Therapeutic drug monitoring (TDM) data for the antipsychotic drug olanzapine were investigated with respect to concentration versus dose relationship, intraindividual versus interindividual variability, and the combined influence of patient characteristics on steady-state concentration. The study included 250 patients, with daily doses ranging from 2.5 to 30 mg. Median concentration to dose ratio was 2.1 (ng/mL)/(mg/d), with 90% of the distribution in a fivefold range. In the first subgroup of patients with two measurements at different doses (n = 21), data were in keeping with linear concentration versus dose relationship. In the second subgroup of patients with repeated measurements at a constant daily dose (n = 40), estimates of within-patient and between-patient variabilities were 30.5% and 49.4%, respectively. In the whole sample, multiple regression analysis of dose-normalized concentration revealed significant effects of time postdose (-18% per 12 hours delay, P < 0.05), age >/=60 years (+27%, P < 0.005), cigarette smoking (-12%, P < 0.05), and comedication with fluvoxamine (+74%, P < 0.001), paroxetine, fluoxetine, or sertraline (considered together, +32%, P < 0.05), venlafaxine (+27%, P < 0.05), and inducers of P450 enzymes (-40%, P < 0.001). The final model included a tendency for higher concentration associated with female gender (+11%, P = 0.07) and accounted for 27% of observed interindividual variability. When considering a worst-case scenario, an elderly, nonsmoking woman prescribed fluvoxamine comedication was predicted to reach a 4.6-fold higher olanzapine concentration than a young male smoker coadministered carbamazepine. The current study suggests that patients characterized by a combination of factors associated with altered metabolism may benefit from olanzapine TDM.

Because of the enormous gap between premarketing studies in physically healthy subjects and clinical practice in patients, the present study reconsidered interindividual variability factors affecting risperidone concentrations under routine therapeutic drug monitoring conditions. The study included 92 patients, 27% of whom were 70 years or older. The patients received risperidone orally (dose range, 0.5-11 mg per day) and had concentrations of risperidone and the active metabolite 9-hydroxyrisperidone measured at steady state by a new, rapid, and sensitive method of high-performance liquid chromatography (HPLC). After normalization to a dose of 4 mg/day, median concentrations were 2.9 ng/ml (80% range, 0.9-27.9 ng/ml) for the parent compound and 24.1 ng/ml (80% range, 12.0-57.6 ng/ml) for the metabolite. When considering linear regression models, age was identified as a major source of interindividual variability, with expected increases of 340% and 220% for concentrations of parent compound and metabolite, with age increasing from 20 to 80 years. Body weight provided an additional significant contribution to the variability of 9-hydroxyrisperidone concentration, a 20-kg higher body weight associated with a concentration decrease of 23%. Serotonin-specific reuptake inhibitor (SSRI) comedication (fluoxetine, two patients; citalopram, two patients; paroxetine, one patient; fluvoxamine, one patient) was significantly associated with 4.6-fold higher concentrations of parent compound, in keeping with an inhibitory action on CYP2D6 enzyme. Significantly higher concentrations of 9-hydroxy-risperidone (+ 29%) were also observed in the 17 patients with biperiden comedication. Therapeutic drug monitoring data, collected in patients representative of the population for which the drug was intended, allowed us to quantify the dose reduction needed in elderly patients and thus provided valuable information in addition to the one collected during premarketing studies performed with strict inclusion and exclusion criteria.

No abstract

Clomipramine is a tricyclic antidepressant medication widely used in Western Europe. Its pharmacokinetics have been studied essentially in healthy volunteers. By combining published information obtained during observational studies, it has been possible to derive a fairly precise picture of the behaviour of both parent compound and main metabolite (demethyl-clomipramine) in humans. Clomipramine can be compared with amitriptyline or imipramine so far as its physicochemical properties are concerned. As a consequence, its pharmacokinetic profile is also similar to that observed for these 2 drugs. Clomipramine is well absorbed from the gastrointestinal tract, but undergoes an important first-pass metabolism to demethyl-clomipramine which is pharmacologically active and participates in both therapeutic and unwanted effects. Protein binding is high, and the apparent volume of distribution is very large (i.e. greater than 1000L). After reaching the systemic circulation, clomipramine is further biotransformed into demethyl-clomipramine, and both active principles are hydroxylated to metabolites which are further conjugated before being excreted in urine. Hydroxylation of parent drug and metabolite is under polymorphic genetic control by the same cytochrome P450 as debrisoquine and sparteine. The apparent elimination half-life of clomipramine is about 24h and that of demethyl-clomipramine, 96h. Accordingly, the time to reach steady-state for both active moieties is in general around 3 weeks. Various pathological or environmental factors influence the behaviour of clomipramine and demethyl-clomipramine. Patients genetically deficient in hydroxylation accumulate demethyl-clomipramine at high concentrations that can produce serious side effects and/or nonresponse. The same is true for the coadministration of neuroleptics, in particular phenothiazines. Smoking induces demethylation, whereas long term alcohol intake appears to reduce this metabolic pathway. Finally, age usually diminishes both demethylation and hydroxylation, leading to a lower daily dose of clomipramine in most elderly patients. Studies relating blood concentrations of clomipramine and demethyl-clomipramine are conflicting. However, analysis of the available information indicates that blood concentrations lower than 150 micrograms/L are usually associated with nonresponse, whereas those above 450 micrograms/L seldom lead to an improvement in the efficacy of therapy. As a consequence clomipramine, like the other tricyclics, is an antidepressant with a fairly narrow therapeutic range. This property, combined with a high interindividual variability, makes this class of drugs ideal candidates for blood concentration monitoring.