No abstract

Busulfan is the most common chemotherapy agent used in allogeneic hematopoietic cell transplant (HCT) conditioning regimens. As narrow therapeutic index and interpatient variability exists in the effectiveness and toxicity of conditioning regimens, personalizing intravenous busulfan therapy is desirable. Population pharmacokinetic-based approaches have been applied to therapeutic drug monitoring for the purpose of personalizing therapy. A population pharmacokinetic analysis with the objective of personalizing therapy in Japanese patients was conducted by integrating pediatric patient data with adult patient data. McCune's model, a 2-compartment model that includes maturation of clearance and allometric scaling of clearance and volume of distribution, was used for the analysis. McCune's model could precisely describe the Japanese data, and the estimated parameters were similar to McCune's results for non-Japanese, indicating that there are no racial differences in busulfan pharmacokinetics. Using this model, the plasma concentrations for once-daily dosing were simulated to adapt new dosage regimens for the benefit and convenience of both patients and medical staff. The predicted busulfan concentrations were within the therapeutic range.

Background and ObjectivesRotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson’s disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects.MethodsIn this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration–time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values).ResultsThe pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0 ± 0.5 mg for Japanese subjects and 2.08 ± 0.58 mg for Caucasians. Plasma concentration–time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine = unconjugated rotigotine + conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1 % of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7 % of absorbed dose in Japanese subjects and 10.8 % of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1 %, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5 % in Japanese subjects and 4.2 % Caucasians. Most adverse events were mild...

Aripiprazole is a new antipsychotic developed in Japan, and is prescribed for schizophrenia as a dopamine-serotonin system stabilizer.1,2) The action of aripiprazole is different from that of other typical and atypical antipsychotics; that is, aripiprazole is a potent partial agonist at dopamine D2 and serotonin (5-HT 1A ) receptors and antagonist at 5-HT 2A receptor.3,4) The results of in vitro studies indicated that aripiprazole is mainly metabolized by human cytochrome P450 isozymes CYP3A4 and CYP2D6.5) It has been reported that CYP3A4 and CYP2D6 are metabolic enzymes for numerous compounds, and also that there are many compounds that inhibit these enzymes. Although individual differences in hepatic levels of CYP3A4 enzyme protein have been reported to vary as much as 40-fold, 6) almost no gene mutations affecting CYP3A4 metabolic activity or ethnic differences have been reported. For CYP2D6, however, a number of polymorphisms and the existence of ethnic differences in the types and distribution of polymorphisms have been reported.6,7) The purpose of the present study was to estimate the population pharmacokinetic parameters of aripiprazole in healthy Japanese males, and to evaluate the effects of CYP2D6 polymorphisms and CYP3A4 inhibition on the pharmacokinetics of aripiprazole, and also its unknown (residual) interindividual variability.In the present study, we used the nonlinear mixed-effects model (NONMEM) method designed for the estimation of population pharmacokinetic parameters.8) This method pools data from all individuals but explicitly models and handles the complicated error structure arising from proper accounting of interindividual (h) and intraindividual (e) random effects. The first-order estimation method is the first estimation method available with NONMEM: it handles the error structure of data using first-order Taylor-series expansion in the random effect h, evaluated at the expected values (i.e. hϭ0).9) On the other hand, a newer analysis method designed for the estimation of population parameters, the firstorder conditional estimation (FOCE) method, is available with NONMEM software. 9) That is, FOCE uses first-order expansions for values of the h, but these values are the conditional (Bayesian) estimates of the h, rather than zero. The FOCE method needs much (20-40-fold) longer computational time than the first-order method, but generally gives precise parameter estimates, especially for the analysis of multiple-dose pharmacokinetic data with multiple compartment models. [9][10][11][12] In the present study, therefore, we used the FOCE method to estimate the population pharmacokinetic parameters of aripiprazole, where a two-compartment model with first-order input was applied for data obtained from single-and multiple-dose clinical trials. MATERIALS AND METHODS Pharmacokinetic DataPlasma aripiprazole concentration data for population pharmacokinetic analysis were obtained in two previous studies. 13,14) Briefly, 68 healthy Japanese male subjects, aged 20-32 years old (mean: 23.1) and w...