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PharmacokineticsMultiple dosingCss,max = D/V x 1/(1 – e -K τ )= 80mg/20L x 1/(1 – e -0.03h-1 x 8h )= 4mg/L x 1/(1 – e -0.24 ) Note: No units in exponential as h -1 and h cancel out)= 4mg/L x 1/(1 – 0.787)= 4mg/L x 1/0.213= 4mg/L x 4.69= 18.76mg/LCss,min = Css,max – D/V= 18.76mg/L – 80mg/20L= 18.76mg/L – 4mg/L= 14.76mg/LThe proposed dosage regime (80mg three times daily) would be unexceptional in a patient with normal renal function,but this patient evidently has very poor kidney function (K only 0.03h -1 ) and consequently the regime would be grosslyexcessive in this case; peak and trough concentrations both exceeded their target values.10.3.3 Aminoglycoside use with poor renal functionAminoglycoside administration in patients with very poor renal function raises a special problem; we want the peaks tobe high enough to produce an adequate antibiotic effect, but we also wish to see troughs low enough to avoid toxicity.With poor renal function, we cannot meet both of these goals simply by adjusting the dose size. The solution is to extendthe dosage interval. The extra time between doses will allow us to have high peak concentrations, but there will still beadequate time for concentration to fall to a suitably low trough.For a patient with very poor renal function, aminoglycosides must be administered with long dosage intervals, inorder to allow enough time for high peak concentrations to decline to a suitably low trough.It is useful to consider how many half-lives need to separate the doses and what the half-life of the drug will be in therelevant patient. Take, as an example, the patient described at the end of Section 10.3.2.K = 0.03h -1t_half = 0.693 / 0.03 -1= 23.1 hoursTarget peak concentration was 5 to 10 mg/L, so make the target = 8 mg/LTarget trough was less than 2 mg/L.So, we need to have concentrations fall four-fold from peak to trough, which means leaving two half-lives between doses.A dosage interval of 2 x 23.1h is therefore indicated. Taking a figure that is clinically realistic, 48 hours should be adequate.(Previously we were trying to use an interval of 8 hours – no wonder it didn’t work!)100Download free ebooks at bookboon.com