TDM Lecture 8 5 th Stage TDM of Digoxin Use of Digoxin Serum Concentrations to Alter Dosages Linear Pharmacokinetics Method This method is used in steady-state condition. We compute the new dose of digoxin by using the following equation: D new / Css new = D old / Css old Or D new = (Css new / Css old) D old Note: we should know at first if the drug has been reached to the steady-state concentration or not. Example1 MJ is a 50-year-old, 0-kg (5 ft 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. A Digoxin tablet dose of 250 μg/day was prescribed and expected to achieve steady-state serum concentration equal to 0.8 μg/l. After a week of treatment, a steady-state serum concentration was measured and was equal to 0.6 μg/l. Calculate a new digoxin tablet dose that will provide a steadystate serum concentration equal to 0.9 μg/l. 1
Answer 1 Check if the patient has been reached to the steady-state concentration or not: CrClest = CrClest = [ (140 - age) * body weight] 2 * serum creatinine (Scr) [ (140-50 y) * 0 Kg] 2 * 0.9 mg/dl CrClest = 9 ml/min - From the following table we will know if the patient has been reached to the steady-state or not: Creatinine clearance ml/min 0 20 30 40 50 60 0 80 90 0 Number of days before steady-state achieved 22 19 16 14 13 12 11 9 8 2
- From the previous table we conclude that this patient has reached to the steadystate concentration (because there is more than days of treatment). Note: This step can be omitted if you know that the patient has reached to steadystate. 2 Compute the new dose: D new = (Css new / Css old) D old D new = (0.9 μg/l / 0.6 μg/l) 250 μg/day D new = 35 μg/day Therefore, the new suggested dose is 35 μg/day to be started at the next scheduled dosing time. Example2 OI is a 65-year-old, 10-kg (5 ft 5 in) female with NYHA class III moderate heart failure. Her current serum creatinine is 4. mg/dl and is stable. A digoxin IV dose of 125 μg/day was prescribed and expected to achieve steady-state serum concentration equal to 1 μg/l. After 3 week of treatment, a steady-state serum concentration was measured and was equal to 2.5 μg/l. Calculate a new digoxin IV dose that will provide a steady-state serum concentration equal to 1.2 μg/l. 1 Check if the patient has been reached to the steady-state concentration or not: The patient is obese (her weight is 10 kg) IBW= 45.5 + (2.3 * 5) = 45.5 + 11.5 = 5 kg The Salazar and Corcoran equation can be used: CrCl = ( 146 - age ) [ ( 0.28 * BW ) + ( 9.4 * Ht2 ) ] 60 * SCr 3
CrCl = ( 146-65 y ) [ (0.28 * 10 kg) + (9.4 * {1.65m}2 ) ] 60 * 4. mg/dl CrCl = 22 ml/min - From the following table we will know if the patient has been reached to the steady-state or not: Creatinine clearance ml/min 0 20 30 40 50 60 0 80 90 0 Number of days before steady-state achieved 22 19 16 14 13 12 11 9 8 - From the previous table we conclude that this patient has reached to the steadystate concentration (because there is more than 16 days of treatment). 4
2 Compute the new dose: D new = (Css new / Css old) D old D new = (1.2 μg/l / 2.5 μg/l) 125 μg/day D new = 60 μg/day (round to lowest 0 or 125 μg) D new = 120 μg every other day (rounded to 125 μg every other day) Therefore, the new suggested dose is 125 μg every other day. A day should be skipped before next dose is given. Pharmacokinetic Parameter Method: In this method, we calculate patient specific drug clearance and employ it to design better therapeutic regimen. D/τ = (Css Cl) / F, this is maintenance dose equation and through rearrangement we can get the following: Cl = [F*(D/τ)]/Css Where Cl: digoxin clearance in L/d, F: bioavailability factor, D/τ: maintenance dose in µg/d and Css: steady state concentration in ng/ml or µg/ml. Example 1: OI is a 65-year-old, 10-kg (5 ft 5 in) female with NYHA class III heart failure. Her current serum creatinine is 4. mg/dl and is stable. A digoxin dose of 125 μg/d given as tablets was prescribed and expected to achieve steady-state concentrations equal to 1 ng/ml. After the 3 weeks of therapy, a steady-state digoxin concentration was measured and equalled 2.5 ng/ml. Calculate a new digoxin dose that would provide a steady state concentration of 1.2 ng/ml. Answer: 1. Estimate creatinine clearance. IBW= 45.5+ (2.3*5) = 5 kg, so the patient is obese and we should apply Salazar and Corcoran equation to estimate creatinine clearance. 5
Note: Foot = 30.48 cm Inch = 2.54 cm Ht= (5 ft*30.48 cm/ft)+(5in*2.54 cm/in) = 165.1 cm, so the height is 1.65 m. By applying the following table, we conclude that the serum concentration had reached to steady state level (because there is more than 16 days of treatment). Creatinine clearance ml/min 0 20 30 40 50 60 0 80 90 0 Number of days before steady-state achieved 22 19 16 14 13 12 11 9 8 6
2. Compute drug clearance. Cl = [F(D/τ)] / Css = [0.(125 μg/d)] / 2.5 μg/l = 35 L/d 3. Compute new dose to achieve desired serum concentration. D/τ = (Css Cl) / F = (1.2 μg/l 35 L/d) / 0. D/τ = 60 μg/d, or 120 μg every other day (rounded to 125 µg every other day).