The plasma concentration-time profile of a drug is essential to explain the relationship between the administered dose and the kinetics of drug action. However, in some cases such as in pre-clinical pharmacology or phase-III clinical studies where it is not always possible to collect all the required PK information, this relationship can be difficult to establish. In these circumstances several authors have proposed simple models that can analyse and simulate the kinetics of the drug action in the absence of PK data. The present work further develops and evaluates the performance of such an approach. A virtual compartment representing the biophase in which the concentration is in equilibrium with the observed effect is used to extract the (pharmaco)kinetic component from the pharmacodynamic data alone. Parameters of this model are the elimination rate constant from the virtual compartment (KDE), which describes the equilibrium between the rate of dose administration and the observed effect, and the second parameter, named EDK(50) which is the apparent in vivo potency of the drug at steady state, analogous to the product of EC(50), the pharmacodynamic potency, and clearance, the PK "potency" at steady state. Using population simulation and subsequent (blinded) analysis to evaluate this approach, it is demonstrated that the proposed model usually performs well and can be used for predictive simulations in drug development. However, there are several important limitations to this approach. For example, the investigated doses should extend from those producing responses well below the EC(50) to those producing ones close to the maximum response, optimally reach steady state response and followed until the response returns to baseline. It is shown that large inter-individual variability on PK-PD parameters will produce biases as well as large imprecision on parameter estimates. It is also clear that extrapolations to dosage routes or schedules other than those used to estimate the parameters should be undertaken with great caution (e.g., in case of non-linearity or complex drug distribution). Consequently, it is advised to apply this approach only when the underlying structural PD and PK are well understood. In any case, K-PD model should definitively not be substituted for the gold standard PK-PD model when correct full model can and should be identified.

The hemodynamic effects of the novel, selective adenosine A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (2-Cl-IB-MECA) were investigated in conscious rats. Intravenous administration of 200 micrograms/kg 2-Cl-IB-MECA resulted in a short-lasting hypotension, which was accompanied by a 50-100-fold increase in plasma histamine concentrations. Administration of a second dose of 2-Cl-IB-MECA did not elicit any hemodynamic effects. Also no histamine release was observed after the second dose. The observation of rapid tachyphylaxis in combination with histamine release suggests that mast cell mediator release plays a key role in the hemodynamic effects of adenosine A3 receptor agonists.

1 A 1 adenosine receptor agonists with reduced intrinsic activity may be therapeutically useful as result of an increased selectivity of action. In this study the tissue selectivity of three 8-alkylamino substituted analogues of N 6 -cyclopentyladenosine (CPA) was investigated for haemodynamic and anti-lipolytic e ects using an integrated pharmacokinetic-pharmacodynamic approach. 2 Chronically instrumented male Wistar rats received intravenous infusions of 4.0 mg kg 71 8-methylaminoCPA (8MCPA), 12.0 mg kg 71 8-ethylaminoCPA (8ECPA), 20.0 mg kg 71 8-butylaminoC-PA (8BCPA) or vehicle during 15 min. During experimentation, serial arterial blood samples were drawn for the determination of agonist concentrations and plasma non-esteri®ed fatty acid (NEFA) levels. Blood pressure and heart rate were monitored continuously. In addition to the CPA analogues, each rat received a rapid bolus infusion of CPA to determine the maximal e ects of the full agonist. 3 The concentration-time pro®les of the CPA analogues could be described by a bi-exponential function. Values for clearance, volume of distribution at steady state and elimination half-life were 44+5, 48+6 and 39+2 ml min 71 kg 71 , 0.97+0.09, 0.84+0.10 and 1.05+0.07 1 kg 71 and 25+2, 28+2 and 40+2 min for 8MCPA, 8ECPA and 8BCPA, respectively (mean+s.e.mean, n=6 ± 8).4 Di erent models were used to derive the concentration-e ect relationships for heart rate and NEFA, yielding estimates of potency (EC 50 ) and instrinsic activity (E max ) for both e ects of the compounds in vivo. On heart rate the compounds acted as partial agonists, with E max values of 7173+14, 7131+11 and 771+6 beats min 71 for 8MCPA, 8ECPA and 8BCPA, respectively. These E max values were signi®cantly lower than the maximal e ect of CPA (7208+8 beats min 71 ). With regard to the antilipolytic e ect all three compounds were full agonists and lowered NEFA levels to the same extent as CPA (69%). The estimated E max values were 63+5, 63+4 and 68+2%, respectively. 5 Furthermore, the compounds were more potent in causing anti-lipolytic than cardiovascular e ects. The EC 50 values for the NEFA and heart rate lowering e ects were 37+15, 68+22 and 659+108 ng ml 71 and 164+22, 341+76 and 975+190 ng ml 71 for 8MCPA, 8ECPA and 8BCPA, respectively (mean+s.e.mean, n=6 ± 8). 6 This study demonstrates that partial agonists for the A 1 adenosine receptor have increased selectivity of action in vivo. The 8-alkylamino analogues of CPA may be useful anti-lipolytics with less pronounced haemodynamic side e ects.