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<strong>Pharmacokinetics</strong>Non-linear pharmacokinetics(a)Rate ofelim=Rate ofadminLinear(b)Rate ofelim=Rate ofadminNon-linear(c)Blood drug conc(d)Blood drug concBlooddrugconcBlooddrugconcRate of adminRate of adminFigure 11.6 The effect of non-linearity upon the relationship between dose and blood concentration at steady state11.4 Clinical significance of non-linear kineticsDotted lines on part (c) of Figure 11.6 indicate two rates of drug administration which differ by a factor of two and theblood drug levels that would be associated with them. Doubling the rate of administration simply doubles the consequentblood levels. For most drugs, there is a very simple rule that an x% change in dose leads to an x% change in blood levels.This makes dosage adjustment very simple – if you want a 25% increase in blood levels, increase the dose by 25%Please click the advert114Download free ebooks at bookboon.com
<strong>Pharmacokinetics</strong>Non-linear pharmacokineticsHowever, this simple relationship certainly does not extend to the likes of phenytoin. From part (d) of Figure 11.6, it isclear that a doubling in dose would achieve far more than a doubling in blood levels.Given the potential toxicity of phenytoin, dosage adjustment is a specialist job; the normal concepts and rules justdon’t apply. General pharmacokinetics assumes first order drug elimination where the elimination rate constant is avalid concept. With non-linear kinetics, there is no longer a constant proportionality between rate of elimination anddrug concentration (Figure 11.6 part b) and the idea of an elimination rate constant linking the two no longer applies.Because the elimination rate constant is intimately linked to half-life and clearance, these two parameters also cease toapply. The only way to describe drug elimination in the non-linear situation is to go all the way back to the fundamentalenzymological constants Vmax and Km. Unlike K, these do have fixed values for a particular drug in a particular patientand can be used to calculate what concentration of drug would arise from a given dosage regime.There are a number of different ways to go about dose adjustment with phenytoin. However, this book is designed toconvey general principles and detailed coverage of the art of pheytoin dose adjustment is well beyond its remit.For most drugs, changes in dose size bring simple, proportionate changes in blood levels. With non-linear drugssuch as phenytoin, changes in blood levels are disproportionately large. Great caution is required.11.5 Non-linear kinetics and drug developmentClinical workers are subjected to considerable additional complexity when trying to use a non-linear drug like phenytoinand given a choice of drugs that are otherwise equally acceptable, they would undoubtedly choose one with simple linearkinetics over a non-linear one. There is therefore a strong commercial disinclination to proceed with the development ofany further non-linear drugs; companies would want to establish at an early stage, that any candidate drug did not sufferfrom this problem.Drug companies want to establish at an early stage that any new candidate drug molecule obeys simple linearkinetics.115Download free ebooks at bookboon.com
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