In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (ϩ)-tramadol [(ϩ)-T] has been explored in rats. Male Wistar rats were infused with (ϩ)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (ϩ)-T, and (ϩ)-O-demethyltramadol [(ϩ)-M1], and measuring antinociception. Pharmacokinetics of (ϩ)-M1, but not (ϩ)-T, was affected by Q pretreatment: early after the start of (ϩ)-T infusion, levels of (ϩ)-M1 were significantly lower (P Ͻ 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (ϩ)-M1. In fact, results from another experiment where (ϩ)-M1 was given in the presence and in absence of Q showed that (ϩ)-M1 elimination clearance (CL ME0 ) was significantly lower (P Ͻ 0.05) in animals receiving Q. Inhibition of both (ϩ)-M1 formation clearance (CL M10 ) and CL ME0 were modeled by an inhibitory E MAX model, and the estimates (relative standard error) of the maximum degree of inhibition (E MAX ) and IC 50 , plasma concentration of Q eliciting half of E MAX for CL M10 and CL ME0 , were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (ϩ)-T was negligible and (ϩ)-M1 was responsible for the observed effects, which depend linearly on (ϩ)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (ϩ)-T administration.Tramadol (T) is a safe and effective analgesic used during the last two decades in the treatment of several types of pain (Rhoda et al., 1993;Raffa et al., 1995). Despite its long-term use, the understanding and prediction of the time course of its pharmacological effects are still hampered by the presence of active metabolites and the coexistence of opioid and nonopioid mechanisms. In fact, T is administered as a racemic mixture of two enantiomers, (ϩ)-T and (Ϫ)-T, which are metabolized in the liver forming, among others, the two main, respectively. Data from literature suggest that (ϩ)-enantiomers show opioid properties, while (Ϫ)-enantiomers are able to inhibit the uptake of norepinephrine. This duality of action makes T an atypical opioid (Raffa et al., 1992;Raffa and Friderichs, 1996).Recently the antinociceptive properties of the two active metabolites of T, (ϩ)-M1 and (Ϫ)-M1, have been evaluated in the pharmacokinetic/pharmacodynamic (pk/pd) perspective in the rat. The results showed that (ϩ)-M1, in accord with its -opioid receptor agonist properties (Lai et al., 1996), was able to produce maximum antinociception in the tail-flick test; however, when (Ϫ)-M1, a monoamine re-uptake inhibitor (Frink et al., 1996), was given alone, no significant effects were found . However, Garrido et al., 2000 showed that in the presence of ...

Pharmacokinetics in the efficacy/safety trial population are essentially similar to pharmacokinetics in healthy subjects, and no patient-specific factor warranting clinical consideration of dose regimen adjustment was identified in these analyses.

Background: Functional stereotactic surgery requires careful titration of sedation since patients with Parkinson disease need to be rapidly awakened for testing. This study reports a population pharmacodynamic model of propofol sedation and airway obstruction in the Parkinson disease population.Methods: Twenty-one patients with advanced Parkinson disease undergoing functional stereotactic surgery were included in the study and received propofol via target-controlled infusion to achieve an initial steady state concentration of 1 g/ml. Sedation was measured using the Ramsay Sedation Scale. Airway obstruction was measured using a four-category score. Blood samples were drawn for propofol measurement. Individual pharmacokinetic profiles were constructed nonparametrically using linear interpolation. Time course of sedation and respiratory effects were described with population pharmacodynamic models using NONMEM. The probability (P) of a given level of sedation or airway obstruction was related to the estimated effect-site concentration of propofol (Ce) using a logistic regression model. Results:The concentrations predicted by the target-controlled infusion system generally exceeded the measured concentrations. The estimates of C 50 for Ramsay scores 3, 4, and 5 were 0.1, 1.02, and 2.28 g/ml, respectively. For airway obstruction scores 2 and 3, the estimates of C 50 were 0.32 and 2.98 g/ml, respectively. Estimates of k e0 were 0.24 and 0.5 1/min for the sedation and respiratory effects, respectively.Conclusions: The pharmacokinetic behavior of propofol in patients with Parkinson disease differs with respect to the population from which the model used by the target-controlled infusion device was developed. Based on the results from the final models, a typical steady state plasma propofol concentration of 0.35 g/ml eliciting a sedation score of 3 with only minimal, if any, airway obstruction has been defined as the therapeutic target.

Population dose-response modeling of all five oucome measures indicated that efficacy in all ED severity groups in the studied population generally increased across the 2 to 25 mg tadalafil dose range. Estimates of maximal improvement (Emax) in the IIEF EF domain score were 7.5, 11.4, and 16.3 points for patients with mild, moderate, and severe ED, respectively. Corresponding tadalafil doses to attain half-maximal improvement (ED50 estimates) were 4.7 mg, 7.1 mg, and 10.1 mg.