جامعة نزوى



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College of Pharmacy & Nursing

School of Pharmacy

CLINICAL PHARMACOKINETICS LAB (PHCY350L)

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Clinical Lab Manual

Spring Semester 2016/2017

Name :

Student ID :

Course Instructor : Dr. Sabin Thomas

Assistant Professor in Pharmacy Practice

Table of Contents

| | | |

|Sl.No |Particulars |Page Numbers |

|1 | |Application of Clinical Pharmacokinetics-Drug Development Process |3 |

|2 | |Drug Potency Calculations |4 |

|3 | |Linear & non-linear Pharmacokinetics Comparison |6 |

|4 | |Maintenance & Loading dose Calculations |7 |

|5 | |Extraction Ratio Calculations |8 |

|6 | |Drug Elimination Process |9 |

|7 | |Half-life Calculations |10 |

|8 | |Bioavailability and Bioequivalence |12 |

|9 | |Nomograms as a Predictive Tool for Drug Dosage |13 |

|10 | |Dosage Regimen Design |14 |

|11 | |Conversion from IV to Oral dosage regimen |17 |

|12 | |Application of Clinical Pharmacokinetic Parameters |18 |

|13 | |Renal Clearance & Vancomycin Clearance Case-1 (Non-obese patient) |20 |

|14 | |Renal Clearance & Vancomycin Clearance Case-2 (Obese patient) |22 |

|15 | |Application of Linear Pharmacokinetics Method (Gentamycin dosing) |24 |

Requirements for the Lab: White Lab coat, pencil, eraser, scale, calculator, lab manual and the class notes are essential requirements for attending clinical pharmacokinetics lab.

Application of Clinical Pharmacokinetics

Topic: Drug Development Process

Draw and submit a Flow Chart of drug development process and mark the following aspects using an A3 size white paper.

a) Conduct of PK/PD evaluations

b) Conduct of population pharmacokinetics (pop-PK)

c) Phase ‘0’

d) Phase ‘2a’ and ‘2b’

e) Investigational New Drug (IND) application process

f) New Drug Application (NDA) process

g) Drug Labeling

Topic: Drug Potency

Case 1

An H2-receptor antagonist (Drug-A) is given to control gastric pH and prevent stress bleeding. The following gastric pHs were observed when steady–state concentrations of the drug were achieved. What are the Emax and EC50 of this drug?

|Plasma Concentration |Resulting PH |

| |(Drug-A) |

|0 |0 |

|0.25 |1 |

|0.5 |1 |

|1 |1.4 |

|2 |2.6 |

|3 |3.8 |

|4 |4.8 |

|5 |4.8 |

Case 2

Another H2-receptor antagonist (Drug-B) with the same plasma concentration has shown gastric pHs as below.

a) What are the Emax and EC50 of this drug?

b) Which drug is more potent? Justify the reason.

|Plasma Concentration |Resulting PH |

| |(Drug-B) |

|0 |0 |

|0.25 |1.5 |

|0.5 |1.6 |

|1 |2.6 |

|2 |4.3 |

|3 |5.8 |

|4 |6.8 |

|5 |7 |

Topic: Linear & non-linear Pharmacokinetics

Two new antibiotics are marketed by a pharmaceutical manufacturer. Reading the package insert, you find the following information.

|Dose |Curacillin steady-state concentrations (mg/L) |Bettermycin steady-state concentrations (mg/L) |

|0 |0 |0 |

|100 |15 |25 |

|250 |37.5 |62.5 |

|500 |75 |190 |

|1000 |150 |510 |

What type of pharmacokinetics does each of these drugs follow?

Topic: Maintenance & Loading dose

A patient with liver failure and a patient with heart failure need to be treated with a new antiarrythmic drug. You find a clinical research study that contains the following information for drug in patients similar to the ones you need to treat;

Normal subjects: clearance = 45 L/h, volume of distribution = 175L:

Patients with liver failure: clearance = 15 L/h, volume of distribution = 300L:

Patients with heart failure: clearance = 30 L/h, volume of distribution = 100L.

Recommend an Intravenous loading dose and continuous intravenous infusion maintenance dose to achieve the steady state concentration of 10mg/L for your two patients based on these data, and estimate the time taken to achieve steady state conditions.

Topic: Extraction Ratio

Calculate the extraction ratio of phenylbutazone in a 80 kg patient, given the following information: liver blood flow is 1.5 L/min; t1/2 = 50 h; Vd = 0.1 L/kg; no non-hepatic elimination.

Topic : Drug Elimination Process

Drug Y is given by an intravenous injection and plasma concentration are then determined as follows :

Time after Injection ( Hours) Concentration ( Mg/L)

0 12

1 9.8

2 7.9

3 6.4

4 5.2

5 4.2

6 3.4

7 2.8

8 2.2

Is this drug eliminated by a first or zero-order process? Defend your answers.

Topic: Half-life

A single 10mg dose of enalapril was given to a hypertensive patient, after first half life of 3 hrs its plasma concentration was 50ng/ml. To reach almost 0.75ng/ml, it will take :

A) 9 hrs

B) 15 hrs

C) 21 hrs

D) 27 hrs

Topic: Bioavailability and Bioequivalence

Problem-1

Determine the F value for a drug available as a 100mg capsule with a calculated AUC of 20mg/dL/h when a 100 mg IV bolus of the same drug exhibits an AUC of 25mg/dL/h.

a) 0.2

b) 0.4

c) 0.8

d) 1.25

Problem-2

A new immunosuppresant, Noreject, is being studied in the renal transplant clinic where you work. Based on previous studies, the following area under the serum concentration/time curves (AUC) were measured after single doses of 10 mg in renal transplant patients: intravenous bolus AUC = 1530 mg ⋅ h/L, oral capsule AUC = 1220 mg ⋅ h/L, oral liquid AUC = 1420 mg ⋅ h/L. What is the bioavailability of the oral capsule and oral liquid? What is the relative bioavailability of the oral capsule compared to the oral liquid?

Topic: Nomograms

The serum concentration of Tobramycin was 7μg/ml after 10 hrs of start of an IV infusion. Using the following Hartford Nomogram model for aminoglycosides, the dose should be given at every

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A. 24 hours

B. 48 hours

C. 36 hours

D. 12 hours

Topic: Dosage Regimen Design

MEDICATION PROFILE

Name: AB

Age: 57yrs

Weight: 200lb

Height: 5’11”

Gender: Male

Allergies: None

Diagnosis: CHF, Ascites, Pedal Edema

LABORATORY TESTS

20/3 Serum sodium 130

Serum Pottassium 35

Creatinine 1.0

Blood Pressure 120/70

Pulse 100

22/3 Serum Digoxin 1.2ng/mL

MEDICATION ORDERS

Date Drug/Strength Route Sig

20/3 Digoxin 0.5mg IV stat (8:00 AM)

20/3 Digoxin 0.25mg IV stat (2:00 PM)

20/3 Digoxin 0.25mg IV stat (8:00 PM)

20/3 Furosemide 40mg IV stat (8:00 AM)

21/3 Furosemide 40mg PO 40mg QD

21/3 Digoxin 0.25mg PO 0.25mg QD

DIETARY ORDERS

Low Sodium diet

Q1) What does stat mean?

A. At 8.00AM

B. at once

C. Within the hour

D. Before noon

E. None of above

Q2) The purpose of digoxin orders on 20/3 in this patient is to

I. achieve rapid depolarization

II. increase cardiac output

III. achieve a digoxin serum level above 2.0ng/mL

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II and III

Give reasons for your answer.

Q3) A second serum digoxin level drawn on 27/3 is reported as 3.1 ng/mL. What are the possible reason(s) for the increase in the level?

I. The patient has reached steady state

II. The blood was drawn 2 hrs post dose

III. The patients renal function has deteriorated

A. I only

B. III only

C. I and II only

D. II and III only

E. I, II and III

Give reasons for your answer.

Topic: Conversion from IV to Oral dose

An adult male asthmatic patient (age 55, 78 kg) has been maintained on an IV infusion of aminophylline at a rate of 34mg/hr. The steady state theophylline drug concentration was 12μg/mL and total body clearance was calculated as 3.0L/hr. Calculate an appropriate oral dosage regimen of theophylline for this patient.

Topic: Application of Clinical Pharmacokinetic Parameters

LK is a 50-year-old, 75- Kg (5 ft10 in) male with chronic bronchitis who requires therapy with oral theophylline. He currently smokes 2 packs of cigarettes daily, and has normal liver and cardiac function. Suggest an initial theophylline dosage regimen designed to achieve a steady-state theophylline concentration equal to 8microgram/ml.

Volume of distribution is assumed to equal 0.5L/Kg for non-obese patients and half- life would assume to equal 5 hours for smokers. (Note: microgram/ml = mg/L and this concentration was substituted for Css in the calculations so that unnecessary unit conversion was not required.)

1- Estimate half-life and elimination rate content according to disease states and condition present in the patient.

2- Estimate volume of distribution and clearance.

3- Compute dosage regimen.

Topic: Renal Clearance & Vancomycin Clearance

Case-1

A 52-year-old, 65-kg, 5-ft 3-in tall female patient with a methicillin-resistant Staphylococcus aureus (MRSA) infection needs to have an initial vancomycin dose computed. In order to do this, an estimated creatinine clearance needs to be calculated. The patient has a serum creatinine value equal to 1.8 mg/dL. Calculate this patient’s estimated creatinine clearance and estimated vancomycin clearance [assume vancomycin

clearance is Cl (in mL/min/kg) = 0.695 (CrCl in mL/min/kg) + 0.05].

Topic: Renal Clearance & Vancomycin Clearance

Case-2

A 66-year-old, 120-kg, 5-ft 2-in tall female patient with a methicillin-resistant Staphylococcus aureus (MRSA) infection needs to have an initial vancomycin dose computed. The patient has a serum creatinine value equal to 3.1 mg/dL. Calculate this patient’s estimated creatinine clearance and estimated vancomycin clearance [assume vancomycin clearance is Cl (in mL/min/kg) = 0.695 (CrCl in mL/min/kg) + 0.05].

Applications of Linear Pharmacokinetics Method

Concept:

Because aminoglycoside antibiotics follow linear, dose-proportional pharmacokinetics, steady-state serum concentrations change in proportion to dose according to the following equation:

Dnew / Css,new = Dold / Css,old or Dnew = (Css,new / Css,old) Dold,

where D is the dose, Css is the steady-state peak or trough concentration, old indicates the dose that produced the steady-state concentration that the patient is currently receiving, and new denotes the dose necessary to produce the desired steady-state concentration. The advantages of this method are that it is quick and simple. The disadvantages are steady-state concentrations are required, and it may not be possible to attain desired serum concentrations by only changing the dose.

The elimination rate constant versus creatinine clearance relationship to estimate the gentamicin elimination rate for patient: ke = 0.00293(CrCl) + 0.014

Case 1

JM is a 50-year-old, 70-kg (5 ft 10 in) male with gram-negative pneumonia. His current serum creatinine is 0.9 mg/dL, and it has been stable over the last 5 days since admission. A gentamicin dose of 170 mg every 8 hours was prescribed and expected to achieve steady-state peak and trough concentrations equal to 9 μg/mL and 1 μg/mL, respectively. After the third dose, steady-state peak and trough concentrations were measured and were 12 μg/mL and 1.4 μg/mL, respectively. Calculate a new gentamicin dose that would provide a steady-state peak of 9 μg/mL.

1. Estimate creatinine clearance.

2. Estimate elimination rate constant (ke) and half-life (t1/2).

3. Compute new dose to achieve desired serum concentration.

4. Check steady-state trough concentration for new dosage regimen.

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