosing is being used, assess whether the potential benefits of using ABW are likely to exceed the potential risks of over-dosing. If the px under consideration is substantially heavier than the pxs in the investigations or if no studies are available, assess whether a LBW or ABW might be preferable.

If non-weight based dosing is being used, assess whether the potential benefits of using larger dose are likely to exceed the potential risks of over-dosing if the px under consideration is substantially heavier than the pxs who were enrolled in the clinical investigations involving the medication, and if the medication has a narrow therapeutic range and a moderate to large Volume of Distribution.

Dosing Concepts in Renal Dysfunction

Mechanism of Drug clearance

• Renal elimination

• Renal drug interactions

NON-RENAL MECHANISM

• Metabolism

• GI absorption

• Volume of Distribution

Selected Drugs with Pharmacologically active

and or TOXIC MetabolitesDrug Metabolites

Acetaminophen n-acetyl-p-benzo-quinoeimine

Allopurinol oxypurinol

Codeine morphine-6-glucuronide

Meperidine normeperidine

Morphine morphine-6-glucuronide

Procainamide n-acetyl procainamide

Propranolol 4-hydroxyl propranolol

Prednisone prednisolone

Dosing Strategies in

Renal Insufficiency

For pre-dialysis CKD patients

Pharmacokinetic Parameters and Maintenance Dosages for some commonly used drugs

Amoxicillin 0.26 15-25 50-70 250-500

mg q8h

q8h q8h-12h

q24h

Cefuroxime 0.13-1.8

33 90 0.75-1.5 g q8h

q8h Q8-12h q12h

Bisoprolol 3 30-50 50 10 mg q24h 100% 75% 50%

V (L/ kg)

PB (%)

Fe (%)

Regimen

70-50

50-10 (GFR)

mL/min

<10

Pharmacokinetic Parameters and Maintenance Dosages for some commonly used drugs

Cefalexin 0.35 20 98 250-500 mg

q6h

q8h q12h q12h

Ciprofloxacin 2.5 20-40 50-70 400 mg q12hn

100% 50%-75%

50%

Levofloxacin 1.1-1.5

24-38 67-87 500 mg q24h

100% 250 mg q24h-48h

250 mg q48h

V (L/ kg)

PB (%)

Fe (%)

Regimen

70-50

50-10 (GFR)

mL/min

<10

Pharmacokinetic Parameters and Maintenance Dosages for some commonly used drugs

Ramipril 1.2 55-70 10-21 10-20 mg q24h

100% 50-75% 25-50%

Tetracycline 0.7 55-90 48-60 250-500 mg q6h

Q8-12 Q12h-q24h

q24h

Ranitidine 1.2-1.8

15 80 150-300 mg q24h

75% 50% 25%

V (L/ kg)

PB (%)

Fe (%)

Regimen

70-50

50-10 (GFR)

mL/min

<10

For continuous renal replacement therapy or intermittent hemodialysis patients

Factors Affecting the

Dialyzability of a Drug

Physicochemical Molecular wt

Properties of the drug water solubility Dialyzability

Lipid solubility

Ionization

Mechanical properties Surface area of dialyzer

of the hemofiltration Dialysate flow rate

of dialysis system Duration of dialysis procedure Dialyzability

Type of membrane used

Blood flow rate

Factors Affecting the

Dialyzability of a Drug

PharmacokineticHalf-life

Factors Volume of Distribution

Protein binding Dialyzability

Dialysis Clearance

Inherent Metabolic

clearance

Red Blood cell partition

Dialysis Clearance and Dosage

Recommendations for Px

Receiving Intermittent

Dialysis

Drug Dialyzer Membrane Type CL10 (mL/ min) Dosage

Recommendation

Meropenem Gambro GFE 11, CU 19 (2.0) 0.5g q24h

15, 18 20 (3.0) 1 g q48-72h

UNK

Piperacillin Baxter CF1511 CU 78.2 (8.4) 4g q12h

Baxter CA219 CA 69. 4 (12)

*CU- Cuprophane

*UNK- Unkown

* CA- Cellulose acetate

Dialysis Clearance and Dosage

Recommendations for Px

Receiving Intermittent

Dialysis

Drug Dialyzer Membrane Type CL10 (mL/ min) Dosage

Recommendation

Metronidazole Multiple CA, CU, RC 70-125 0.5-1.0 g q8h

Phenobarbital UNK UNK 60.5 (26.4) 30 mg q6-8h

*CU- Cuprophane

*UNK- Unkown

*CA- Cellulose acetate

* RC- Regenerated Cellulose

Pharmaco

kineti

cs and

Clearanc

e

Of Drugs

in Pa

tients

Receivin

g CVVH

Drug Hemofilter UFR (mL/min) CLt CL CVVH Dosage

(mL/ min)b Recommendation

Meropenem PA 1500-1800 76 16.7 0.5-1.0g q 12h

PAN 6000-9000 52 22

PS 2760 143.7 49.7

PAN 100-2000 64.7 24.9

Piperacillin NR 1560 42 (23) NR 4g q12h

Patients, with acute and chronic renal impairment and those receiving IHD or CRRT, present many challenges to the pharmacotherapist as they are at increased risk for adverse events due to accumulation of drugs and their active metabolites.

Clinicians play a critical role in providing rationale drug therapy to these patients including DOSE ADJUSTMENTS based on renal function.