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Variability in drug dosage requirements

In the second article in a series intended to remind pharmacists about the basic principles of pharmacokinetics, pharmacodynamics and therapeutic
drug monitoring, Alison Thomson describes inter-individual variability issues that should be considered when recommending a dosage regimen

Callie Stewart
he main challenge in designing a “stan- volume of distribution of fat-soluble drugs,

T dard” drug dosage regimen is the variabil-

ity in drug handling that exists from
patient to patient. Understanding the sources
such as diazepam, is higher in the elderly.
Age also affects drug binding.The binding
of drugs to albumin in the plasma is reduced
of this variability and adjusting drug doses in neonates and in the elderly whereas bind-
accordingly is an area in which pharmacists ing to alpha-1-acid glycoprotein (an “acute
can make a major impact on risk manage- phase reactant” that is released in response to
ment and patient care. inflammation and trauma) is generally low in
There are three main sources of variability: infants but may be elevated in elderly
those related to observable clinical character- patients, especially if other disease processes
istics, those that are genetically determined are present.
and those related to other drug therapy. The clearance of drugs that are eliminated
by the kidney is significantly influenced by
Age age. Renal function is low at birth, particu-
Pharmacokinetic variability is particularly larly in premature neonates, and increases
important at the extremes of age.This reflects dramatically over the first two weeks of life, Identify knowledge gaps
differences in body composition and which means that the dose requirements of 1. List three clinical factors that influence drug
function. The weight-related volume of renally cleared drugs are highly variable dur- clearance.
distribution of water-soluble drugs (eg, ing this period. In later years, renal function 2. List three types of pharmacokinetic drug
aminoglycoside antibiotics) is higher in progressively declines and may be substan- interaction.
neonates than in adults because of the greater tially reduced in elderly patients, despite 3. List three effects of age on drug dosage
proportion of water per kilogram of body apparently “normal” serum creatinine con- requirements and serum concentrations.
weight. This means that if an adult and a centrations.
neonate are each given a 5mg/kg dose of Age also affects the hepatic metabolism of Before reading on, think about how this article
a water soluble drug, such as gentamicin, drugs. At birth, most drug metabolising may help you to do your job better. The Royal
the maximum concentration will be around enzymes are present but the activity of many Pharmaceutical Society’s areas of competence
16–20mg/L in the adult and 10–11mg/L enzyme systems is low, so this can result in for pharmacists are listed in “Plan and record”,
in the neonate. In contrast, the relative drug accumulation and toxicity. In contrast, (available at: www.rpsgb.org/education). This
the evidence that elderly patients have signif- article relates to “clinical pharmacy” and “effects
Alison Thomson, PhD, MRPharmS, icantly reduced hepatic function is limited, of age, other inter-patient varition and disease
is area pharmacy specialist and it is often unnecessary to reduce the dose states on drug therapy” (see appendix 4 of “Plan
at the Western Infirmary, of drugs that are cleared by hepatic metabo- and record”).
Glasgow lism unless other factors (eg, cardiac disease,

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 CPD
hepatic disease or drug interactions) are given less frequently to a patient with renal clearance but also, for some drugs, to an
involved. impairment. In contrast, the dose, rather than increase in bioavailability caused by a reduc-
the dosage interval, is usually altered for a drug tion in first-pass metabolism. For example, the
Body weight that has a long elimination half-life, such as bioavailabilities of morphine and labetalol
Many drug doses are based on the body digoxin, because it is easier for the patient to have been reported to double in patients with
weight of the patient (expressed as mg/kg), take a daily dose than a dose on alternate days. cirrhosis.
but the influence of obesity or malnourish- Another factor that could become impor-
ment on dosage requirements is not always tant if renal function continues to deteriorate Genetic factors
considered. If a drug is highly water soluble, is the influence of renal replacement therapy Genetic polymorphisms that lead to the pro-
it will have a limited distribution into fat and on drug clearance and dosage requirements. duction of isoenzymes with reduced or no
its volume may, therefore, be better correlated Haemodialysis is an efficient way of removing activity or to multiple copies of an enzyme
with “ideal body weight” or lean body mass. many drugs, although the relatively short with high activity make a major contribution
In contrast, total body weight may be more period of dialysis (typically four hours, three to the variability in the dose requirements of
relevant for a drug that is highly lipid soluble. times a week) means that the total amount of drugs that are eliminated by hepatic metabo-
However, although renal and hepatic func- drug removed is often small. Doses generally lism. Of particular note is the cytochrome
tion are related to body size, obesity may not correspond to those recommended for a P4502D6 isoenzyme (CYP2D6), which
produce a corresponding increase in renal glomerular filtration rate (GFR) less than catalyses the metabolism of many anti-
and hepatic function. Consequently, the use 10ml/min and the timing of doses is not crit- arrhythmic, antidepressant and antipsychotic
of total body weight to determine a drug ical. However, some antibiotics and antifungal drugs. Genetic variability in transporter pro-
dosage regimen could result in toxic effects if drugs are often deliberately given after dialy- teins, such as P-glycoprotein, the expression
the patient is grossly obese. sis to ensure that therapeutic concentrations of which is controlled by the MDR1 gene,
are maintained. In contrast, continuous pro- are also increasingly being recognised for
Sex cedures, such as haemofiltration, especially their importance to pharmacokinetic vari-
Although differences in drug handling be- the newer forms of haemodiafiltration with ability.
tween males and females have been observed high flow rates, produce a higher overall drug P-glycoprotein is present in many body
for a number of drugs, even after correcting clearance and, consequently, dosage recom- tissues, where it can influence drug absorp-
for weight, such differences are often consid- mendations based on a GFR of 10 to tion, distribution and elimination. For exam-
ered to be too small to warrant a dose 20ml/min are often used. ple, low digoxin bioavailability has been
change. However, doses can differ if the drug associated with high levels of P-glycoprotein,
is being used for a sex-specific indication, for Liver function which reduces bioavailability by pumping the
example, buserelin for endometriosis (300µg Unlike in renal disease, where creatinine drug back through the intestinal wall into the
intranasally three times a day) or for prostate clearance estimates provide a reasonable guide gut.
cancer (200µg intranasally six times a day). to alterations in drug dosage requirements, In the future, genetic screening may be
indicators of hepatic disease, such as elevated used to help determine the initial doses of
Renal function liver enzymes, low serum albumin concentra- drugs for which genetically determined vari-
Because many drugs are partially or mainly tions and clotting abnormalities, cannot ability in pharmacokinetics has been charac-
cleared by excretion through the kidneys, be directly related to drug clearance. terised.
deterioration in renal function is one of the Nevertheless, patients with severe cirrhosis
principal reasons for drug dosage adjustment will often need reduced doses of hepatically Drug interactions
in clinical practice. As demonstrated with cleared drugs to avoid toxicity. The increased Many of the clinically significant interactions
many antibiotics, the increase in elimination exposure demonstrated in such patients may between drugs are pharmacokinetic in ori-
half-life may mean that a drug should be not simply be due to a decline in hepatic gin, often due to induction or inhibition of

Table 1: Drugs affecting the action of cytochrome P450 enzymes

CYPP450 isoenzyme Inducer Inhibitor Drug substrate
1A2 cigarette smoke, omeprazole amiodarone, cimetidine, ciprofloxacin, amitriptyline, caffeine, clozapine, fluvoxamine, haloperidol,
clarithromycin, fluvoxamine, ofloxacin naproxen, ondansetron, paracetamol, theophylline, verapamil

3A4,5,7 efavirenz, nevirapine, phenobarbital, amiodarone, antiretrovirals, cimetidine, amitriptyline, amlodipine, antiretrovirals, atorvastatin, aztemizole,
rifampicin, St John’s wort ciprofloxacin, clarithromycin, erythromycin, carbamazepine, clarithromycin, clonazepam, ciclosporin,
fluconazole, fluvoxamine, grapefruit juice, diazepam, diltiazem, erythromycin, felodipine, glibenclamide,
itraconazole, ketaconazole, verapamil ketoconazole, lovastatin, methadone, midazolam, nifedipine
ondansetron, sertraline, sildenafil, simvastatin, sirolimus, tacrolimus,
taxol, terfenadine, verapamil

2C9 rifampicin amiodarone, fluconazole, fluvastatin, fluoxetine, diclofenac, glibenclamide, ibuprofen, naproxen, phenytoin,
fluvoxamine, isoniazid, lovastatin, paroxetine, piroxicam, S-warfarin, losartan, rosiglitazone
sertraline, zafirlukast

2C19 carbamazepine cimetidine, fluoxetine, fluvoxamine, ketoconazole, amitriptyline, citalopram, cyclophosphamide, diazepam,
lansoprazole, omeprazole, paroxetine lansoprazole, moclobemide, nelfinavir, omeprazole, pantoprazole,
phenobarbitone, R-warfarin

2D6 rifampicin amiodarone, celecoxib, cimetidine, fluoxetine, amitriptyline, carvedilol clozapine, codeine, dextromethorphan,
haloperidol, indinavir, methadone, paroxetine, fluoxetine, fluvoxamine, haloperidol, methadone, metoprolol,
ritonavir, sertraline ondansetron, paroxetine, perphenazine, risperidone, thioridazine,
timolol, tramadol, venlafaxine

2E1 ethanol, isoniazid disulfiram ethanol, paracetamol, theophylline

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 CPD
three days whereas induction may take any- impair the recirculation of oral contraceptives
Action: practice points thing from hours to weeks. If the interacting by altering the bacterial flora of the gut).
drug has a long elimination half-life, the
Reading is only one way to undertake CPD and the interaction may persist for some time after it Other factors
Society will expect to see various approaches in a has been discontinued. It is, therefore, impor- A range of other factors, such as pregnancy,
pharmacist’s CPD portfolio. tant not only to consider potential interac- cardiac disease, respiratory disease and infec-
1. Examine Appendix 1 in the British National tions when two drugs are given together but tion can lead to variability in drug concen-
Formulary and reflect on which interactions also when one is stopped. tration-time profiles. In addition, variations in
have a pharmacokinetic basis. adherence, which may take the form of
2. Examine Appendix 2 in the BNF and consider Absorption Recent studies have demon- missed doses, missed days or simply variations
which drugs that you routinely encounter in strated the importance of intestinal CYP3A4 in the times of dosing, will lead to unequal
your practice require a dose adjustment in and P-glycoprotein in drug absorption. dosage intervals and may affect the patient’s
patients with liver disease. Induction of these mechanisms by rifampicin response to therapy.This is a particular prob-
3. Reflect on which patients in your practice and by St John’s wort have been shown to lem when the drug has a short elimination
have or are at risk of renal impairment and reduce the bioavailability of digoxin. half-life and the aim is to maintain concen-
may require a dosage adjustment as Absorption can also be altered by drug trations above a minimum value. For exam-
recommended in the BNF Appendix 3. interactions within the gut that result from ple, variability in the dosage intervals of
binding to other drugs, such as cholestyra- antiretroviral drugs can lead to low concen-
mine or antacids, or to enteral feeds, as in the trations that facilitate the development of
Evaluate case of phenytoin. drug resistance.
For your work to be presented as CPD, you need to
evaluate your reading and any other activities. Distribution Drug distribution can be altered Summary
Answer the following questions: by interactions that cause displacement from A range of factors, including clinical charac-
plasma protein binding but these do not nor- teristics, genetic factors, concomitant disease
What have you learnt? mally alter maintenance dose requirements states and other drug therapy can influence
How has it added value to your practice? (Have unless there is also a reduction in the clear- the pharmacokinetics of a drug and conse-
you applied this learning or had any feedback?) ance of unbound drug. quently the patient’s response to drug ther-
What will you do now and how will this be apy. Drug dosage adjustments are often
achieved? Clearance Drug clearance can be altered by required to ensure that the patient achieves
enzyme induction or inhibition. Due to the an adequate dose without risk of toxicity.
wide variability in enzyme activity, the clini-
Topics in this series cal significance of an interaction is often dif-
Further articles in this back to basics series will ficult to predict on an individual basis. References
look at drug concentration-time profiles and Interactions are often dose-dependent and 1. Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on
therapeutic drug monitoring. the timescale of the offset and onset of the pharmacokinetics and drug dosing. Pharmacy World and
effect depends on the pharmacokinetics of Science 1998;20:183–92.
not only the two (or more) drugs concerned
metabolising enzymes or transporter proteins. but also the isoenzyme(s) responsible for their Further reading
■ Begg E. Instant Clinical Pharmacology, Blackwell Publishing
However, interactions can also occur between metabolism. Ltd., Oxford, 2002
drugs and food supplements or herbal reme- Other pharmacokinetic interactions have ■ Bunn R, Ashley C Eds. The Renal Drug Handbook, Second
dies. been reported that involve changes in renal Edition, Radcliffe Medical Press Ltd, Oxon 2004.
Table 1 contains a list of isoenzymes of clearance (eg, probenecid reduces the renal ■ Ritschel WA, Kearns GL. Handbook of Basic
CYP450, some of their major inducers and clearance of many antibiotics by competing Pharmacokinetics. 5th Edition. American Pharmaceutical
inhibitors and the substrates that are associ- for the anion secretion transport mechanism) Association, Washington DC, 1999.
ated with them. Interactions involving com- and changes in biliary secretion and entero- ■ Stockley IH, Ed, Drug Interactions. London: Pharmaceutical
petitive inhibition often occur within two to hepatic recirculation (eg, penicillins can Press. Electronic version, 2003.

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