Abbreviated kinetic profiles in area-under-the-curve monitoring of cyclosporine therapy

Abstract Abbreviated kinetic profiles can reduce the number of phlebotomies and drug assays, and thereby the cost of area-under-the-curve (AUC) monitoring. In the present investigation, we used two independent data sets: group 1, 101 AUC profiles from 77 stable renal-transplant patients, which included a 5-h sample in addition to the usual 0-, 2-, 4-, 6-, 10-, 14-, and 24-h samples; and group 2, 100 profiles from 50 stable renal-transplant patients before and after a change in their daily oral dose of cyclosporine. Group I demonstrated a fair correlation between cyclosporine trough concentrations and the AUC calculated from a complete set of seven concentrations (r2 = 0.820 and 0.758 for the 24- and 0-h samples, respectively). Stepwise multiple linear-regression analysis revealed that the abbreviated set of three time points (2, 6, and 14 h) explained 96% of the variance in AUC values calculated from the full set of seven samples; additional time points increased the accuracy only slightly. For group 2, we examined the difference between the observed and the predicted concentrations by linear extrapolation; the error in the observed AUC value, compared with the predicted value calculated from seven time points (-13.2% to -1.2%), was similar to the error from just three time points (-11.5% to 4.5%). Abbreviated AUC profiles involving three time points used with a model equation seem to provide a reliable alternative to full seven-point profiles.</jats:p

Description of the time course of the prolactin suppressant effect of the dopamine agonist CQP201-403 by an integrated pharmacokinetic-pharmacodynamic model.

Six male volunteers (mean age 24 years) received a single oral dose of 0.025 mg CQP201-403 and placebo in a randomised double-blind crossover design. Fifteen plasma samples were collected over 48 h and were assayed by radioimmunoassay for drug substance and prolactin (PRL). Three of the samples were drawn during sleep on the first study day. The pharmacological effect (E%) of CQP201-403 was expressed as reduction in plasma PRL levels. The pharmacokinetic (PK)-pharmacodynamic (PD) model consisted of two kinetic compartments and an effect compartment linked to the central compartment. A sigmoid Emax model (Hill equation) described the relationship between the drug concentration in the effect compartment and E%. Curve-fitting of PK and PD data provided individual parameter estimates which served to generate computer-simulated PK and PD profiles after single and multiple doses in order to: investigate the in vivo concentration-effect relationship; evaluate the consequence of dosage reduction on the steady-state PD profile; and study the robustness of the response to changes in drug potency and bioavailability