Functional imaging for the assessment of the in vivo pharmacokinetics and pharmacodynamics (PK/PD) of drugs either preclinically or in early clinical trials has become an important step in pharmacological research and drug development. Positron Emission Tomography (PET) is a noninvasive imaging tool that allows the assessment of PK/PD parameters directly at the level of the drug target, as opposed to traditional models where tissue PK/PD is estimated indirectly via knowledge of plasma concentrations and/or through measurements of biomarkers as indicators of target modulation. With the administration of radiolabeled drugs, PET allows the direct measurement of tissue concentration of radioactivity, and through knowledge of the specific radioactivity, ratio of radioactivity concentration and concentration of non-radioactive compound, the drug concentration kinetic profile can be obtained with high accuracy. Alternatively, with the administration of a PET tracer with high affinity and specificity for the target, parameters can be extracted from the tissue kinetic profiles which are relevant for target expression, notably binding potential which is proportional to Bmax/kD.
During a tissue PK PET scan the labeled drug is commonly administered to the subject by an i.v. bolus injection. After the absorption phase, the tracer level in tissue reaches a maximum and usually starts to decrease due to metabolism and/or washout. Eventually, the tracer is eliminated through the main excretion routes, the liver or the kidney and the urinary bladder. However, most drugs are administered orally which generates an entirely different tissue kinetics as compared to i.v. By recording the kinetics of radioactivity in plasma during the PET scan, the exchange parameters between plasma and tissue can be estimated and applied on the plasma PK from the oral drug administration and thereby calculate the tissue PK of the cold drug [1
]. Alternatively it should be possible to generate an i.v. administration scheme which simulates the PK profile obtained from oral administration and thereby direct observe the proper tissue concentration profile in the PET study.
A concept has been suggested in which the radiotracer is administered such to obtain a steady state in tissue and hence constitute the baseline, from which perturbations due to for example a blocking compound, can be identified and consequently quantified.
Various methods have been used to approach the issue of controlling blood concentrations of drugs or tracers. Usually, these techniques have aimed to achieve a steady state concentration of the radiotracer/compound in the blood/plasma. The most common approach is the bolus injection followed by a constant infusion [2
]. This method is simple but has some drawbacks; it often takes some time until steady-state is achieved, with over- or under-exposures at early time points, and may yield large deviations from targeted concentrations after long time periods. This approach works well if you are only interested in achieving a steady state of a radiotracer in the plasma or in some target tissue. It can not be used to produce more complex TACs. This method also usually needs more time to reach the steady state, at least if the bolus curve is decaying exponentially which usually is the case. Constant subsequent infusion can not compensate well for the washout in this case. If the bolus curve would decay linearly however, then constant infusion would compensate perfectly.
Target controlled infusion (TCI)-systems usually aim to set the tissue concentration of a drug to a steady state level by administrating a bolus followed by exponentially declining infusion rates, where the subsequent infusion parameters are determined from a model of the PK/PD parameters of the compound in the subject [5
]. This method has been sparsely used in combination with PET [7
In this study we present a novel approach for controlling tissue concentration of either drug or PET tracer in a PET study. The method is versatile and can be applied with a variety of tracers in different tissues and allows an arbitrary tissue kinetic curve to be generated. The computerized infusion system, UIpump, utilizes an algorithm that compensates for the difference between the bolus curve and the finally desired curve at each discrete time point. The method is designed to infuse a short bolus injection followed by subsequent discrete infusions. The subsequent discrete infusions are designed to compensate the elimination of the tracer by modifying the concentration to the level of the desired curve. The tissue level of radioactivity and mass concentration can be determined at will and hence the total administered amount (μg/kg) over an entire study can be ensured to be below toxicity levels respectively such as the tracer dose by itself is not perturbing the target system [8
]. The concept was validated using a well known radiotracer, [N
C]flumazenil which binds to central benzodiazepine receptors (BZR) with high affinity and specificity.