PERSPECTIVES IN P H A R M A C Q T H E R A P Y
A Simpler Approach to Pharmacokinetic Dosage
Adjustments
James P McCormack, Pharm.D., and Bruce Carleton, Pharm.D.
(Pharmacotherapy 1997;17(6):1349-135 1)
This journal recently published a process by
which a simple bolus equation provides dosing
estimates using a nonprogrammable calculator.
The authors premise is that the guaranteed error
associated with this equation is usually small and
inconsequential. They suggest the error is
acceptable because it is offset by the advantage of
easier use of nonprogrammed calculators and
easier comprehension by novices. Whereas
their premise is correct, we have used another
method of dosing adjustment for many years. It
is simple, does not require a calculator, and can
be done in most cases in a few seconds, assuming
serum concentrations were measured appropriately.
Although the following principles may seem
obvious, it is our experience that a number of
students and clinicians-including ourselves
early in our careers-are not aware of or did not
learn the principles sufficiently to use them in
this type of approach. Thus they often resort to
using calculators or computers routinely when
designing dosage regimens in clinical practice.
Changing Dose
Equation 1 is even simpler than the recom-
mended bolus equation, and it does not matter
whether or not the drug is given by a bolus
infusion:
New dose =
Desired concentration
x old dose (Eq. 1)
Measured concentration
From the Faculty of Pharmaceutical Sciences, University
of British Columbia ( b o t h a u t h o r s ) ; t h e Pharmacy
Department, St. Pauls Hospital (Dr. McCormack), and
British Columbias Childrens Hospital (Dr. Carleton),
Vancouver, Canada.
Address reprint requests to James McCormack, Pharm.D.,
Pharmacy Department, St. Pauls Hospital, 1081 Burrard
Street, Vancouver, British Columbia, Canada V6Z 1Y6.
This equation is based on the fact that increases
or decreases in doses (keeping the interval the
same) produce proportional changes in peaks,
troughs, or steady-state serum concentrations.
In other words, if the dose is doubled, peak and
trough concentrations are doubled. This propor-
tional dose approach is pharmacokinetically
correct if the following conditions are met:
serum concentrations are measured at steady
state and are correctly and accurately drawn; the
drug follows first-order and one-compartmental
pharmacokinetics; the dosing interval is not
changed; and the infusion times of the present
dosage and the times the concentrations are
measured are the same for the new dosage within
reason, say, plus or minus 5-10 minutes. For
example, if the peak concentration was measured
at 30 minutes after a 45-minute infusion, the
new desired concentration is one that will be
achieved at approximately 30 minutes after a 45-
minute infusion. Although this approach is
pharmacokinetically correct, we do realize there
is often much confusion and debate about the
definition of the peak concentration,2 but that is
beyond the scope of this discussion.
This approach may be best demonstrated with
examples that would typically apply to
aminoglycosides and vancomycin (Table 1).
The same idea applies when one has only a
trough concentration (e.g., digoxin). If a dosage
of 0.25 mg every 24 hours gives a steady-state
s e r u m trough concentration of 2 nmol/L,
reducing the dose to 0.125 mg will give a trough
concentration of 1 nmoVL.
These examples show that if the interval is not
altered, a dose change produces proportional
changes in peak and trough concentrations.
Consequently, with this method one does not
have to worry about exponential functions,
infusion rates, half-lives, volumes of distribution,
1350 PHARMACOTHERAPY Volume 17, Number 6, 1997
Table 1. Dosage Adjustment Examples for Patients Receiving Intravenous Drugs by Bolus or Infusion
Present Dosing Peak Trough
Regimen as Concentration Concentration
Bolus or Measured X Measured Z
Infusion over Minutes after End Minutes before next Dosing
Y Minutes of Bolus or Infusion Bolus or Infusion Regimen
Ex 1 8 0 m g q 8 h 6.5 mg/L 1.2 mg/L
E x 2 lOOOmgq12h 42mgL 16 mg/L
elimination rate constants, or where the calculator
or computer is located.
Changing Dose and Dosing Interval
If simply changing the dose size does not allow
one to attain acceptable concentrations, both
dose and dosing interval may have to be changed.
This can be done almost as simply as the above
examples by applying a couple of pharmacokinetic
principles.
Consider a patient who is receiving 100 mg
every 8 hours and the measured steady-state peak
and trough concentrations are 8.6 and 1.4 mg/L,
respectively. Assume the desired peak and trough
concentrations are 30 and 1 m a . If we quadruple
the dose, the achieved concentrations of 34.4 and
5.6 mg/L may be too far from the desired concen-
trations. Therefore, to achieve the desired concen-
trations, we must change both the dose and interval.
Step 1: Determine the New Dose
In our example, every time the patient receives
a 100-mg dose the serum concentration increases
from 1.4 to 8.6 mg/L, a difference of 7.2 mg/L.
The patients volume of distribution determines
this change in concentration. The desired con-
centrations are 30 and 1 mg/L, a difference of 29
mg/L. The new dose required is determined by
proportionally changing the dose to achieve the
desired change in serum concentrations 29/7.2 x
100 mg = 403 mg. One would then round the
dose to a practical amount, say 400 mg.
Step 2: Determine the New Dosing Interval
The dosing interval is determined by making a
rough estimate of the half-life. In this patient,
the serum concentration drops from 8.6 to 1.4
mg/L over approximately 8 hours. In one half-
life the serum concentration falls to 4.3 mg/L, in
a second half life to 2.2 mg/L, and after three
half-lives it will be approximately 1.1 mg/L. In
other words, 8 hours is just less than three half-
lives and therefore the half-life is approximately
Peak Concentration Trough
that Will Be Achieved Concentration that
New with New Dosage X Will Be Achieved Z
Minutes after End of Minutes before next
Bolus or Infusion Bolus or Infusion
120 mg q8h 120/80 x 6.5 = 9.8 mg/L 120/80 x 1.2 = 1.8 mg/L
750 mg ql2h 750/1000 x 42 = 32 mg/L 750/1000 x 16 = 12 mg/L
2.5 hours (8 divided by 3 ) . In theory, a 7-hour
interval would be used if the concentration was
measured 30 minutes after a 30-minute infusion;
however, this 1-hour difference is unlikely to
have an important impact unless the drug has a
very short half-life. In our example, approximately
five half-lives separate the desired concentrations
(30 to 15 to 7.5 to 3.8 to 1.9 to 0.9 mg/L). Fide
half-lives multiplied by the half-life of 2.5 hours
is 12.5; therefore, the new dosing interval would
be 12 hours. The new dosage would be 400 mg
every 12 hours. ,
Discussion
We believe this is a simple and accurate way to
adjust dosages based on serum concentrations. It
does not require sophisticated calculations or
even a calculator, yet it is based on pharmacokinetic
principles. Although the concept may seem
obvious and many clinicians may be familiar with
this approach, we are aware of only one paper
that alludes to some of these issue^.^ In addition,
we are not aware of this approach being discussed
or demonstrated in a succinct manner in any
pharmacokinetic textbook.
Whereas we think clinicians should be familiar
with this method when providing pharmacokinetic
consultations, it is important to remember that
dosing changes should be made only after
considering both the patients response to the
drug and potential toxicities4 Clinicians should
also evaluate evidence to support so-called
therapeutic concentrations for specific agents
before embarking on therapeutic drug moni-
toring2. Although this method does not require
clinicians to have a thorough understanding of
pharmacokinetic principles, such an understanding
will allow them to use this method with confi-
dence and appreciate its potential limitations
(e.g., it cannot be used with nonsteady-state
concentrations or if doses have been missed,
etc.). Thus by eliminating sophisticated and time-
consuming pharmacokinetic calculations, they
should have more time to identify and resolve the
 SIMPLER PHARMACOKINETIC DOSAGE ADJUSTMENTS McComack and Carleton
most important drug-related problems in their
patients.
References
1. Murphy JE, Winter ME. Clinical pharmacokinetic pearls: bolus
versus infusion equations. Pharmacotherapy 1996;16:698-700.
2. McCormack JP, Jewesson PJ. A critical reevaluation of the
therapeutic range of aminoglycosides. Clin Infect Dis
1351
1992;14:320-39.
3. Goldman MP, Fuller MA. A practical alternative to conventional
aminoglycoside dosing methods. Ann Pharmacother
1993;27:1333-9.
4. Brown G , Miyata M, McCormack JP. Drug concentration
monitoring; an approach to rational use. Clin Pharmacokinet
1993;24:187-94.
5. Polk R. Unexamined life: antibiotic serum concentration
monitoring and clinical pharmacy. J Infect Dis Pharmacother
1995;1:3-24.