Modeling Alzheimer's Disease Progression Using Disease Onset Time and Disease Trajectory Concepts Applied to CDR-SOB Scores From ADNI.

Disease-onset time (DOT) and disease trajectory concepts were applied to derive an Alzheimer's disease (AD) progression population model using the clinical dementia rating scale-sum of boxes (CDR-SOB) from the AD neuroimaging initiative (ADNI) database. The model enabled the estimation of a DOT and a disease trajectory for each patient. The model also allowed distinguishing fast and slow-progressing subpopulations according to the functional assessment questionnaire, normalized hippocampal volume, and CDR-SOB score at study entry. On the basis of these prognostic factors, 81% of the mild cognitive impairment (MCI) subjects could correctly be assigned to slow or fast progressers, and 77% of MCI to AD conversions could be predicted whereas the model described correctly 84% of the conversions. Finally, synchronization of the biomarker-time profiles on estimated individual DOT virtually expanded the population observation period from 3 to 8 years. DOT-disease trajectory model is a powerful approach that could be applied to many progressive diseases.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e78; doi:10.1038/psp.2013.54; advance online publication 2 October 2013.

Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model.

The plasma concentration-time profile of a drug is essential to explain the relationship between the administered dose and the kinetics of drug action. However, in some cases such as in pre-clinical pharmacology or phase-III clinical studies where it is not always possible to collect all the required PK information, this relationship can be difficult to establish. In these circumstances several authors have proposed simple models that can analyse and simulate the kinetics of the drug action in the absence of PK data. The present work further develops and evaluates the performance of such an approach. A virtual compartment representing the biophase in which the concentration is in equilibrium with the observed effect is used to extract the (pharmaco)kinetic component from the pharmacodynamic data alone. Parameters of this model are the elimination rate constant from the virtual compartment (KDE), which describes the equilibrium between the rate of dose administration and the observed effect, and the second parameter, named EDK(50) which is the apparent in vivo potency of the drug at steady state, analogous to the product of EC(50), the pharmacodynamic potency, and clearance, the PK "potency" at steady state. Using population simulation and subsequent (blinded) analysis to evaluate this approach, it is demonstrated that the proposed model usually performs well and can be used for predictive simulations in drug development. However, there are several important limitations to this approach. For example, the investigated doses should extend from those producing responses well below the EC(50) to those producing ones close to the maximum response, optimally reach steady state response and followed until the response returns to baseline. It is shown that large inter-individual variability on PK-PD parameters will produce biases as well as large imprecision on parameter estimates. It is also clear that extrapolations to dosage routes or schedules other than those used to estimate the parameters should be undertaken with great caution (e.g., in case of non-linearity or complex drug distribution). Consequently, it is advised to apply this approach only when the underlying structural PD and PK are well understood. In any case, K-PD model should definitively not be substituted for the gold standard PK-PD model when correct full model can and should be identified.

Population pharmacokinetics of ibandronate in Caucasian and Japanese healthy males and postmenopausal females.

INTRODUCTION: Ibandronate is a potent, nitrogen-containing bisphosphonate that is licensed as a once-monthly oral preparation and is currently in clinical development as a novel intermittent intravenous (i.v.) injection in osteoporosis. Ibandronate pharmacokinetic (PK) data were used to develop a PK model that could ultimately be incorporated into a PK pharmacodynamic (PD) model to assist the ibandronate development program through computer-assisted trial design. This manuscript reports the use of non-linear mixed-effects modeling to characterize the PK of ibandronate, to examine the possible influence of ethnicity on the disposition of ibandronate and to develop an appropriate population PK model for ibandronate. METHODS: A retrospective, cross-study population PK analysis was performed using PK data from five phase I studies with i.v. ibandronate (0.125 - 2.0 mg) conducted in Caucasian and Japanese healthy male volunteers, postmenopausal Caucasian women without osteopenia and postmenopausal Japanese women with osteopenia. The following covariates were investigated to establish their influence on the central volume of distribution (V1) and drug clearance (CL): age, body weight, gender, disease status (healthy versus osteopenic), creatinine clearance (CLCR), and ethnicity (Japanese versus Caucasian). Serum concentrations of ibandronate were quantified by GC-MS or ELISA, and data were modeled using non-linear mixed-effects modeling implemented by the software program NONMEM. RESULTS: The PK of ibandronate was adequately described by a linear 3-compartment model. Disease status, body weight, gender and CLCR significantly influenced ibandronate CL (10 34%) and the latter 3 also influenced V1 (20 29%). Ethnicity was not a determinant for ibandronate PK in the final model. Although gender was the most influential covariate, differences in V1 and CL between the sexes were modest (29 and 34%, respectively) and the overall effects on ibandronate exposure (Cmax and AUC) were not clinically relevant. The final model described the observed PK of ibandronate well, and all PK parameters were estimated with an acceptable degree of precision (SE < 13%). CONCLUSION: The PK of i.v. ibandronate was well described by a linear 3-compartment population PK model that included disease status, body weight, gender and CLCR as covariates, but without greatly affecting ibandronate exposure (Cmax and AUC). Ethnicity did not influence ibandronate PK and was not included in the final model.

Clinical utility of a pharmacostatistical model for ibandronate in postmenopausal osteoporosis.

Ibandronate, a potent, nitrogen-containing bisphosphonate for the treatment of postmenopausal osteoporosis, is the subject of an ongoing clinical development program to explore novel oral and intravenous (i.v.) dosing regimens. As part of this program, an extensive modeling and simulation project was undertaken to develop and validate a pharmacologically realistic mathematical model for ibandronate in osteoporosis, the aim being to identify practical dosing regimens for clinical evaluation. A simplified kinetics of drug action or kinetic-pharmacodynamic (K-PD) model (developed from a 4-compartment pharmacokinetic-pharmacodynamic [PK-PD] model) accurately described the urinary excretion of the C-telopeptide of the alpha-chain of type I collagen (uCTX). The model was extended to consider the effects of supplemental calcium therapy and allow simultaneous fitting of i.v. and oral ibandronate data, and then externally validated. This model was used successfully in the selection of appropriate once-monthly doses for further clinical evaluation and recent clinical studies have confirmed the efficacy of the doses identified. Further development of the model may include investigating the effects of ibandronate on bone mineral density and fracture risk, which would further enhance its clinical utility and predictive value. Although modeling and simulation has been used to explore the efficacy of other bisphosphonates, the extensive program with ibandronate has produced a comprehensively validated model that is the first to be prospectively tested by evaluating novel dosing regimens.

Explicit solutions for a class of indirect pharmacodynamic response models.

Explicit solutions for four, ordinary differential equation (ODE)-based, types of indirect response models are presented. These response models were introduced by Dayneka et al. in 1993 [J. Pharmacokinet. Biopharm. 21 (1993) 457] to describe pharmacodynamic responses utilizing inhibitory or stimulatory E(max) type functions. The explicit solutions are expressed in terms of hypergeometric 2F1 functions and their analytical continuations. A practical application is demonstrated for modeling the kinetics of drug action for ibandronate, a potent bisphosphonate that suppresses bone turnover resulting in a reduction in the markers of bone turnover. Ten times shorter model evaluation times, with the explicit solution compared with the differential equation implementation, may enhance situations where a large number of model evaluations are needed, such as clinical trial simulations and parameter estimation.

Population pharmacokinetic analysis of the major metabolites of capecitabine.

Capecitabine has been developed as an orally administered tumor selective fluoropyrimidine for use in the treatment of breast and colorectal cancer. The metabolic pathway for capecitabine includes 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), which is then converted to the pharmacologically active agent 5-fluorouracil (5-FU). A previous analysis showed that systemic exposure to 5'-DFUR and alpha-fluoro-beta-alanine (FBAL), a catabolite of 5-FU, was predictive of dose limiting toxicities. Therefore, a multi-response population pharmacokinetic (PK) model for the description of plasma concentrations of 5'-DFUR, 5-FU and FBAL following oral administration of capecitabine was developed using NONMEM. PK data from a bioequivalence study in 24 patients with various solid tumors were used to develop the PK structural part of the population PK model. The 5'-DFUR, 5-FU and FBAL plasma concentrations were described by a linear disposition PK model with first order absorption and lag time. Sparse plasma concentration data from 54 phase II breast cancer patients were added to the bioequivalence data and the influence of covariates on the apparent oral clearances of 5'-DFUR, 5-FU and FBAL and on the apparent volume of distribution of FBAL was investigated. This was conducted by including all significant (p < 0.05) single covariate-PK parameter pairs in the full PK model, followed by one by one deletion (p < 0.001) from the population model. Statistically significant effects were found for the influence of gender, body surface area and total bilirubin on 5'-DFUR clearance and the influence of creatinine clearance on FBAL clearance. However, none of these effects were considered to have clinical relevance.

Pharmacometrics: modelling and simulation tools to improve decision making in clinical drug development.

There is broad recognition within the pharmaceutical industry that the drug development process, especially the clinical part of it, needs considerable improvement to cope with rapid changes in research and health care environments. Modelling and simulation are mathematically founded techniques that have been used extensively and for a long time in other areas than the pharmaceutical industry (e.g. automobile, aerospace) to design and develop products more efficiently. Both modelling and simulation rely on the use of (mathematical and statistical) models which are essentially simplified descriptions of complex systems under investigation. It has been proposed to integrate pharmacokinetic (PK) and pharmacodynamic (PD) principles into drug development to make it more rational and efficient. There is evidence from a survey on 18 development projects that a PK/PD guided approach can contribute to streamline the drug development process. This approach extensively relies on PK/PD models describing the relationships among dose, concentration (and more generally exposure), and responses such as surrogate markers, efficacy measures, adverse events. Well documented empirical and physiologically based PK/PD models are becoming available more and more, and there are ongoing efforts to integrate models for disease progression and patient behavior (e.g. compliance) as well. Other types of models which are becoming increasingly important are population PK/PD models which, in addition to the characterization of PK and PD, involve relationships between covariates (i.e. patient characteristics such as age, body weight) and PK/PD parameters. Population models allow to assess and to quantify potential sources of variability in exposure and response in the target population, even under sparse sampling conditions. As will be shown for an anticancer agent, implications of significant covariate effects can be evaluated by computer simulations using the population PK/PD model. Stochastic simulation is widely used as a tool for evaluation of statistical methodology including for example the evaluation of performance of measures for bioequivalence assessment. Recently, it was suggested to expand the use of simulations in support of clinical drug development for predicting outcomes of planned trials. The methodological basis for this approach is provided by (population) PK/PD models together with random sampling techniques. Models for disease progression and behavioral features like compliance, drop-out rates, adverse event dependent dose reductions, etc. have to be added to population PK/PD models in order to mimic the real situation. It will be shown that computer simulation helps to evaluate consequences of design features on safety and efficacy assessment of the drug, enabling identification of statistically valid and practically realisable study designs. For both modelling and simulation a guidance on 'best practices' is currently worked out by a panel of experts comprising representatives from academia, regulatory bodies and industry, thereby providing a necessary condition that model-based analysis and simulation will further contribute to streamlining pharmaceutical drug development processes.

Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients.

OBJECTIVE: The aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibitor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empirical mathematical modelling. DESIGN AND SETTING: A randomised, non-blind, multicentre, dose-ranging 8-week study of monotherapy with 400, 800 or 1200 mg of saquinavir-SGC or 600 mg of the hard gelatin capsule (HGC) formulation, both administered 3 times daily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, were fitted to 2 measures of systemic drug exposure, the area under the plasma concentration-time curve (AUC) and trough plasma concentration (Cmin), using 6 exposure-response models of progressively increasing complexity. Akaike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic-pharmacodynamic relationship. RESULTS: A total of 88 patients were randomised; pharmacokinetic and pharmacodynamic data were available for 84 patients. In terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-parameter maximum effect (Emax) model, which predicted a typical maximum reduction in viral load of 1.94 log10 copies/ml [coefficient of variation (CV) 12%], with a half-maximal antiviral response occurring at a Cmin of 50 micrograms/L (CV 40%). Saquinavir-SGC 1200 mg administered 3 times daily produced a median AUC to 24 hours (AUC24) of approximately 20,000 micrograms/L.h, corresponding to 85% of the maximum achievable antiviral effect as defined by the model. None of the models yielded a satisfactory fit for CD4+ cell count. CONCLUSION: Empirical mathematical modelling confirmed that, when administered 3 times daily, the optimum dose of saquinavir-SGC is 1200 mg, corresponding to 3600 mg/day.

Pharmacokinetic and pharmacodynamic interactions between fluoxetine and moclobemide in the investigation of development of the "serotonin syndrome".

OBJECTIVE: To assess the tolerability, safety, pharmacokinetics, and pharmacodynamics of combined treatment with fluoxetine and moclobemide in healthy subjects. METHODS: Fluoxetine (20 to 40 mg/day) was administered for 23 days to 18 subjects. At (nor)fluoxetine steady state, subjects were randomized in a 2:1 ratio to receive in addition either moclobemide (ascending doses up to 600 mg/day) of placebo. A single 300 mg dose of moclobemide was administered before and at the end of the fluoxetine regimen to assess the effects of the latter on the pharmacokinetics and pharmacodynamics of moclobemide. Adverse events and vital signs were recorded and pharmacokinetic parameters of fluoxetine and moclobemide were determined. Plasma concentrations of 3,4-dihydroxy-phenyl-glycol, 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and serotonin uptake into platelets were assessed as pharmacodynamic measures. RESULTS: The number, intensity, or type of adverse events did not change when moclobemide was added to fluoxetine. No clinically relevant changes in safety parameters occurred. Fluoxetine markedly inhibited the metabolism of moclobemide. However, multiple dosing of moclobemide did not lead the excessive accumulation. 3,4-Dihydroxyphenylglycol, 5-hydroxyindoleacetic acid, and 3,4-dihydroxyphenylacetic acid plasma levels and serotonin uptake did not reveal a pharmacodynamic interaction. CONCLUSIONS: Combination treatment with fluoxetine and moclobemide did not provide any indication of development of the "serotonin syndrome."

Exploring clinical study design by computer simulation based on pharmacokinetic/pharmacodynamic modelling.

Computer simulations have been successfully applied in various industries (e.g. automobile, aerospace) to make product development more efficient. Just recently, it was suggested to use simulations in support of clinical drug development for predicting clinical outcomes of planned trials. The methodological basis for this approach is provided by pharmacokinetic and pharmacodynamic mathematical models together with Monte Carlo techniques. In the present paper, the basic notions of clinical trial simulation are introduced and illustrated with the example of an oral anticancer drug. It is shown that computer simulation helps to evaluate consequences of design features on safety and efficacy assessment of the drug which are not easily obtained otherwise. An overview of existing simulation resources with respect to training and software is provided.

Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide.

Irreversible, nonselective monoamine oxidase (MAO) inhibitors have been reported adversely to interact with indirectly acting sympathomimetic amines present in many cough and cold medicines. This study investigated the safety and tolerability of concomitant administration to 12 healthy subjects of both genders (aged 19-36 years) of ephedrine and moclobemide, a reversible MAO-A inhibitor. A 2-day, randomized, crossover administration of placebo or ephedrine (two doses of 50 mg with a 4-h interval) was followed by 9 days open-label dosing with moclobemide, 300 mg b.i.d.. On the last 2 days of moclobemide dosing, the randomized crossover treatment of ephedrine and placebo was repeated. No subject was withdrawn from the study for tolerability reasons. Moclobemide treatment, however, increased the incidence of adverse events elicited by ephedrine, particularly palpitations and headache. The pharmacodynamic interaction between the two drugs was quantified by calculation of the area under the effect-time course (AUE) for systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR). The difference in AUE between monotreatment with ephedrine and placebo was statistically significant for all three vital signs. Moclobemide potentiated the effect of ephedrine by a median factor of 3.2 for SBP, 3.8 for DBP, and 0.6 for HR. Ephedrine had no significant influence on the plasma concentrations of moclobemide or its metabolites. In conclusion, the combined use of moclobemide and high doses of sympathomimetic drugs should be approached with caution.

Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol.

1. Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double-blind, placebo controlled six-way cross over experiment in 12 healthy volunteers, aged 19-26 years. 2. Bretazenil (0.5 mg), diazepam (10 mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target-blood concentration of 0.5 g l-1 or a control infusion of 5% w/v glucose at 1 week intervals. 3. CNS effects were evaluated between 0 and 3.5 h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales. 4. Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol > diazepam+alcohol > or = bretazenil > diazepam > alcohol > placebo. 5. There were no consistent indications for synergistic, supra-additive pharmacodynamic interactions between alcohol and bretazenil or diazepam. 6. Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests. 7. No significant pharmacokinetic interactions were found. 8. Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.

Pharmacokinetics and pharmacodynamics of Ro 41-3696, a novel nonbenzodiazepine hypnotic.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

Integrated pharmacokinetics and pharmacodynamics of the novel catechol-O-methyltransferase inhibitor tolcapone during first administration to humans.

OBJECTIVES: To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. METHODS: In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes. RESULTS: Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. CONCLUSIONS: The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

Effects of bretazenil vs. zolpidem and placebo on experimentally induced sleep disturbance in healthy volunteers.

The effects of bretazenil 0.25 and 0.5 mg, a partial agonist at the benzodiazepine receptor, on sleep electroencephalogram (EEG), subjective sleep quality and morning psychomotor performance were compared to zolpidem 10 mg and placebo using noise as an experimental sleep disturbing factor in a single dose, double-blind, crossover study. Twelve healthy volunteers were subjected to prerecorded traffic noise with a mean sound level of 52 dB(A) during eight hours in bed. Significant effects of noise were found on sleep electroencephalogram (EEG) parameters (rapid eye movement [REM] sleep, stage 2 sleep and number of arousals), and subjective sleep quality assessments, but not on psychomotor performance (choice reaction time, digit span memory, and symbol digit substitution). Both drugs reduced the number of shifts between sleep stages and the number of arousals and increased REM sleep latency. Only after 0.5 mg bretazenil, stage 2 sleep increased and REM sleep decreased. Both doses of bretazenil significantly affected performance in the symbol digit substitution test. Sleep quality improved under drug treatments compared to placebo. The results suggest that experimental sleep disturbance can be a valuable tool in the investigation of potential sleep promoting compounds.

Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state.

Pharmacodynamic interactions of low doses of diazepam and alcohol were investigated in a double blind, randomised, 2 x 2 factorial, cross-over study in eight healthy volunteers. Alcohol or glucose 5% were administered intravenously at rates calculated to maintain breath alcohol levels of 0.5 g/l from 1.5 to 5.5 h after starting the alcohol infusion. Diazepam 5 mg or placebo were administered orally at 1.5 h. Evaluation of pharmacodynamic interactions was performed for the average results of tests performed at 2, 3.5 and 5 h. Plasma concentrations of (desmethyl-) diazepam and breath alcohol levels were measured for pharmacokinetic analysis. Breath alcohol reached pseudo steady state levels of 0.38 g/l (range: 0.24-0.57) after alcohol alone and 0.37 g/l (range: 0.27-0.52) in combination with diazepam. Alcohol effects were demonstrated for latency of saccadic eye movements, smooth pursuit eye movements and subjective drug effects. Diazepam impaired smooth pursuit and saccadic eye movements, adaptive tracking, digit symbol substitution and body sway. The effects of combined alcohol and diazepam were mostly additive without significant synergistic interactions. However, in two subjects large supra-additive effects occurred at 3.5 h following alcohol+diazepam, which were not explained by increased drug levels. The design and methods used in this study proved advantageous in evaluating low dose pharmacodynamic interactions. Despite the absence of significant synergistic interactions, unanticipated impairment of performance may occur in susceptible individuals when taking combined low doses of alcohol and diazepam.

Interaction studies with moclobemide.

Drug interactions with moclobemide given to healthy subjects and depressed patients are reviewed. The drugs investigated for safety were antihypertensives, digoxin, oral contraceptives, anticoagulants and benzodiazepines. Cimetidine was studied for the pharmacokinetic effect, and possible interactions with alcohol (stimulation and/or sedation) were included. Finally, since inhibition of monoamine oxidase (MAO) can increase noradrenergic transmission, possible interaction with neuronal reuptake inhibitors such as tricyclic antidepressants (TCAs) was investigated. Whereas replacement of the older, irreversible MAO inhibitors by a TCA was held to be dangerous and to require a therapy-free interval, the studies reviewed here provide evidence that amitriptyline can replace or be added to moclobemide without any sign of impaired tolerance, need for dose reduction or a therapy-free interval. Combined administration of moclobemide and desipramine was also tolerated well. Moclobemide did not interact with the direct-interacting sympathomimetics norepinephrine and isoproterenol and only to a negligible extent with phenylephrine. The combination of moclobemide with antihypertensive agents did not cause postural hypotension or an increase in other side effects. No clinically relevant interaction was observed between moclobemide and phenprocoumon, glibenclamide, oral contraceptives, digoxin or benzodiazepines. Cimetidine increased the concentration of moclobemide in plasma after a single oral dose by about 100%. If moclobemide is to be used in a patient pretreated with cimetidine, treatment should therefore start with the lowest therapeutic dose and then be adjusted to clinical needs. Since moclobemide is devoid of anticholinergic effects, no interaction with alcohol was anticipated. High therapeutic doses (600 mg/day) induced an effect similar to that of low doses of a TCA, but with 100-300 mg no interaction with alcohol was seen, even in elderly people.

Potentiation of the pressor effect of oral and intravenous tyramine during administration of the selective MAO-A inhibitor moclobemide in healthy volunteers.

The interaction between tyramine and the new short-acting and reversible mono amine oxidase inhibitor moclobemide was investigated in a double-blind placebo-controlled study in six healthy volunteers. There were two consecutive study periods of 8 days during which the subjects received moclobemide three x 200 mg daily or placebo. On day 5 of each study period changes in systolic blood pressure (SBP) were determined after incremental intravenous bolus doses of tyramine and on days 6, 7 and 8 changes in SBP were determined after oral tyramine (100, 200 and 300 mg, respectively). Oral tyramine was administered together with a standard breakfast, before which moclobemide had been given. On days 5- 8 blood was taken for determination of blood drug levels. On days 6-8 blood samples were taken before and at 15, 30 and 45 min after tyramine administration for determination of plasma tyramine and plasma norepinephrine concentrations. When SBP had increased by approximately 30 mmHg no further doses of either intravenous or oral tyramine were given. Moclobemide was well tolerated by all subjects. Plasma trough levels of moclobemide were within the therapeutic range. The tyramine induced increases in SBP were greater during moclobemide than during placebo. After intravenous tyramine the dose-response curve for SBP was shifted to the right by a factor of approximately 3. When compared to placebo the pressor response to 100 mg tyramine orally was not significantly different, but the pressor response to the other two doses was enhanced during moclobemide.

Blood pressure response to tyramine-enriched meal before and during MAO-inhibition in man: influence of dosage regimen.

In an open study oral tyramine in variable doses was administered to six healthy volunteers under three different conditions: 1) without moclobemide, 2) under moclobemide steady-state conditions (3 X 200 mg moclobemide daily) one hour after moclobemide intake and 3) under moclobemide steady-state conditions simultaneously with moclobemide. It was shown that the amount of tyramine effecting 30-50 mmHg systolic blood pressure increase was roughly doubled when moclobemide was administered together with tyramine instead of one hour before tyramine intake. The time interval between tyramine ingestion and maximal blood pressure increase did not differ significantly between conditions 2) and 3). The conclusion of this study is that moclobemide should always be taken at the end of a meal, which is anyway the usual time for drug intake.

Interaction of moclobemide, a new reversible monoamine oxidase inhibitor with oral tyramine.

In a double-blind placebo-controlled cross-over study in 8 healthy volunteers possible interactions between moclobemide and tyramine were studied. Eight volunteers received either moclobemide or placebo for a period of 6 days and received tyramine on day 5 and day 6 of each treatment period. Moclobemide was given in a daily dose of 450 mg to be taken in three divided doses at the end of the meals. Tyramine was administered in the form of an artificially tyramine enriched cheese (camembert) together with a meal at noon. The total tyramine doses administered were 50 mg on day 5 and 100 mg on day 6 of each treatment period. Comparisons of blood pressure and heart rate changes after tyramine ingestion between moclobemide and placebo conditions did not indicate any relevant moclobemide-tyramine interaction. It is concluded that tyramine in quantities of up to 100 mg does not lead to clinically relevant blood pressure reactions in moclobemide-treated subjects, if moclobemide is taken at the end of the meal.