tablets, which are confounded by the high
incidence tablet-dumping by poorly/partially com-
pliant patients, are documented in various ways
by the following studies (Rudd et al., 1989;
Waterhouseet al., 1993; Pocock and Abdalla,
1998). Readers of Pocock and Abdalla (1998)
should take note that the authors were seemingly
oblivious to the well-documented fact (Pullaret al.,
1989; Ruddet al., 1989; Waterhouseet al., 1993)
thatasubstantialfractionofpatientsdiscardsomeor
all of their untaken dosage forms before returning
the tablet container to the investigator.
But what are the advantages of measuring com-
pliance in the different phases of development of a
drug?
The past decade of research with electronic
methods for compiling dosing histories in ambula-
tory patients has taught a number of notable les-
sons, which can now be incorporated economically
and with little risk into phase II testing (Sheiner,
1997; Urquhart, 2002). The main lessons have to
do with the reliability of interpreting what are
inherently observational data, derived from
patients’ reliably compiled actual dosing patterns
and their clinical correlates. Novel statistical meth-
ods (Loeys and Goetghebeur, 2003), new insights
into the impact of drug holidays on the actions of
drugs and astute use of data on time-sequence of
events, together create the opportunity to greatly
enrich the yield of pragmatic information from
phase II ambulatory trials.
27.6 During early phases of drug
development (phase I and II
studies)The implementation of a pharmionic program to
compile dosing histories electronically in ambu-
latory patients can simplify the design and can
reduce the variance of PK/PD studies.
For studies, in which present practice calls for
volunteers to be confined in a hospital-type
setting, a pharmionic program could allow
shorter periods of confinement. Once the initial
safety issues are resolved, the pharmionicapproach can provide reliable measurement
of external drug exposure, without the need
for ongoing confinement, thus reducing costs,
facilitating recruitment of volunteers and
allowing longer periods of follow-up.For population PK studies, well-controlled
intensive sampling days are recommended to
assess the PK profile at what is often erro-
neously assumed to be a steady state. A phar-
mionic program exposes this error and its
negative impact on the results and the time
and costs of analysis. One can, with reliably
compiled drug-dosing histories, reduce the
number and length of intensive sampling per-
iods. Reduced costs of patient reminders, such
as phone calls can also be expected. The time
involved in trying to extract information on
drug exposure from diary entries can mostly
be avoided, as such data are mostly useless
(Vrijens, 2002; Vrijenset al., 2003).
With the information available today, it is
not yet possible to determine to what extent
between-patient variance can be reduced, but
within-patient variance can be reduced by
55% (Vrijenset al., 2003). Thus, based on
current evidence, we expect that a pharmionic
program will result in considerable reduction
in study costs while improving the quality of
the collected data and the resulting definition
of pharmacokinetic parameters.The implementation of a pharmionic program
will enhance the quality and the relevance of
collected data.The determination of the optimum dose (i.e. a
dose that is likely to be both safe and effective)
is often compromised by unrecognized under-
dosing by thesubjects involved indose-ranging
studies, some of which is caused by simple
forgetfulness, and some of which occurs
because patients tend to ‘auto-adjust’ their
exposure toprescribedtherapy. It isnot unusual
that patients receiving the highest dose inten-
tionally reduce their dug exposure due to per-
ceived side effects. Adherence to prescribed
therapy across different doses in dose-ranging358 CH27 PATIENT COMPLIANCE: PHARMIONICS, A NEW DISCIPLINE