PHA 5128 Case Study 4 (Answers) Total Cp = Unbound Cp/fu.

Transcription

1 PHA 58 ase Study 4 (Answers) Spring 4. PT is a patient stabilized on chronic phenytoin therapy. She has just been diagnosed with rheumatoid arthritis and her physician would like to start her on high dose aspirin therapy. However, the physician is concerned about a possible drug interaction with aspirin. You find in your pocket reference that high dose aspirin is known to displace phenytoin from its plasma protein binding sites. Describe (as you would to the physician) the clinical relevance of this interaction and your therapeutic recommendations. While it is true that aspirin displaces phenytoin from its plasma protein binding sites, there is no reason to alter the phenytoin dose or switch from aspirin to another agent just because of the drug interaction. Specifically, phenytoin is a low extraction, restrictively cleared drug. This means that it s clearance is determined by unbound clearance and fraction unbound. Addition of aspirin to the regimen will lead to an increased unbound fraction of phenytoin. This will increase phenytoin s clearance and decrease it s total drug concentration. HOWEER, unbound concentration will be unchanged as it is determined only by dose and unbound clearance. Therefore the free (and pharmacologically active) phenytoin concentration will be unchanged in spite of this drug interaction, thus changes in dosage will be unnecessary. However, it is important for the physician to understand that the total phenytoin concentration will decrease, in spite of no change in the free concentration. For example, if phenytoin free fraction increases from % to 5%, the following total concentration will change as follows: Total p Unbound p/fu. Remember unbound p doesn t change in this interaction because unbound clearance doesn t change. Here is an example of what can be observed: Before aspirin: total p - mcg/ml fu -. unbound p -. mcg/ml After aspirin: total p - 8 mcg/ml fu -.5 unbound p -. mcg/ml If the medical team is unaware of this, and measures a total phenytoin level, the normal reaction would be to increase the dose, which would be inappropriate and likely to lead to toxicity.

2 . A phenytoin patient has a plasma concentration of mg/l at 3mg/day and 5mg/L at 4mg/day. Using graph paper, determine the Km and as well as the dose needed to produce a concetration of 5mg/L Dose needed to produce a concentration of 5mg/L 35mg/day

3 3. E. A., (37y, 7 kg, male), had been taking 3mg/day of phenytoin; however, his dose was increased to 35 mg/day because his reported plasma concentration was only 8 mg/l. Now his reported plasma phenytoin concentration is mg/l. Both of the reported plasma concentrations represent steady-state level. alculate a new daily dose of phenytoin that will result in a steady state level of 5 mg/l (Salt factor.9). K m R R when salt factor is considered, it can be rewritten as: K m R R S S Now, we have levels of phenytoin () resulting from different daily doses (R ), so we can set up equations with unknown parameters (Km and ), and caculate K m and by solving the equations, which turn out to be: K m ( D ( D ( D ( D D ( S ( D ) D D D S ( D * daily dose, D R ) In this case, (3.9) (35.9) ( 8) ( 8) 36.5( mg / day) (3.9) 8 (35.9) ( ) K m.5( mg / L) 3.9 Then, the new daily dose will be:

4 m R 337.5( mg / ) ( K + ) S (.5 + 5).9 day m

5 4..S., a 36-year-old, 7-kg woman, is to be given carbamazepine as an anticonvulsant agent. alculate a daily dose that will produce an average steadystate plasma concentration of 6 mg/l. Maintenance dose (L)(ssave)( τ ) ( S )( F ) (.64L / kg / hr 7kg )(6mg / ()(.8 ) L )(4hr / day) 86.4mg / day Start on the initial daily dose of to 4 mg, with increase of about mg every 7 to 4 days till it reaches 8 mf daily.

6 5. O.S., a 48-year-old, 59 kg male patient, received a living-related renal transplant ½ years ago. He is currently receiving cyclosporine 3 mg orally as the solution BID and, in addition, prednisone 3 mg/day and azathioprine 75 mg/day. O.S. s current serum creatinine is. mg/dl and his steady-state cyclosporine trough concentration is 59 µg/l. The physician has ruled out the possibility of rejection and feels that the recent rise in serum creatinine is due to cyclosporine toxicity. What questions would one ask O.S. and how would one adjust his cyclopsporine regimen in order to achieve a new steady-state cyclosporine concentration of approximately µg/l? - confirm that O.S. has been taking his cyclosporine 3 mg BID as prescribed and determine if any new medications have been added to his regimen - verify that the time of sampling relative to when he took his last dose to ensure that the level is in fact a trough and not a peak concentration - if there are no obvious reasons for the elevated cyclosporine level, at least one cyclosporine dose should be held and then O.S. should be restarted on a new regimen - to calculate the new dose: Dosedesired cpssdesired cpsscurrent Dosecurrent µg 59µg / / L L 3mg.7mg mg