Electrophysiologic effects of a novel selective adenosine A1 agonist (CVT-510) on atrioventricular nodal conduction in humans.

BACKGROUND: CVT-510, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside, is a selective A(1)-adenosine receptor agonist with potential potent antiarrhythmic effects in tachycardias involving the atrioventricular (AV) node. This study, the first in humans, was designed to determine the effects of CVT-510 on AV nodal conduction and hemodynamics. METHODS AND RESULTS: Patients in sinus rhythm with normal AV nodal function at electrophysiologic study (n = 32) received a single intravenous bolus of CVT-510. AH and HV intervals were measured during sinus rhythm and during atrial pacing at 1, 5, 10, 15, 20, 30, 45, and 60 minutes after the bolus. Increasing doses of CVT-510 (0.3 to 10 microg/kg) caused a dose-dependent increase in the AH interval. At 1 minute, a dose of 10 microg/kg increased the AH interval during sinus rhythm from 93 +/- 23 msec to 114 +/- 37 msec, p = 0.01 and from 114 +/- 31 msec to 146 +/- 44 msec during atrial pacing at 600 msec, p = 0.003). The AH interval returned to baseline by 20 minutes. CVT-510 at doses of 0.3 to 10 microg/kg had no effect on sinus rate, HV interval, or systemic blood pressure, and was not associated with serious adverse effects. At doses of 15 and 30 microg/kg, CVT-510 produced transient second/third degree AV heart block in all four patients treated. One of these patients also had a prolonged sedative effect that was reversed with aminophylline. CONCLUSIONS: CVT-510 promptly prolongs AV nodal conduction and does not affect sinus rate or blood pressure. Selective stimulation of the A(1)-adenosine receptor by CVT-510 may be useful for immediate control of heart rate in atrial fibrillation/flutter and to convert paroxysmal supraventricular tachycardia to sinus rhythm, while avoiding vasodilatation mediated by the A(2)-adenosine receptor, as well as the vasodepressor and negative inotropic effects associated with beta-adrenergic receptor blockade and/or calcium channel blockers.

Pronounced differences in the dispositon of clomipramine between Japanese and Swedish patients.

The aim of this study was to compare the disposition of the tricyclic antidepressant clomipramine (C) in Japanese and Swedish patients receiving continuous treatment. Therapeutic drug monitoring data for C and the active metabolite N-desmethylclomipramine (DC) in Japanese patients receiving monotherapy (N = 12) and in those receiving C plus benzodiazepines (BZDs) (N = 96) as well as in Swedes receiving C monotherapy (N = 131) and in those receiving C plus BZDs (N = 43) were used. A population kinetic approach with Bayesian feedback was used to estimate the individual clearance values for C. The relationships between kinetic variables and covariates were evaluated by linear multiple regression. The median (25% and 75% quartiles, respectively) oral clearance of C was 12.7 L/hr (11.6, 30.6) in Japanese patients receiving C monotherapy, 18.1 L/hr (5.6, 31.8) in Japanese patients receiving C plus BZDs, 62.7 L/hr (40.0, 90.6) in Swedish patients receiving C monotherapy, and 56.5 L/hr (34.3, 74.1) in Swedish patients receiving C plus BZDs. When combining all populations in a linear multiple regression, clearance was correlated with ethnic group (p < 0.00001) and age (p < 0.0005), but it was uncorrelated with gender, body weight, and administration of BZDs. The C/DC plasma concentration ratios were 1.08 in Japanese patients receiving C monotherapy, 0.90 in Japanese patients receiving C plus BZDs, 0.51 in Swedish patients receiving C monotherapy, and 0.49 in Swedish patients receiving C plus BZDs. Thus, the lower oral clearance of C in Japanese patients compared with that in Swedish patients is not accounted for by the lower body weight in Japanese patients or by concomitant treatment with BZDs and is therefore likely to be a true ethnic difference. The higher C/DC ratio implicates a more pronounced serotonergic than noradrenergic effect in Japanese patients than in Swedish patients.

Lack of association between debrisoquine 4-hydroxylase (CYP2D6) gene polymorphisms and schizophrenia.

Debrisoquine 4-hydroxylase (CYP2D6) is a cytochrome P450 enzyme involved in the metabolism of most neuroleptics, which are the drugs of choice for the treatment of psychotic symptoms. CYP2D6 in the brain was suggested to be functionally similar to the dopamine transporter, thus possibly influencing a neurotransmitter system involved in schizophrenia. Swedish schizophrenic patients (n = 124) and control individuals (n = 85) were investigated for two CYP2D6 polymorphisms, responsible for approximately 90% of mutations leading to poor debrisoquine metabolism. No significant CYP2D6 allele or genotype difference was found between schizophrenic patients and control individuals. Taken together with previous results, no major effect appears to be caused by the CYP2D6 gene on schizophrenia.

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose.

AIMS: To investigate the kinetics of the (+)RS- and (-)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers. METHODS: Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method. RESULTS: A two-compartment model adequately described the disposition of (+)RS-MQ. CL/F was 6.5 +/- 1.8 l h(-1), V(ss)/F 815 +/- 165 l, and k 0.0081 +/- 0.0023 h(-1). The kinetics of (-)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92 +/- 0.25 vs 2.14 +/- 0.63 l h(-1), 95% CI for the difference 0.86-1.60 l h(-1)) and a longer half-life (345 vs 185 h, 95% CI for the difference 47-291 h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (-)SR-MQ was significantly correlated within subjects (r = 0.69, P < 0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (-)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound. CONCLUSIONS: The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.

Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method.

AIMS: To evaluate the distribution of population kinetic parameters for clozapine and their relationship to age and gender in patients on continuous treatment with the drug. METHODS: Retrospective therapeutic drug monitoring data (391 samples from 241 patients) were evaluated using the nonparametric maximum likelihood method. Patients treated concomitantly with drugs known to interact with clozapine were not included. The distribution of clozapine clearance was compared with the distribution of the activity of the drug metabolic enzyme CYP1A2 found in other populations, as recent studies indicate that CYP1A2 is a major determinant for clozapine elimination. The kinetic linearity for clozapine was studied in 41 patients who each provided data from more than one dose level. RESULTS: Clozapine clearance was highly variable in the population and skewed towards high values. Men had higher clearances CL/F (median with 25% and 75% quartiles 38.2 (22.0, 60.0) vs 28.3 (15.2, 48.6) l h(-1)) and a larger volume of distribution V/F (694 (224, 970) vs 401 (189, 932) l) than women. Clearance did not decrease with age in any gender. Clozapine clearance was similarly distributed as the indices of CYP1A2-activity found in other populations by other authors. Evidence of nonlinear kinetics was not found. CONCLUSION: The large kinetic variability for clozapine found in this study implies that the dose of clozapine needs to be individualised over a wide dose range. The similarity of the distribution of clozapine clearance in this study and the CYP1A2-activity in other populations support the assumption that CYP1A2 is a major determinant for clozapine elimination.

Population pharmacokinetics and pharmacodynamics: potential use for gathering dose-concentration-response.

The population approach is a general term covering different aspects of kinetic and dynamic data collected mainly from drug-treated patients and new techniques allowing evaluation of sparse observations from each subject. Such data originate from clinically relevant conditions and can give information on several qualities of a drug. An example is given with the tricyclic antidepressant nortriptyline for which the kinetics and the concentration-effect relationship have been thoroughly documented previously with conventional techniques. We have evaluated retrospective data from a therapeutic drug monitoring service using a nonparametric population kinetic method (NPML) that allows description of kinetic outliers and nonlinear relationships between kinetic parameters and covariates. In addition, drug interactions, nonlinear kinetics and dosing habits were studied with other techniques corroborating previous results and adding new information. The concentration-effect relationship could not be evaluated from our data as information on efficacy and adverse effects was of too low quality. However, several controlled studies have defined a therapeutic concentration interval and a discussion on dosing strategies is based on this interval. Collection of sparse data in patients during phases II-IV of drug development as a complement to conventional studies is highly recommendable.

The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol.

BACKGROUND: Most antidepressant and neuroleptic agents are metabolized by the polymorphic cytochrome P450 enzyme CYP2D6. This study evaluates the importance of the CYP2D6 genotype for the disposition of the neuroleptic agents perphenazine and zuclopenthixol. METHODS: Patients treated with neuroleptic agents (n = 36) were studied prospectively with regard to CYP2D6 genotype and neuroleptic plasma concentration during oral treatment. Because no patient provided enough samples for individual kinetic modeling, a bayesian approach was used for determination of the clearance. Population kinetic parameters for this procedure were collected from retrospective therapeutic drug monitoring data (n = 113) by use of a nonparametric approach. RESULTS: The CYP2D6 genotype significantly predicted the oral clearance of perphenazine and zuclopenthixol (p < 0.01 by multiple regression). The difference in clearance between homozygous extensive metabolizers and poor metabolizers was threefold for perphenazine and twofold for zuclopenthixol. CONCLUSION: The results show that the genotype for CYP2D6 is closely related to the oral clearances of perphenazine and zuclopenthixol. If this finding can be confirmed in a larger population, genotyping may become an important tool for the dosing of these two neuroleptic agents.

Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma.

OBJECTIVE: To compare concentrations of the separate enantiomers of mefloquine (MQ), total racemic MQ and the carboxylic acid metabolite in different blood fractions at steady state. SETTING: Human volunteer laboratory, Unit of Clinical Pharmacology, Karolinska Institute. VOLUNTEERS: Ten healthy adult Caucasian volunteers. METHODS: Drug concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: Trough concentrations of the (+)RS enantiomer were higher in venous whole blood than in plasma and serum (mean ratios, 1.41 and 1.38). For the other enantiomer, (-)SR, concentrations were lower in whole blood than in plasma (mean ratio 0.89) and for the metabolite this ratio was 0.5. CONCLUSION: Stereoselective distribution might be important for antimalarial activity and should be considered when pharmacokinetic studies are performed.

Dosing of antidepressants--the unknown art.

Data from a therapeutic drug monitoring service, in total 2,393 observations in 1,606 patients, were used to analyze factors associated with the prescribed daily doses of the tricyclic antidepressants amitriptyline and nortriptyline. The achieved concentrations in plasma were evaluated in relation to suggested therapeutic ranges. The doses of both drugs were greatly reduced with increasing age, despite the fact that age is of minor importance for their kinetics. Interactions with concomitantly given drugs were not handled by dose adjustments of the antidepressant. Therapeutic drug monitoring increased the proportion of concentrations within the therapeutic range for patients on amitriptyline, but not for those on nor-triptyline. The large interindividual kinetic variability for most antidepressants requires individualized dosing, but this individualization is performed on incorrect grounds.

Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6--an evaluation with the nonparametric maximum likelihood method.

Therapeutic drug monitoring data for nortriptyline (674 analyses from 578 patients) were evaluated with the nonparametric maximum likelihood (NPML) method in order to determine the population kinetic parameters of this drug and their relation to age, body weight and duration of treatment. Clearance of nortriptyline during monotherapy exhibited a large interindividual variability and a skewed distribution. A small, separate fraction with a very high clearance, constituting between 0.5% and 2% of the population, was seen in both men and women. This may be explained by the recent discovery of subjects with multiple copies of the gene encoding the cytochrome-P450-enzyme CYP2D6, which catalyses the hydroxylation of nortriptyline. However, erratic compliance with the prescription may also add to this finding. A separate distribution of low clearance values with a frequency corresponding to that of poor metabolizers of CYP2D6 (circa 7% in Caucasian populations) could not be detected. Concomitant therapy with drugs that inhibit CYP2D6 resulted in a major increase in the plasma nortriptyline concentrations. This was caused by a decrease in nortriptyline clearance, whereas the volume of distribution was unchanged. The demographic factors age and body weight had a minor influence on the clearance of nortriptyline which was also unaffected by the duration of treatment.

Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service.

Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups--patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.

The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline.

Therapeutic drug monitoring data for amitriptyline (AT) and nortriptyline (NT) collected during 10 years (total of 4,278 analyses in 2,937 patients) were evaluated to study how other drugs affect the kinetics at steady state. The distribution of the ratio concentration/daily dose (C/D) in patients treated with the antidepressant only was compared with that in patients on different concomitant drugs. Patients on phenothiazines or dextropropoxyphene had a significantly higher mean C/D of NT than controls, both when AT and when NT had been given. The highest values were seen with levomepromazine and thioridazine. On the contrary, the mean C/D of both AT and NT in patients on carbamazepine was about 50% lower than in those treated with the antidepressant only. Benzodiazepines did not affect the steady-state kinetics of AT or NT. Intraindividual comparisons of the ratio C/D in subjects with analyses performed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D6) inhibit the metabolism of NT and that carbamazepine induces the metabolism of both AT and NT. Modeling of the dose dependency of the NT interactions with levomepromazine, perphenazine, and thioridazine revealed that the ratio C/D was most affected at low doses of the antidepressant and at high doses of the phenothiazine. The distribution of the doses given was the same in patients on monotherapy as in patients with interacting drugs, which means that many patients treated with phenothiazines had concentrations above the therapeutic range and that most patients treated with carbamazepine had subtherapeutic levels. The present study shows that therapeutic drug monitoring may serve as a valuable tool to discover and quantify drug interactions.

Nonlinear kinetics of nortriptyline in relation to nortriptyline clearance as observed during therapeutic drug monitoring.

From routine therapeutic drug monitoring data, samples from 105 patients with two analyses of nortriptyline at different daily doses were collected. The ratio between concentration and daily dose, which is the reciprocal of the apparent clearance, was compared intra-individually to study the occurrence of dose-dependent kinetics. Subjects with a low or intermediate ratio at the low dose had a higher mean ratio at the high dose, indicating a nonlinear relationship between dose and concentration. The magnitude of the difference was inversely correlated to the ratio at the low dose. No major difference was seen in the ca. 10% of the patients that exhibited the highest ratio at the low dose. This fraction corresponds to the frequency of poor metabolizers of debrisoquine in the population. The metabolism of nortriptyline has been shown to be partly dependent on the debrisoquine hydroxylase CYP2D6. We conclude that dose-dependent kinetics of nortriptyline occurs in subjects with a high or intermediate capacity to eliminate the drug, in accord with debrisoquine hydroxylase being a high-affinity, low-capacity pathway in the elimination of nortriptyline.

On the question of interindividual variations in chloroquine concentrations.

In a review of studies using appropriate methods for drug determinations and controlled intake, an interindividual variation in chloroquine concentrations of 2.3 to 5.6-fold was found. In our department, steady-state concentrations were evaluated in 40 patients with rheumatic diseases. The variation in whole blood concentrations was 11-fold for chloroquine and 10-fold for the desethylchloroquine metabolite. The mean ratio between desethylchloroquine and chloroquine concentrations was 0.53 and the Spearman-Rank correlation 0.92. The correlation between age and the ratio of chloroquine concentration/dose was 0.36 (P < 0.05) and the corresponding correlation for body weight was -0.43 (P < 0.05). Our data indicate that body weight and age are important independent factors for the disposition of chloroquine. However, when extensive 100-fold variations in concentrations are found between individuals we suggest that the reliability of the dose intake should be questioned.