TDM Lecture 7 5 th Stage. TDM of Digoxin. Uses: Digoxin is usually used in heart failure associated and atrial fibrillation.

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1 TDM Lecture 7 5 th Stage TDM of Digoxin Digoxin uses and elimination Uses: Digoxin is usually used in heart failure associated and atrial fibrillation. Elimination: About 75% of digoxin clearance occurred by renal function, while about 25% of it occurred by hepatic function, therefore, it is mainly eliminated by kidney. Digoxin dosage forms: - Digoxin injection is 100 μg/ml and 250 μg/ml (rounded to lowest 100 or 125 μg) - Digoxin tablets is 125 μg and 250 μg (rounded to lowest 125 μg) Initial Dosage Determination Methods of Digoxin Pharmacokinetic Dosing method 1 Estimate digoxin clearance (Cl): Cl = (CrCl) + Cl NR Where Cl is digoxin clearance in ml/min Cl NR is non-renal digoxin clearance ml/min; CrCl is creatinine clearance in ml/min What is the value of Cl NR? a - A digoxin non renal clearance Cl NR value of 40 ml/min is used for patients without heart failure or who have only mild heart failure (CHF classes I or II). 1

2 b - A digoxin non-renal clearance Cl NR value of 20 ml/min is used for patients with moderate or severe heart failure (CHF classes III or IV) which leads to a reduction in liver blood flow and digoxin hepatic clearance. 2 Estimate volume of distribution: a For normal patients (patients without diseases and conditions), volume of distribution (V) is 7 L/kg. - For patients that are significantly overweight (more than 30% over IBW) use ideal body weight (IBW) instead of actual body weight. b For patients with renal impairment (Cr Cl is equal or less than 30 ml /min) use the following equation to estimate volume of distribution: V = { * CrCl CrCl } (Wt/70) - For patients that are significantly overweight (more than 30% over IBW) use ideal body weight (IBW) instead of actual body weight. 3 Select Steady-state concentration: - Digoxin Css are selected based on the disease being treated: a - For heart failure, value of ng/ml are usually used. An initial target digoxin concentration of 0.8 ng/ml is reasonable. b - For atrial fibrillation, value of ng/ml are usually used. An initial target digoxin concentration of 1.2 ng/ml is reasonable. 4 Pharmacokinetic equations: a Calculate maintenance dose (D/τ) Css = [ F ( D / τ ) ] / Cl D / τ = ( Css * Cl ) / F 2

3 Where F is the bioavailability fraction (for IV, F = 1); (for oral tablets F = 0.7) D is digoxin dose in μg; τ is the dosage interval in days Cl is digoxin clearance in ml/day; D / τ is the maintenance dose Note: For concentration units ng/ml = μg/l Conversion factors are needed to change milliliters to liters (1000 ml/l) and minutes to days (1440 min/d). b Calculate loading dose: LD = (Css * V) / F Where LD is digoxin loading dose in μg; Css is the desired steady state digoxin concentration in μg/l V is digoxin volume of distribution in L; F is the bioavailability fraction (for IV, F = 1); (for oral tablets F = 0.7) - Loading dose is usually given in divided doses separated by 6 hours (50% dose initially, followed by two additional 25% doses) in order to avoid toxicity. Example1 MJ is a 50-year-old, 70-kg (5 ft 10 in) male with atrial fibrillation for less than 24 hours. His current serum creatinine is 0.9 mg/dl, and it has been stable over the last 5 days since admission. Compute an intravenous digoxin dose for this patient to control ventricular rate. Answer 1 Estimate digoxin clearance (Cl): CrClest = [ (140-50) * 70 Kg] 72 * 0.9 mg/dl CrClest = 97 ml/min Cl = (CrCl) + Cl NR 3

4 Cl = (97 ml/min) + 40 ml/min Cl = 167 ml/min 2 Estimate volume of distribution: For normal patients (patients without diseases and conditions), volume of distribution (V) is 7 L/kg. V = 7 L/Kg * 70 kg V = 490 L 3 Select steady-state concentration: For atrial fibrillation, the desired target digoxin concentration would be ng/ml. A serum concentration equal to 1.2 ng/ml will be chosen. - Concentration units ng/ml = μg/l - Conversion factors are needed to change milliliters to liters (1000 ml/l) and minutes to days (1440 min/d). 4 Pharmacokinetic equations: a Calculate maintenance dose (D/τ): D/τ = (Css * Cl) / F (F = 1 for IV) D/τ = (1.2 μg/l * 167 ml/min * 1440 min/d) / (1 * 1000 ml/l) D/τ = 288 μg/d, round to 250 μg/d b Calculate loading dose (LD): LD = (Css * V) / F = (1.2 μg/l * 490 L) / 1 LD = 588 μg rounded to 500 μg - Loading dose is usually given in divided doses separated by 6 hours (250 μg initially, followed by two additional 125 μg) to avoid toxicity. 4

5 Example2 The same patient profile as in example 1, but serum creatinine is 3.5 mg/dl indicating renal impairment. Compute an intravenous digoxin dose for this patient to control ventricular rate. Answer 1 Estimate digoxin clearance (Cl): CrClest = [ (140-50) * 70 Kg] 72 * 3.5 mg/dl CrClest = 25 ml/min Cl = (CrCl) + Cl NR = (25 ml/min) + 40 ml/min Cl = 73 ml/min 2 Estimate volume of distribution: For patients with renal impairment (Cr Cl is equal or less than 30 ml /min): V = {226 + V = {226 + V = 364 L 298 * CrCl CrCl } (Wt/70) 298 * 25 ml/min ml/min } (70/70) 3 Select steady-state concentration: For atrial fibrillation, the desired target digoxin concentration would be ng/ml. A serum concentration equal to 1.2 ng/ml will be chosen. - Concentration units ng/ml = μg/l - Conversion factors are needed to change milliliters to liters (1000 ml/l) and minutes to days (1440 min/d). 5

6 4 Pharmacokinetic equations: a Calculate maintenance dose (D/τ): (F = 1 for IV) D/τ = (Css * Cl) / F = (1.2 μg/l * 73 ml/min * 1440 min/d) / (1 * 1000 ml/l) D/τ = 125 μg/d b Calculate loading dose (LD): LD = (Css * V) / F = (1.2 μg/l * 364 L) / 1 LD = 437 μg rounded to 400 μg - Loading dose is usually given in divided doses separated by 6 hours (200 μg initially, followed by two additional 100 μg) to avoid toxicity. Example3 The same patient profile as in example 1, but serum creatinine is 3.5 mg/dl indicating renal impairment. In addition, the patient is being treated for CHF class III (moderate heart failure), not atrial fibrillation. Compute an oral digoxin tablet maintenance dose for this patient. Answer 1 Estimate digoxin clearance (Cl): CrClest = [ (140-50) * 70 Kg] 72 * 3.5 mg/dl CrClest = 25 ml/min Cl = (CrCl) + Cl NR Cl = (25 ml/min) + 20 ml/min Cl = 53 ml/min 6

7 2 Select steady-state concentration: For heart failure, the desired target digoxin concentration would be ng/ml. A serum concentration equal to 0.8 ng/ml will be chosen. - Concentration units ng/ml = μg/l - Conversion factors are needed to change milliliters to liters (1000 ml/l) and minutes to days (1440 min/d). 3 Pharmacokinetic equations: Calculate maintenance dose (D/τ): D/τ = (Css * Cl) / F (F = 0.7 for oral tablets) D/τ = (0.8 μg/l * 53 ml/min * 1440 min/d) / (0.7 * 1000 ml/l) D/τ = 87 μg/day (round to lowest 125 μg) D/τ = 174 μg for 2 days rounded to 125 mg every other day Example 4: OI is a 65-year-old, 170-kg (5 ft 5 in) female with CHF class III (moderate heart failure). Her current serum creatinine is 4.7 mg/dl and is stable. Compute an intravenous digoxin loading and maintenance dose for this patient. 1 Estimate digoxin clearance (Cl): The patient is obese (weight is 170 kg); IBW= (2.3 * 5) = = 57 kg The Salazar and Corcoran equation can be used: CrCl = ( age ) [ ( * BW ) + ( 9.74 * Ht 2 60 * SCr CrCl = ( y ) [ (0.287 * 170 kg) + (9.74 * {1.65m} 2 ) ] 60 * 4.7 mg/dl CrCl = 22 ml/min ) ] 7

8 Cl = (CrCl) + Cl NR Cl = (22 ml/min) + 20 ml/min Cl = 48 ml/min 2 Estimate volume of distribution: For patients with renal impairment (Cr Cl is equal or less than 30 ml /min): V = {226 + V = 288 L 298 * CrCl CrCl } (Wt/70) = { * 22 ml/min ml/min } (57/70) 3 Select steady-state concentration: For heart failure, the desired target digoxin concentration would be ng/ml. A serum concentration equal to 0.8 ng/ml will be chosen. 4 Pharmacokinetic equations: a Calculate maintenance dose (D/τ): (F = 1 for IV) D/τ = (Css * Cl) / F = (0.8 μg/l * 48 ml/min * 1440 min/d) / (1 * 1000 ml/l) D/τ = 55 μg/d D/τ = 110 μg for 2 days rounded to 100 μg every other day b Calculate loading dose (LD): LD = (Css * V) / F = (0.8 μg/l * 288 L) / 1 LD = 230 μg rounded to 200 μg Loading dose is usually given in divided doses separated by 6 hours (100 μg initially, followed by two additional 50 μg) to avoid toxicity. 8

9 Jelliffe Method: This method focuses on calculating loading dose (LD) by estimation of total body store TBS of digoxin required to produce the desired therapeutic effect. LD (μg/day) = TBS (μg/day)/ F, where F is the bioavailability. For oral dose F =0.7 and for intravenous dose F = 1. Total body store TBS of digoxin for inotropic effect is 8-10 μg/kg while for chronotropic effect μg/kg. For renal failure (creatinine clearance less than 30 ml/ min), TBS of digoxin should be considered 6-10 μg/kg. For obese individuals (over 30% of their ideal body weight), the ideal body weight should be used. The administration of loading dose should successfully increase serum concentration to steady-state level; the maintenance dose on the other hand should replace daily losses of digoxin (lost through elimination) and maintain Css. %lost/d = 14% (CrCl), where 14% is non-renal loses and CrCl accounts for renal elimination. Maintenance dose (μg/day) = [TBS (μg/day) * %lost/d]/ (F * 100) Maintenance dose (μg/day) = {TBS (μg/day) * [ (CrCl)]} / (F * 100) Example 1 MJ is a 50-year-old, 70-kg (5 ft 10 in) male with atrial fibrillation for less than 24 hours. His current serum creatinine is 0.9 mg/dl, and it has been stable over the last 5 days since admission. Compute an intravenous digoxin dose for this patient to control ventricular rate. Answer: 1. Estimate creatinine clearance. CrClest = [(140 age)bw]/ (72 SCr) = [( y)70 kg]/ ( mg/dl) CrClest = 97 ml/min 2. Estimate total body store (TBS) and maintenance dose(d). Digoxin total body stores of μg/kg are effective in the treatment of atrial fibrillation. TBS = 14 μg/kg 70 kg = 980 μg 9

10 D = {TBS [ (CrCl)]} / (F 100) = {980 μg [ (97 ml/min)]} / (1 100) = 328 μg/d, round to 375 μg/d 3. Compute loading dose. LD = TBS/ F = 980 μg / 1 = 980 μg, round to 1000 μg. When digoxin loading dose is administered, it is usually given in divided doses separated by 4 6 hours (50% of dose at first, followed by two additional doses of 25%). In this case, an initial intravenous dose of 500 μg would be given initially, followed by two additional intravenous doses of 250 μg each. 10