clinical pharmacokinetics of Procainamide

some reports that procainamide follows nonlinear pharmacokinetics, for the purposes of clinical drug dosing in patients, linear pharmacokinetic concepts and equations can be effectively used to compute doses and estimate serum concentrations.

1. CLINICAL PHARMACOKINETICS OF Procainamide/ N -acetyl Procainamide JU School Of Pharmacy Jimma, Ethiopia 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie 1 By Behailu T erefe ( BPharm , PGY1 clinical pharmacy student) [email protected] / [email protected] Phar 611

2. Contents 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie 2 Introduction Therapeutic And Toxic Concentrations Adverse Events Basic Clinical Pharmacokinetic Parameters Disease States And Conditions Affecting Pk And Dosing Initial Dosage Determination Methods Use of Serum Conc. to Alter Doses

3. INTRODUCTION 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Procainamide type IA antiarrhythmic agent that is used I.V and PO. used for the treatment of SV or ventricular arrhythmias . MOA :- inhibits trans-membrane Na + influx thereby ↓ conduction velocity. Increases the duration of the action potential, threshold potential toward zero, and 3

4. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie 4 decreases the slope of phase 4 of the action potential and Automaticity net effect ↑ refractoriness and ↓conduction in heart conduction tissue, which establishes a bidirectional block in reentrant pathways.

5. THERAPEUTIC AND TOXIC CONCENTRATIONS 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie therapeutic range for procainamide is 4-10 μg /ml. When given intravenously , the serum PDC-time curve follows a two-compartment model (see figure below). 5

6. Date of download: 12/5/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. Procainamide serum concentrations initially drop rapidly after an intravenous bolus as drug distributes from blood into the tissues during the distribution phase. During the distribution phase, drug leaves the blood due to tissue distribution and elimination. After 20-30 minutes, an equilibrium is established between the blood and tissues, and serum concentrations drop more slowly since elimination is the primary process removing drug from the blood. A two-compartment model describes this type of serum concentration/time profile. Legend : From: Cardiovascular Agents Applied Clinical Pharmacokinetics, 3e, 2015

7. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie To maintain therapeutic procainamide concentrations, an I.V LD (over 25-30 minutes) is followed by a CII . distribution phase is still seen due to the adm. of LD. administration of a LD may not establish steady-state conditions immediately, and the infusion needs to run 3-5 t 1/2 until Css are attained 7

8. Date of download: 12/5/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. To maintain therapeutic procainamide concentrations, an intravenous loading dose (over 25-30 minutes) of procainamide is followed by a continuous intravenous infusion of the drug. A distribution phase is still seen due to the administration of the loading dose. Note that the administration of a loading dose may not establish steady-state conditions immediately, and the infusion needs to run 3-5 half-lives until steady-state concentrations are attained. Legend : From: Procainamide/N-acetyl Procainamide Applied Clinical Pharmacokinetics, 3e, 2015

9. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie When oral dosage forms are given, absorption occurs more slowly than distribution so a distribution phase is not seen . 9

10. ADVERSE EVENTS 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie can be concentration dependent or independent. 10

11. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Recommendations during I.V procainamide therapy , Continuous monitoring of B.P Ensuring availability or actual giving of phenylephrine or NE Constant ECG monitoring equipment to treat ventricular a systole, fibrillation, or both. RX of Procainamide toxicity Have desirable attributes for extracorporeal drug removal. peritoneal dialysis, hemodialysis , hemoperfusion , and continuous arteriovenous hemofiltration/ hemodiafiltration . 11

12. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie NAPA or acecainide , has type III antiarrhythmic effects . Prolongs action potential via K + channel blockade . effective concentration is 10-30 μ g/ mL. Conc. dependent A/ Es , similar to procainamide. does not appear to cause a SLS. 12

13. BASIC CLINICAL PHARMACOKINETIC PARAMETERS 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Absorption and distribution of procainamide average oral F`(both IR and SR DFs) is 83 %. lag time of 20-30 minutes occurs in some patients Plasma protein binding is only about 15%. Vd 2.7 L/kg (V = 2-3.8 L/kg) 13

14. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Elimination half-life is 3.3 hours (range: 2.5-4.6 hours) both hepatic metabolism (~50%) and renal elimination of unchanged drug (~50 %). Hepatic metabolism by N - acetyltransferase II (NAT-II ) and CYP2D6. “ slow acetylator ” and “rapid acetylator ” phenotypes. 14 Mainly via NAT-II. NAPA is 1 active metabolite. t 1/2 = 6 hr and Vd of 1.4 L/kg.

15. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie 15

16. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie R enal clearance procainamide CL R / CL cr is 2 to 3 NAPA primarily eliminated unchanged in the urine via GF and renal tubular secretion. When given orally, 85% of the administered dose is recovered in the urine as unchanged drug. 16 Implies that net renal tubular secretion is taking place in the kidney. Probably in PCT.

17. EFFECTS OF DISEASE STATES AND CONDITIONS ON THE PK AND DOSING OF PROCAINAMIDE 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Renal dysfunction clearance rate ↓ as Clcr ↓ But it is not as reliable parameter to aid in the estimation of procainamide clearance. Why???? the major route of CL R for procainamide is via proximal tubular secretion 17

18. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie In patients with RF, the average procainamide t 1/2 is 13.9 hours and Vd is 1.7 L/kg NAPA t 1/2 ↑ to 41 hours on the average NAPA/Procainamide Css exceeds 1. Reason :-NAPA elimination is much more dependent on renal function. 18 Thus, in patients with RF, NAPA may be the predominant antiarrhythmic agent present in the serum.

19. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Uncompensated heart failure Reduces both procainamide CL and Vd (V = 1.6 L/kg) Proca . t 1/2 equal to 5.5 hours (t 1/2 = [0.693• ↓V]/↓ Cl ). the effect on procainamide pharmacokinetics is highly variable and difficult to accurately predict. ↓ initial procainamide doses by 25%-50 %. 19

20. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Liver cirrhosis or hepatitis have not been adequately studied But recommended to ↓ the initial doses by applying the Child-Pugh classification system normal liver function is 5 15 is grossly abnormal ≥8 is grounds for a ↓ of 25% in the initial daily drug dose while a score >10 suggests a ↓ of 50 %. 20

21. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie 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 PT (seconds prolonged over control) <4 4-6 >6 Ascites Absent Slight Moderate HE None Moderate Severe TABLE 8-4Child-Pugh Scores for Patients With Liver Disease 21

22. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Obesity 30% above the IBW. Studies investigating the impact of obesity on PK of procainamide shows best correlation of, Vd-IBW and, CL-TBW(0.52 L/h/kg TBW for normal renal function) 22

23. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie DRUG INTERACTIONS Cimetidine , trimethoprim , ofloxacin , levofloxacin , and ciprofloxacin - compete for tubular secretion. procainamide CL R ↓ ses by 30%-50% and NAPA renal clearance ↓ ses by 10%-30%. Amiodarone ↑ ses the Css of procainamide and NAPA by 57% and 32%, respectively. 23

24. INITIAL DOSAGE DETERMINATION METHODS 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Goal: to compute the best dose possible dose . Several methods to initiate procainamide therapy are available. Pharmacokinetic Dosing Method Literature-based recommended dosing 24

25. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Pharmacokinetic Dosing Method most flexible of the techniques. allows individualized target serum concentrations each pharmacokinetic parameter can be customized to reflect specific disease states and conditions 25

26. Half-Life and Elimination Rate Constant Estimate 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie procainamide half-life moderate HF (NYHA CHF class III), 5.5 hours, renal failure, 3.9 hours . adjusted t 1/2 ( hrs )= CrCl is adjusted for body SA (ml/min/1.73m 2 ).   26

27. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie multiple concurrent disease states or conditions. disease state or condition with the longest t 1/2 should be used to compute doses. avoid accidental over dosage as much as currently possible. k = 0.693/t 1/2 27

28. Volume of Distribution Estimate 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie chosen according to the disease states and conditions help to compute procainamide clearance 1.7 L/kg for RF, 1.6 L/kg for uncompensated HF and 2.7 L/kg for all other patients. f or obese patients, IBW is used to compute Vd. E.g., for a non obese 80-kg patient without HF or liver disease, procainamide Vd is 2.7L/Kg* 80 kg = 216 L 28

29. Selection of Appropriate Pharmacokinetic Model and Equations 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie some reports that procainamide follows nonlinear pharmacokinetics , for the purposes of clinical drug dosing in patients, linear pharmacokinetic concepts and equations can be effectively used to compute doses and estimate serum concentrations. 29

30. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Oral administration of procainamide follows a one-compartment pharmacokinetic model or clearance in L/h is computed: For example , what is the estimated clearance of procainamide for a patient with an estimated K E of 0.210 h −1 and an estimated V d equal to 189 L : Cl = 0.210 h −1 • 189 L =39.7 L/h= 39.7 L/h   30

31. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie When intravenous therapy is required, similar equation is widely used and allows dosage calculation for a continuous infusion: or . L oading dose (LD in mg), Intravenous procainamide loading doses should be infused no faster than 25-50 mg/min .   31

32. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie M ethods to administer procainamide LD. administers 100 mg q5` to a maximum of 500 mg; a 10 minute waiting period to allow drug distribution to tissues is utilized if more than 500 mg is needed to abate the arrhythmia. administers the loading dose as a short-term infusion at a rate of 20 mg/min over 25-30 minutes, not to exceed a total dose of 17 mg/kg . 32

33. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Steady-State Concentration Selection therapeutic range procainamide is 4-10 μg /ml. + NAPA “total procainamide” is 10-30 μg / mL. but, are not equipotent anti- arrhythmics . individualized for each patient in order to achieve optimal responses and minimal S/ Es . 33

34. USE OF PROCAINAMIDE AND N APA SERUM CONC. TO ALTER DOSES 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Because procainamide follows linear, dose-proportional pharmacokinetics in most patients, serum Css (procainamide and NAPA) change in proportion to dose according to the following equation : C ss , new = ( D new / D old )C ss, old 34

35. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Example 1 LK is a 50-year-old, 75-kg (height = 5 ft 10 in) male with VT who requires therapy with oral procainamide SR tablets. He has normal liver and cardiac function. Suggest an initial oral procainamide dosage regimen designed to achieve a steady-state procainamide concentration equal to 4 μg / mL . 35

36. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Estimate t 1/2 and K E according to disease states and conditions present in the patient . t 1/2 is 3.3 hours. So, K E = 0.693/t 1/2 = 0.693/3.3 h =0.210 h −1 . Estimate the V d and CL V = 2.7 L/kg • 75 kg = 203 L. Cl = kV = 0.210 h −1 • 203 L = 42.6 L/h. Compute dosage regimen 36

37. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Oral SR procainamide tablets will be prescribed to this patient (F = 0.83 ). Because the patient has a rapid procainamide CL and short t 1/2 , the initial dosage interval (τ) will be set to 6 hours. The dosage equation for oral procainamide is: 𝐷=(𝐶𝑠𝑠∗𝐶𝐿∗𝜏)/𝐹= (4 mg/L • 42.6 L/h • 6 h)/0.83 = 1231 mg, rounded to 1250 mg every 6 hours . 37

38. Literature-Based Recommended Dosing 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie very commonly used method Doses are based on those that commonly produce Css in the lower end of the therapeutic range . procainamide Css expected from the lower end of the dosage range is 4-6 μg /mL and 6-10 μg /mL for the upper end of the dosage range. See table on next sld. 38

39. Half-Life and Elimination Rate Constant Estimate 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Disease state/Condition Procainamide, oral tablets Procainamide Continuous Intravenous Infusion Adult, normal RF ( clcr >50 mL/min) 50 mg/kg/d 2-6 mg/min Adult, renal dysfunction Clcr =10-50 mL/min: 25-50% ↓ <10 mL/min: 50%-75% ↓ Clcr =10-50 mL/min: 25-50% ↓ <10 mL/min: 50%-75% ↓ Adult, uncompensated HF CHF NYHA class II: 25% dosage ↓, class III or IV: 50% dosage ↓ CHF NYHA class II: 25% dosage ↓, class III or IV: 50% dosage ↓ Adult, liver disease Child/Pugh score = 8-10: 25% dosage ↓ >10: 50% dosage ↓ Child/Pugh score = 8-10: 25% dosage ↓ >10: 50% dosage ↓ Adult, obese Base dose on TBW according to other disease states/ conditions Base dose on TBW according to other disease states/ conditions 39

40. Pediatric doses 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie similar to those given to adults when adjusted for differences in body weight. The recommended I.V LD is 2-6 mg/kg over 5 minutes ( maximum dose 100 mg ), repeating as necessary every 5-10 minutes to a maximum dose of 15 mg/kg ( no > 500 mg should be given within a 30`). 40

41. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie For patients with VT and poor perfusion 15 mg/kg infused over 30-60 minutes as a single dose can be considered if cardio version is ineffective. I.V maintenance infusion rates equal 20-80 μg /kg/min (max. dose 2 g/d ). Oral maintenance doses are 15-50 mg/kg/d. 41

42. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie The dosage interval chosen should be appropriate for dosage form administered to the patient. For the example given on slide no. 34. procainamide maintenance dose of 50 mg/kg/d is suggested. The suggested initial dose would be 3750 mg/d (50 mg/kg/d • 75 kg = 3750 mg/d), rounded to 4000 mg/d or 1000 mg every 6 hours. 42

43. IV TO PO CONVERSION OF PROCAINAMIDE DOSE 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie Assuming that equal procainamide serum Css are desired, Intravenous [ ] and oral [ ] corrected for procainamide salt form are prescribed: or D po is equivalent oral dose in mg,   43

44. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie 44 Bauer, Larry A.. "Chapter 8. Procainamide/N-Acetyl Procainamide." Applied Clinical Pharmacokinetics, 2e. Ed. Larry A. Bauer. New York, NY: McGraw-Hill, 2008,http://accesspharmacy.mhmedical.com/content. Lange  RA, Hillis  LD. Cardiovascular testing. In: Dipiro  JT, Talbert  RL, Yee  GC, Matzke  GR, Wells  BG, Posey  LM, eds. Pharmacotherapy. New York, NY: McGraw-Hill; 2011:55–81.

45. 12/5/2016 Clinical Pharmacokinetics of procainamide by Behailu & Bezie 45 Thanks!!!!!!