Clinical pharmacokinetics

General Principles of Clinical Pharmacokinetics:

General Principles of Clinical Pharmacokinetics First Symposium on Application of Pharmacokinetics in Clinical Practice on May 11, 2011 in Intercontinental Hotel Jeddah Mansoor Khan, BS,MS, BCOP Clinical Pharmacist, NGHA, Jeddah

Outline:

Outline Definition of PK and PD Review of Concepts Clearance, K, Half-Life, Volume of Distribution, Steady state Factors affecting selection of the drug Hepatic & renal Dosing

What is Clinical Pharmacokinetics (PKs)?:

What is Clinical Pharmacokinetics (PKs)? Pharmacokinetics (PKs): science of the rate of movement of drugs within biological systems Clinical PKs: deals with the application of PK principles to the safe and effective therapeutic management of drugs in an individual patient

ADME:

Drug in tissues Metabolism Metabolite(s) in tissues ADME Drug and/or metabolite(s) in urine, feces, bile Drug at site of administration Drug in plasma Absorption (input) Distribution Elimination (output)

Why study PK and PD?:

Why study PK and PD? Application of Therapeutic Drug Monitoring (TDM) and individualization of drug therapy Monitor medications with a narrow therapeutic index Decrease the risk of adverse effects while maximizing pharmacologic response of the medications

Pharmacokinetics (PK) & Pharmacodynamics (PD):

Pharmacokinetics (PK) & Pharmacodynamics (PD) PK - What the body does to the drug? Absorption, distribution, metabolism, excretion (ADME) PD - What the drug does to the body? Drug concentration at the site of action or in the plasma is related to a magnitude of effect

PK & PD after Drug Administration:

PK & PD after Drug Administration Dose Plasma Site of action Effects PK PD

PK vs. PD Concept:

PK vs. PD Concept Fluoxetine increases plasma concentrations of amitriptyline. This is a pharmacokinetic drug interaction. Fluoxetine inhibits the metabolism of amitriptyline and increases the plasma concentration of amitriptytline.

PK vs. PD Concept:

PK vs. PD Concept If fluoxetine is given with tramadol, serotonin syndrome can result. This is a pharmacodynamic drug interaction. Fluoxetine and tramadol both increase availability of serotonin leading to the possibility of “serotonin overload” This happens without a change in the concentration of either drug.

PK Parameters of Drug :

PK Parameters of Drug Absorption Bioavailability of drugs (F) Absorption rate constant (ka) Metabolism Disposition=Distribution + Elimination Clearance (CL) Volume of distribution (V d ) Half life ( t 1/2 ) Steady state Concentration Plasma protein binding P-Glycoprotein

Cytochrome P450 Enzymes & Substrates :

Cytochrome P450 Enzymes & Substrates CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 Acetaminophen Diclofenac Diazepam Codeine Alprazolam Caffeine Ibuprofen Omeprazole Fluoxetine Cyclosporine Theophylline Naproxen Paroxetine Carbamazepine Tacrine Phenytoin Metoprolol Nifedipine R-warfarin S-warfarin Risperidone Simvastatin Venlafaxine Verapamil Tacrolimus

Clearance (CL):

Clearance (CL) Ability of organs to eliminate drugs (e.g. kidney, liver to “clear” drug from the bloodstream Volume of fluid which is completely cleared of drug per unit time Units are in L/hr Pharmacokinetic term used in determination of maintenance doses

Volume of Distribution (Vd):

Volume of Distribution (V d ) Theoretical volume Gives information on HOW the drug is distributed in the body Used to calculate a loading dose

Half-Life:

Half-Life Half-life is the time taken for the drug concentration to fall to half its original value It determines the time required to reach steady state concentration and dosage interval t ½ = 0.693 / Kel Kel = CL / Vd

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Log Concn . Time C 0 C 0 /2 t 1/2 t 1/2 t 1/2 Time to eliminate ~ 4 t 1/2

What is Steady State (SS) ? Why is it important ? :

What is Steady State (SS) ? Why is it important ? Rate in = Rate Out Reached in 4 – 5 half-lives (linear kinetics) Important when interpreting drug concentrations in TDM or assessing clinical response

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100 187.5 194 175 150 75 87.5 94 97 50 200 100 … … Accumulation to Steady State

Plasma Protein Binding:

Plasma Protein Binding Affects efficiency of the drug The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse Common blood proteins: Serum Albumin , Glycoprotein , Lipoprotein and Serum Globulins Pharmacologic effects from unbound drug

P-glycoprotein (P-gp):

P-glycoprotein (P-gp) P-glycoprotein (P-gp) is a efflux pump for drugs Mediator of multidrug resistance in cancer. Numerous drugs can induce P-gp expression. P-gp has role in drug pharmacokinetics and Pharmacodynamics. P-gp is present in organ systems that influence drug absorption (intestine), distribution to site of action (central nervous system and leukocytes), and elimination (liver and kidney), as well as several other tissues.

Drugs That Affect Pgp:

Drugs That Affect Pgp Inhibitors Amiodarone Clarithromycin Cyclosporin Diltiazem Erythromycin Itraconazole Sirolimus Inducers Rifampin St. John’s Wort

Calculation of Loading Dose for IV Voriconazole:

Calculation of Loading Dose for IV Voriconazole Q: What is loading dose required for 60 Kg patient? V d = 4.6 L/Kg Target Conc = 2.75 mg/L (Ref 1-5.5 mg/L)

Loading Dose Formula:

Loading Dose Formula Dose = Cp(Target) x V d

Answer: Loading dose of Voriconazole:

Answer: Loading dose of Voriconazole LD = Target Concentration x V d V d = 4.6 L/Kg X 60 = 276L LD= 2.75 mg X 276 L = 759 mg IV per day in 2 divided doses 759/2 = 379.5 mg IV BID = 6.3 mg/Kg IV BID

Maintenance Dose Calculation:

Maintenance Dose Calculation Maintenance Dose = CL x CpSSav (mg/hr)

Calculation of Maintenance Dose for IV Voriconazole:

Calculation of Maintenance Dose for IV Voriconazole Q: What is maintenance dose required for 60 Kg patient? CL = 7.4L/hour Target Conc = 2.75 mg/L (Ref 1-5.5 mg/L)

Answer: Maintenance Dose of Voriconazole:

Answer: Maintenance Dose of Voriconazole MD = Target Concentration x CL MD= 2.75 mg X 7.4L = 20 mg/h X 24h in 2 divided doses 20 mg X 24h = 480 mg/d IV in 2 divided doses = 240 IV BID MD= 240/60 = 4 mg/Kg IV BID

Factors Affecting Selection of Drug Doses:

Factors Affecting Selection of Drug Doses Patient age, sex, height, weight, allergies Diagnosis, disease site, physical exam, I/O Past medical history Current drug therapy Lab work up: RFTs, LFTs, Microbiology, CBC etc

Weight: ABW Vs IBW Vs AdjBW :

Weight: ABW Vs IBW Vs AdjBW Use ABW when close to IBW or < IBW IBW for Males = 50Kg + 2.3 Kg/Inch over 5 feet IBW for females = 45Kg + 2.3 Kg/Inch over 5 feet AdjBW= IBW + 0.4 (ABW-IBW) If Obese

Examples of weight based doses:

Examples of weight based doses Vancomycin, Enoxaparin Use Actual body weight Aminoglycosides IBW or AdjBW TPN, Chemotherapy AdjBW

Selection of initial drug doses that are eliminated hepatically:

Selection of initial drug doses that are eliminated hepatically Bilirubin, ALT, AST, Alk Phos, GGT, Albumin, INR, Child pugh Score Dosage adjustment required for drugs that are primarily eliminated by liver (> 60% excretion) in hepatically compromised patients.

Child Pugh Score:

Child Pugh Score 1 point 2 points 3 points Bilirubin < 34 µmol 34-50 µmol > 50 µmol Albumin < 35 G/L 28-35 G/L < 28 G/L INR < 1.7 1.7-2.20 > 2.20 Ascites None Mild Severe Hep Enceph None Grade I-II Grade III-IV Class A=5-6 Class B=7-9 Class C=> 9

Case 1: Hepatic Dose Adjustment:

Case 1: Hepatic Dose Adjustment 40 Y male patient with NHL requiring doxorubicin based chemotherapy. He was found to have impaired LFTs, Bili 3 mg/dL, and normal serum aminotransferases. Do we need to adjust the dose of doxorubicin ? If yes, then how much? Answer: Bili 1.2-3 mg, decrease dose by 50%

Case 2: Hepatic Dose Adjustment:

Case 2: Hepatic Dose Adjustment 51 Y old Male with invasive respiratory aspergillosis. His laboratory parameters showed bilirubin 2.5 mg/dL, INR 1.9, albumin 2.6 G/dL, mild ascites and no evidence of hepatic encephalopathy. His current medications include full doses of Voriconazole + Caspofungin Q: Do we need to adjust his med? If yes, then how much?

Case 2: Hepatic Dose Adjustment:

Case 2: Hepatic Dose Adjustment Child pugh score = 10 (Class C) Vori & Caspo are not recommended; clinical data lacking

Selection of initial drug doses that are eliminated renally:

Selection of initial drug doses that are eliminated renally Assess renal function (Serum Creat) and Calculate Creatinine Clearance (CrCl) Use Cockcroft-Gault Equation in adults Dosage adjustment required for drugs that are primarily eliminated by kidney (> 60% excretion) renally compromised patients

Estimation of Creatinine Clearance:

Estimation of Creatinine Clearance Estimate Cockroft Gault equation (140-Age) x (IBW in kg) ------------------------------ x (0.85 for females) 72 x (Scr in mg/dL)

Measurement of creatinine clearance:

Measurement of creatinine clearance Time consuming Requires 24 hr urine collection U Creat (mg/dL) x 24 h Urine Vol (ml) --------------------------------------------- S Creat (mg/dL) X 1440

Case 3: Renal Dose Adjustment:

Case 3: Renal Dose Adjustment A 62 Y old F weighing 56 Kg and 165 cm tall with E.Coli Bacteraemia. Her Lab parameters shows serum creat of 250 umol/L and BUN 15 mmol/L. Her physician would like to start her on Tazocin Question : Do we need to adjust the dose of Tazocin if yes then how much?

Answer: Renal Dose Adjustment:

Answer: Renal Dose Adjustment CrCl= 18.2 ml/min Reduce Tazocin to 2.25G Q8 Hours

Summary:

Summary Clinical PK is the discipline that describes applying pk principles to the safe and effective management of drugs in an individual patient Necessary to have knowledge of various factors that will impact pk and pd Physiochemical properties of drugs with patient factors will determine the response seen.

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Thank you!