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Chapter 1
18
standard method fails to estimate the true causal effect of treatment on the clinical
outcome, both methods offer a sophisticated solution.
Treatment
Effect of treatment ?
Marker
confounder and
intermediate
Event
Figure 1. Directed graph presenting the model of the effect of treatment on a clinical event in the
presence of a maker which is both a confounder as well as an intermediate.
Pharmacokinetic and pharmacodynamic models
Modelling the immediate biological effect of an antiviral-drug on the virus decay has
proven to be an important tool in predicting early response to therapy of chronic viral
hepatitis. 32 Estimation of the parameters of the viral decay not only gives insight in the
action of the drug but may also suggest a different treatment regimen: prolongation
of therapy, more frequent administration or using a higher dose. To describe how the
individual patient reacts to treatment often a pharmacokinetic-study is considered,
measuring the viral load (the HBV DNA) frequently the fi rst 4 weeks of treatment as well
as the weeks after treatment is stopped.
Entecavir and Tenovovir are new nucleoside/nucleotide analogues (NA) against hepatitis
B virus. In phase II studies treatment effects during the fi rst 4 weeks are investigated.
Next to the evaluation of effi cacy and safety in a dose escalating study the pharmacodynamics
(PD) is compared between the different doses. An overall picture of the dose
effect, however, is only achieved, if also the recurrence of the virus after withdrawal of
therapy is investigated in detail.
During treatment with NA’s the viral decline of hepatitis B is well described by an exponential
bi-phasic model (fi gure 2): an initial phase of fast elimination of free virus and a slow
second phase indicative of the death rate of infected cells. After treatment a rebound is
observed, where the mechanism that takes place during viral replication shows a new biphasic
pattern (fi gure 3): a fast doubling time followed by a more graduate increase to a
more a less a steady state approaching the pre-treatment viral concentration. To describe
this relapse-curve the mirror image of the viral dynamic model during therapy was used.