This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.
The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).
Agonists for the 5-hydroxytryptamine (HT)(1A) receptor induce a hypothermic response that is believed to occur by lowering of the body's set-point temperature. We have developed a physiological model that can be used to predict the complex time course of the hypothermic response after administration of 5-HT(1A) agonists to rats. In the model, 5-HT(1A) agonists exert their effect by changing heat loss through a control mechanism with a thermostat signal that is proportional to the difference between measured and set-point temperature. Agonists exert their effect in a direct concentration-dependent manner, with saturation occurring at higher concentrations. On the basis of simulations, it is shown that, depending on the concentration and the intrinsic efficacy of a 5-HT(1A) agonist, the model shows oscillatory behavior. The model was successfully applied to characterize the complex hypothermic response profiles after administration of the reference 5-HT(1A) agonists R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) and S-8-OH-DPAT. This analysis revealed that the observed difference in effect vs. time profile for these two reference agonists could be explained by a difference in in vivo intrinsic efficacy.
The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokineticpharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with setpoint control. Both buspirone and 1-PP behaved as partial agonists relative to R-(ϩ)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine 1A agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.Buspirone is a selective 5-HT 1A agonist that is used clinically as an anxiolytic drug (for reviews on its pharmacological properties, see New, 1990 andFulton and Brogdon, 1997). In vivo buspirone is metabolized into 1-(2-pyrimidinyl)-piperazine (1-PP), which also possesses affinity to the 5-HT 1A receptor. This metabolite could therefore contribute to the effect of buspirone (Bianchi et al., 1988;Manahan-Vaughan et al., 1995;Cao and Rodgers, 1997). At present there is limited quantitative information on the magnitude of this effect. In theory the contribution of the metabolite to the effect is determined by the relative concentrations of buspirone and 1-PP, their relative in vivo potency and intrinsic activity, and the nature of the pharmacodynamic interaction between the two.Recently we have developed a physiological pharmacokinetic-pharmacodynamic (PK-PD) model to quantitatively characterize the pharmacodynamics of 5-HT 1A receptor agonists in vivo using the hypothermic effect as a pharmacodynamic endpoint (Zuideveld et al., 2001(Zuideveld et al., , 2002a. The hypothermic response is considered a robust marker of 5-HT 1A activity (Millan et al., 1993;Cryan et al., 1999). It has been shown that the PK-PD model allows for the estimation of the in vivo potency and intrinsic activity of a wide array of different 5-HT 1A agonists such as R-8- -100,635), and Flesinoxan (Zuideveld et al., 2001, 2002a, 2002b. In the present investigation we apply this model to determine the relative in vivo po...
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