PHA Case Studies V (Answers)

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1 PHA 5128 Case Studies V (Answers) 1. A 100 kg patient is to be treated p.o. with sodium phenytoin capsules. Assuming a phenytoin volume of distribution of 0.7 L/kg, Km of 4 mg/l and Vmax of 7 mg/kg/day, calculate the following: For a 100 kg patient, Vd 0.7 L/kg 100kg 70 L Km 4 mg/l (a) 7mg / day Vmax 100kg 700mg / day k The loading dose to produce an initial concentration of 18 mg/l. How would you administer this dose? For a loading dose to produce a Cp of 18 mg/l, Vd Cp LD (70L)(18mg / L) (0.92)(1) ~ 1370mg Given as IV infusion of 50 mg/min or 3 oral doses of 500, 400, 400 mg every 2hrs. (b) The daily maintenance dose to produce an average steady state concentration of 15 mg/l. The concentration at steady-state is given by D Cpss Cl τ Since phenytoin exhibits nonlinear clearance, Vm Cl Km+ C pss Inserting this expression for Cl into the equation above and solving for dose D gives F:\INTRDEPT\Derendorf\cs5-ans-02.doc 1

2 Vm C pss τ D ( Km + C pss) S F For Cpss of 15 mg/l, the daily dose is (700mg / day)(15mg / L)(1day) D (4mg / L + 15mg / L)(0.92)(1) 600mg/day 2. A patient (35 years old, 65 kg) is to be started on intravenous phenobarbital sodium. The therapeutic range is mg/l. A loading dose is given so as to yield a Cp 0 of 30 mg/l. Calculate this loading dose and the daily maintenance dose to produce an average steady state concentration of 20 mg/l. Based on average PK parameters for a 65 kg patient, Vd (0.7L/kg)(65kg) 45.5L Cl (4 ml/hr/kg)(65 kg) 260 ml/hr 6.24 L/day The loading dose is Vd Cp LD L)(30mg / L) (0.9)(1) 1517mg ~ 1500mg To maintain an average plasma concentration of 20 mg/l, Cl Cpss τ MD ( 6.24L / day)(20mg / L)(1day) (0.9)(1) ~ 140 mg/day F:\INTRDEPT\Derendorf\cs5-ans-02.doc 2

3 3. Estimate a digoxin loading dose that will produce a plasma concentration of 1.5 µg/l for a 70 kg patient R.J., being treated for mild to moderate congestive cardiac failure. How should this loading dose be divided and what would be an appropriate interval between doses? Assume R.J. is a 50- year-old male with a serum creatinine of 1.0 mg/dl. Calculate a maintenance dose that will achieve an average plasma digoxin concentration of 1.5 µg/l. If the patient had had a serum creatinine of 5 mg/dl, would the estimated loading dose have been different? Assuming population average parameters, the Vd for a 70 kg patient is Vd (7.3 L/kg)(70 kg) 511 L (i) Assuming loading dose is administered orally as tablets (S 0.7), Vd Cp LD 0 (511L)(1.5µ g / L) 1095µ g ~ 1000µ g (0.7)(1) (ii) For a 70 kg male patient, 50 y.o. patient with CHF (moderate) and SCr of 1.0 mg/dl, Cl(ml/min) (0.33 ml/min/kg)(weight in kg) + (0.9) Cl creat (in ml/min) In order to use this equation, Cl creat must be determined. Cl creat (140 age)( weight) ( male) 72 Scr (140 50)(70) 87.5ml/ min (72)(1) The digoxin clearance is then Cl (0.33 ml/min/kg)(70) + (0.9)(87.5 ml/min) 1L 60min 24hr 101.9ml/ min 1000ml 1hr 1day L/day The daily dose of digoxin is then found to be F:\INTRDEPT\Derendorf\cs5-ans-02.doc 3

4 Cl C pss τ Dose ( 146.7L / day)(1.5µ g / L)(1day) (0.7)(1) 314.4µg (iii) If Scr is 5 mg/dl rather than 1.0 mg/dl, a different loading dose would be calculated. Although Vd and Cl are independent kinetic parameters, certain disease states may affect them both. An empirical expression for the Vd of digoxin has been derived in terms of Cl creat : Vd(L) (3.8 L/kg)(weight in kg) + (3.1) Cl creat (ml/min) An increased Scr indicates renal dysfunction and a smaller Cl creat. Thus, based on this equation, Vd is decreased and a smaller loading dose is needed, Vd Cp LD 0 F:\INTRDEPT\Derendorf\cs5-ans-02.doc 4

5 4. GH is a 56 year old liver transplant patient. In the hospital, he received 300 mg QD cyclosporin as an iv infusion which resulted in a trough level of 200 ng/ml. After he is discharged, he will continue with oral cyclosporine treatment. Make a dose recommendation for GH. If 300 mg cyclosporine provides correct plasma levels, dose simply needs to be converted to oral dose (F 0.3) New dose F F current NewFormulation x Current dose 1 (300mg ) 1000mg / day 0.3 Give 500 mg every 12 hours. F:\INTRDEPT\Derendorf\cs5-ans-02.doc 5

6 5. Camille Carton is a 36 year old female with newly diagnosed atrial fibrillation with accompanying severe obesity. She is 5'7" tall and weights 338 Ibs. Her cardiologist calls the pharmacy and states that he has had trouble in dosing similar patients in the past and would like some assistance in designing a loading and maintenance IV Lanoxin dosage regimen. She has no other complicating drugs or diseases (serum creatinine 0.7 mg%) except that she is being continued on Quinidex Extentabs 300 mg Q8H which she has been reliably taking for 3 years. Respond to the physician's request and in addition, volunteer some helpful TDM guidelines. Upon receiving your recommended digoxin regimen for 5 days, you have the following serum digoxin concentrations: Start date 2/2/92 at 8 a.m., SDC 1.3 ng/ml at 7 a.m. 2/4/92 and 1.7 ng/ml at 7 a.m., 2//7/92. Prepare a follow-up consult and include a warning as to what might be expected if quinidine were discontinued but digoxin remained at the current dosage. Given information: 5'7", 36 y.o. female 338 lbs Scr 0.7 For any calculations, IBW should be used. IBW x (height above 5') 45 + (2.3)(7) 61.1 kg Creatinine clearance may now be calculated: Cl creat (0.852)(140 age) weight (female ) (72) Scr ( 0.85)(140 36)(61.1) (72)(0.7) 107 ml/min Cl and Vd may be estimated using the empirical equations in the text (p. 201) Cl TOT (0.8 ml/min/kg)(ibw) + Cl creat (ml/min) (0.8 ml/min/kg)(61.1 kg) ml/min 156 ml/min Since quinidine is being co-administered, this value is multiplied by 0.5. Thus, for this patient F:\INTRDEPT\Derendorf\cs5-ans-02.doc 6

7 Cl TOT (156 ml/min)(0.5) 78 ml/min 1440 min/day 1L/1000 ml 112 L/day Vd 3.8L / kg IBW Cl ( ml creat ( 3.8L / kg)(61.1kg) + (3.1)(107) / min) 564 L (564 L)(0.7) 395 L if on quinidine as well To obtain an initial concentration of 1.5 µg/ml Cp 0 D Vd is solved for D (or LD/loading dose) to give LD Cp 0 Vd (1.5 µg/l)(395 L) 593 ~ 600 µg A maintenance dose to provide the same concentration is MD Cl C pss τ (112 L/day)(1.5 µg/l)(1 day) 168 µg/day ~ 175 µg/day Since two points are given, a better estimate of the clearance for this patient may be obtained using Cl ( Dose / τ) ( Cp Cp average 2 Cp1) Vd t (See page ; see also equation 58 p. 87) F:\INTRDEPT\Derendorf\cs5-ans-02.doc 7

8 (175µ g / day) Cl 1.5µ g / L 66.5 L/day [( ) µ g / L(564L) /3days] If the patient were to be continued on the current dosing regimen of 175 µg/day, the average would be Cpss D C pss Cl τ 175µ g / day (66.5L / day)(1day) 2.6µ g / L This is above the therapeutic range (although concentrations above 2 µg/l are used for atrial fibrillation according to the book). To provide an average concentration of 1.5 µg/ml, MD Cl C pss τ (66.5 L/day)(1.5 µg/day)(1 day) ~ 100 µg/day This dose is small since clearance had been overestimated for this patient. If quinidine were discontinued, clearance would increase (double) and maintenance dose would need to be increased to provide therapeutic concentrations. F:\INTRDEPT\Derendorf\cs5-ans-02.doc 8