Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions.

Drug-drug interactions can be associated with patient morbidity due to either increased toxicity or a potentially ineffective concentration. Because interactions cannot always be anticipated during drug development and actual patients receiving a drug for therapeutic use often differ from those included in clinical trials, postmarketing surveillance is essential. Therapeutic drug monitoring (TDM) databases offer a unique opportunity in this respect. Prerequisites for TDM databases to provide valid information in a pharmacoepidemiological perspective include the following: precise description of exposure to the potentially interacting drugs; measurement of parent compound and active metabolites through accurate and precise analytical techniques; documentation of relevant patient characteristics that may act as confounding factors (e.g. gender, age, smoking habits); repeated assessments over time if possible; and sound pharmacokinetic framework for data selection, analysis and interpretation. The contribution of TDM to the documentation of drug-drug interactions takes advantage of different possible study designs, discussed on the basis of recently published studies. The single case report plays an important role as an alert signal. It is illustrated for a patient on long-term treatment, who displayed an unexpectedly high clozapine concentration after the introduction of ciprofloxacin comedication. The prospective on and off comedication panel study shows advantages in terms of carefully selected inclusion criteria and control of treatment modalities. A study of the thioridazine-fluvoxamine interaction is presented, with patients followed on thioridazine monotherapy, after introduction of fluvoxamine and after its discontinuation. The main advantage of the retrospective large-scale TDM database screen is representativeness of patients actually treated, whereas drawbacks are related to quality of data and suitability for valid interpretation. Such an approach is illustrated by a review of data collected over 10 years of routine TDM that allowed documenting induction of nortriptyline metabolism by carbamazepine and inhibition by several phenothiazines. Finally, population pharmacokinetics is well suited to observational data collected for TDM purpose, provided quality is ascertained. Focus is placed on interindividual variability and relationship between pharmacokinetic parameters and patient characteristics, including comedication. The population approach is discussed with respect to a study that documented a 32% increase of haloperidol clearance associated with anticonvulsant comedication, in addition to effects of age and bodyweight. Among factors to consider for improved effectiveness in the use of TDM databases for postmarketing surveillance of drug-drug interactions, integration of efficacy and safety data in future studies and communication of expert recommendations to prescribing physicians are essential.

Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in clinical samples by capillary electrophoresis using charged cyclodextrins.

Capillary electrophoresis (CE) was used for the simultaneous chiral determination of venlafaxine (Vx), a new antidepressant drug and its main active metabolite. O-desmethyl venlafaxine (ODV). Among the charged cyclodextrins (CD) tested, phosphated gamma-CD was the most appropriate. Resolution of Vx and ODV was obtained with 50 mM phosphate buffer (pH 2.5) containing 20 mg/ml of phosphated gamma-CD. After optimisation of the method (including robustness), validation was carried out. Vx and ODV concentrations, as well as the enantiomeric ratio, were investigated in clinical samples. Chiral determination of Vx and ODV was performed after a simple liquid-liquid extraction (LLE). In the tested concentration range (25-500 ng/ml), coefficients of correlation were superior to 0.996. Within-day and between-day accuracy and precision were determined at three different concentrations for each enantiomer. Analyses of clinical samples (n = 16) exhibited non-racemic ratios for Vx and ODV, which suggests a stereoselective metabolism in humans.

Clomipramine concentration as a predictor of delayed response: a naturalistic study.

OBJECTIVES: The aim of the present study was to characterise onset of response to clomipramine treatment in a naturalistic setting and to investigate the relationship between concentration and delayed response, postulated to reflect drug-specific response to antidepressant therapy. METHODS: Ninety-eight depressed patients were prescribed clomipramine in an open flexible manner and followed for depressive symptoms (Montgomery-Asberg depression scale) over a maximum 12 weeks follow-up period. All patients had at least one concentration measurement for therapeutic drug monitoring purpose. RESULTS: Firstly, survival analysis revealed a probability of 15.4% for patients not to show 50% improvement over baseline by week 12, and thus to be considered as non-responders. Median time to onset of response was 31 days for responders, indicating a relatively high probability of delayed response under routine treatment. Secondly, pattern analysis indicated a significant association between early and abrupt response on the one hand and delayed and gradual response on the other. A tendency towards an association between delayed and persistent response was also observed. Finally, receiver operating characteristics analysis allowed identification of a highly significant lower threshold of 230 ng x ml(-1) for the sum of clomipramine and desmethyl-clomipramine, as measured at week 3, with respect to response from week 3 onward. Predictive values were 68.8% and 81.0% for concentrations above and below this threshold to predict delayed response and non-response, respectively. Thresholds were 55 ng x ml(-1) for parent compound and 180 ng x ml(-1) for metabolite. CONCLUSION: This approach supports the hypothesis that delayed response may be concentration dependent and thus may reflect true drug effect. As a consequence, monitoring clomipramine concentration about 3 weeks after initiation of therapy may valuably contribute to help clinicians decide about the adequacy of ongoing therapy.

Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors.

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.

Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions: evaluation of a paired approach for psychotropic medication.

The present study investigated the potential of therapeutic drug monitoring data to document pharmacokinetic drug interactions with psychotropic medication, both in terms of methodology and applicability. It focused on 105 patients exposed to one of five agents known for their capacity to induce (phenytoine, phenobarbital, and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. These patients were matched by gender, age, and monitored psychotropic medication to 105 patients randomly selected from a pool of subjects nonexposed to target comedication. Such a paired approach was shown to be effective in reducing variability for a majority of substances. Power analysis suggested that eight to 10 pairs of exposed and nonexposed patients would effectively allow the detection of twofold effects of interacting substances. In keeping with the literature, analysis of the ratios of dose-normalized exposed to nonexposed concentrations indicated that phenothiazine comedication led to significantly higher concentrations of desmethylated metabolites but not parent compounds, when clomipramine, imipramine, or amitriptyline were administered. A similar, as yet undocumented interaction was observed for the tetracyclic antidepressant mianserine. In contrast, the present study revealed that maprotiline concentrations were increased, but its metabolite was largely unaffected by phenothiazine comedication. Increased concentrations were also observed for moclobemide, but not citalopram or its metabolite. In addition to its long recognized capacity to decrease haloperidol concentrations, carbamazepine was shown to induce the metabolism of clopenthixol and possibly flupenthixol. The consistency of such a picture substantiates the need to consider therapeutic drug monitoring databases as cost-effective and reliable tools for postmarketing surveillance.

Therapeutic drug monitoring and drug-drug interactions: a pharmacoepidemiological perspective.

The present study investigates the potential of therapeutic drug monitoring databases to document co-medication as a possible risk factor for subtherapeutic or excessively high concentrations of psychotropic drugs. Exposure was defined with respect to co-medication including one of five agents known for their capacity to induce (phenytoin, phenobarbital and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. 87 patients exposed to such co-medication were matched by sex, age and monitored psychotropic medication with 87 patients randomly selected from a pool of subjects whose co-medication did not include any substance known to interact. Outcome was defined with respect to dose-normalized concentrations being below or above therapeutic range. When taking all psychotropic drugs together, the estimated relative risk to reach concentrations above the therapeutic range was 7.8 for patients exposed to phenothiazine co-medication. The relative risk to remain at subtherapeutic level was 2.7 for patients with inducers. When considering the different psychotropic drugs separately, a coherent picture was observed, with increased risk ratios for all substances.

Metabolic interaction between fluoxetine and clomipramine: a case report.

An 83-year-old patient suffering from a depressive episode was treated with a combination of clomipramine and fluoxetine. As no marked improvement was observed and cardiac side-effects were observed, a blood sample was taken for therapeutic drug monitoring. The result showed that the concentrations of clomipramine and desmethylclomipramine were very high (i.e. in the subtoxic range). A metabolic interaction was suspected and both antidepressants were immediately discontinued. Over time, concentrations of clomipramine and its metabolite decreased slowly and, simultaneously, the mood improved and side-effects disappeared. When clomipramine and desmethylclomipramine concentrations reached the lower limit of the optimal therapeutic range, monotherapy was restarted with clomipramine, and the patient improved enough to be discharged from the hospital.

Potential of concentration monitoring data for a short half-life drug: analysis of pharmacokinetic variability for moclobemide.

The pharmacokinetic variability of moclobemide, a new short half-life reversible selective inhibitor of monoamine oxidase (MAO) was investigated through analysis of concentrations measured during early open clinical use. Eighty-nine depressed patients, aged 21-96 years, were included in the present study. Doses ranged from 200 to 900 mg/day, and the time interval between blood sampling and last drug intake on the previous day was between 8 and 23 h. Intraindividual variability was generally moderate, with a few patients displaying consistently high concentrations despite moderate doses. Interindividual variability for measured concentrations was approximately 300-fold. After concentration decrease with time was taken into account (average half-life estimate of 4.6 h), age was identified as a major factor responsible for between-patient variability. Average concentration increase per decade of age was 38%. Neither gender, weight, height, smoking, nor alcohol intake explained a significant additional part of the variance. Analysis of residuals also suggested that phenytoin co-medication may induce moclobemide metabolism. The present study indicates that concentration monitoring of a newly marketed drug can contribute to gaining insight into its pharmacokinetic behavior and to enhancing its rational use in clinical practice.

Clomipramine therapy in the geriatric hospital: experience with therapeutic drug monitoring.

Sixty-nine patients, aged 63-98 years and admitted at the Geneva Geriatric Hospital, were included in the present retrospective study. They received clomipramine orally, 50 or 75 mg/day. Blood concentrations of clomipramine were measured as part of a routine drug monitoring program. Comparison with a reference population of patients aged < or = 65 years indicated that elderly patients with concomitant somatic diseases reach higher dose-normalized concentrations of clomipramine and increased parent drug to demethylated metabolite ratios, as a consequence of impaired demethylation (approximately 50%) and hydroxylation (approximately 25%). Sixty-five percent of patients showed clinical improvement, with a maximum rate of satisfactory response observed in major depression. Severe side effects, such as symptomatic hypotension or confusion, were seen in 20% of patients. Because of 10- and 15-fold interindividual variations in the concentrations of clomipramine and its metabolite, respectively, therapeutic drug monitoring can provide valuable assistance to clinical judgment in individual dose adjustment for patients whose old age, associated somatic diseases, and comedication necessitate additional precautions.

Pharmacokinetic optimisation of the treatment of psychosis.

Psychosis is a generic term covering (for the purposes of the present article)) schizophrenia, brief reactive psychoses and manic episodes. Traditionally, research has focused on the effect of antipsychotic agents on positive or productive symptoms such as hallucinations or delusions. More recently, attention has been focused on negative symptoms such as emotional withdrawal or impairment of social participation. Typical antipsychotic medications such as phenothiazines have little effect on these clinical manifestations. This has raised interest in atypical antipsychotics such as clozapine. Acute psychotic episodes are less difficult to treat than long term schizophrenic manifestations. Current research indicates that antipsychotics are effective only if a threshold concentration is reached, but that above a certain level, dose escalation is of no benefit to the patient. This implies the existence of an optimal therapeutic concentration range. Due to interindividual variability caused by age, genetic and interethnic factors or drug-drug interactions, antipsychotic plasma concentrations show a wide range of values for the same dosage regimen. This is why clinical pharmacokinetic principles and therapeutic drug monitoring are essential tools for dosage individualization. Clinical pharmacokinetics in therapeutics implies that the pharmacokinetic parameters of the medication under scrutiny are known. This is, however, not always the case with antipsychotics since, due to the difficulties encountered in conducting phase I studies in healthy volunteers with these substances, published data are not always complete.

Persistent impairment of clomipramine demethylation in recently detoxified alcoholic patients.

The purpose of the present study was to investigate whether the metabolism of clomipramine is altered by chronic alcohol drinking. Eleven recently detoxified alcoholic patients were included (experimental group EG) and compared to a reference group of patients with no history of alcoholism (reference group RG, n = 102). Blood concentrations of clomipramine and its metabolites were measured as part of the routine drug monitoring program. Clearances were estimated from trough concentrations, according to a model developed previously. Results indicate strong inhibition of demethylation clearance in group EG, when compared to group RG (median values 9.9 and 24.2 L/h), with significant increase of the clomipramine to desmethylclomipramine ratio (median values 1.00 and 0.36). No difference was found for hydroxylation. In addition, high correlation is observed between hydroxylation and demethylation clearances in group EG (Spearman rs = 0.82), but not in reference group RG (rs = 0.29). Follow-up data indicate that impairment of demethylation capacity can persist for several weeks or months after withdrawal from alcohol. The interest of calculating clomipramine to desmethylclomipramine ratios during routine drug monitoring is emphasized, values of 1 or larger often being associated with liver disease and/or alcohol-related problems.

Clinical pharmacokinetics of clomipramine.

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.

Clomipramine metabolism. Model-based analysis of variability factors from drug monitoring data.

A steady-state model is here developed as a framework for the analysis of blood concentrations of clomipramine, obtained during routine drug monitoring. A model is proposed to account for its major metabolic pathways, hydroxylation and demethylation, including first-pass effect. Impaired hydroxylation capacity is shown to lead to a dramatic increase in the concentration of demethyl-clomipramine, with a concomitant moderate increase in that of the parent drug. Deficient demethylation capacity is associated with a reduced ratio of demethyl metabolite to parent drug. A nomogram is provided to allow easy determination of hydroxylation and demethylation capacities from routinely measured blood concentrations. Data from 150 patients are analysed in order to identify interindividual variability factors. Average pseudo-clearances, calculated from trough blood concentrations at steady-state, are 17 L/h for hydroxylation, 23 L/h for demethylation and 40 L/h for elimination of hydroxylated metabolites. Maximum to minimum ratios are 8, 27 and 11, respectively. The metabolising capacity through either process significantly decreases with increasing age, clearance estimates being 40 to 50% lower for patients 75 years or older than for those 40 years or younger. Tobacco smoking and chronic alcohol consumption induce and reduce the demethylation clearance, respectively. Inhibition of hydroxylation in the presence of phenothiazine comedication is also shown. Finally, small but significant differences according to sex are observed. Potential implications of the proposed model-based approach include adaptation of the dosage regimen to individual characteristics at the very beginning of antidepressant therapy, and early detection of patients with impaired metabolising capacities.