QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of lorazepam and moclobemide. Please also consult the relevant specialist information.
|Moclobemide||1 [0.7,3.83] 1||1|
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for lorazepam, when combined with moclobemide (100%). We do not expect any change in exposure for moclobemide, when combined with lorazepam (100%). The AUC is between 70% and 383% depending on the CYP2C19
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Lorazepam has a high oral bioavailability [ F ] of 85%, which is why the maximum plasma level [Cmax] tends to change little during an interaction. The terminal half-life [ t12 ] is 14.3 hours and constant plasma levels [ Css ] are reached after approximately 57.2 hours. The protein binding [ Pb ] is moderately strong at 91.9% and the volume of distribution [ Vd ] is very large at 111 liters. The metabolism does not take place via the common cytochromes and the active transport takes place in particular via UGT2B7.
Moclobemide has a mean oral bioavailability [ F ] of 54%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 1.64 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is rather weak at 50% and the volume of distribution [ Vd ] is very large at 95 liters. which is why, with a mean hepatic extraction rate of 0.45, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism mainly takes place via CYP2C19.
|Serotonergic Effects a||3||Ø||+++|
Recommendation: The risk of a serotonergic syndrome is increased, but without an exact answers to the cognitive, vegative and neuromuscular symptom questions we cannot make any recommendations for action.
Rating: Moclobemide greatly increases serotonergic activity. According to our knowledge, lorazepam does not increase serotonergic activity.
|Kiesel & Durán b||1||Ø||+|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Moclobemide only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. The anticholinergic effect of lorazepam is not relevant.
QT time prolongation
Moclobemide can potentially increase QT time, but we do not know about torsades de pointes arrhythmias. We do not know of any QT-prolonging potential for lorazepam.
General adverse effects
|Side effects||∑ frequency||lor||moc|
Rebound effect: lorazepam
Respiratory depression: lorazepam
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: No Abstract available
Abstract: Moclobemide is a reversible and selective inhibitor of the enzyme monoamine oxidase (MAO) subtype A with a broad spectrum of antidepressant activity. Controlled clinical studies suggest that the short term clinical efficacy of moclobemide is significantly superior to that of placebo, and comparable to that of the tricyclic antidepressants clomipramine, amitriptyline, imipramine and desipramine, the irreversible MAO inhibitor tranylcypromine and the second-generation antidepressants maprotiline, mianserin and fluvoxamine in the treatment of major depressive illness. Moclobemide appears to be equally effective in endogenous and nonendogenous depression, producing marked amelioration of clinical features of psychomotor retardation and depressed mood. Moclobemide is well tolerated, being largely devoid of the anticholinergic adverse effects, symptomatic postural hypotension and weight gain variously associated with the tricyclic antidepressants and irreversible MAO inhibitors, and appears considerably safer on overdosage than the tricyclic and second generation antidepressants. Moreover, moclobemide offers the advantage over the older, irreversible MAO inhibitors of causing only minimal potentiation of the pressor response to dietary tyramine (the so-called 'cheese effect'). Consequently, the risk of potentially fatal hypertensive crisis, a major deterrent to the wider acceptance of these earlier compounds, is substantially reduced with moclobemide, and the need for dietary precautions is minimised. With its efficacy against endogenous and nonendogenous depression, relatively rapid onset of antidepressant activity, and absence of carry-over effects on treatment withdrawal, moclobemide is likely to make an important contribution to the treatment of major depressive illness. Its favourable tolerability profile, safety on overdosage and beneficial effect on age-related cognitive impairment may be of particular value in the elderly and those with concurrent physical illness.
Abstract: The influence of cimetidine on the absorption and disposition of moclobemide was examined in eight healthy male subjects. A single 100 mg intravenous and 100 mg oral dose of moclobemide was administered before and after 2 weeks of cimetidine administration (200 mg five times a day). The data on intravenous administration indicated that cimetidine produced a statistically significant alteration in the following disposition parameters (mean values for control versus cimetidine): systemic clearance, 46.6 versus 28.3 L/hr; mean residence time, 2.1 versus 3.2 hours; elimination half-life, 1.6 versus 2.3 hours. There was no significant difference in the steady-state volume of distribution. The absolute oral bioavailability of moclobemide increased significantly after cimetidine administration (54% versus 68%), as did the maximum plasma concentration after a single oral dose (575 versus 787 ng/ml). There were no differences in the mean absorption time or time to achieve maximum concentration. The values of systemic and apparent oral clearances of moclobemide after cimetidine administration were directly related to the corresponding control values before cimetidine. In contrast, the percentage change in clearance was essentially independent of the corresponding initial control clearance value.
Abstract: This study was undertaken to determine the absolute bioavailability and steady-state concentrations of moclobemide after doses of 150 mg. In 14 healthy human volunteers, no differences in tmax, t 1/2 beta, C1/F, Cmax and AUC were found between a single oral dose of 100 mg and one of 150 mg. The mean absolute oral availability was 0.66 and 0.69 respectively. Plasma concentration profiles of moclobemide on repeated dosing with 150 mg 3 times daily for 15 days were essentially superimposable, although the mean concentration was higher than after the single 150 mg dose. This concentration increased over the first week and then remained relatively constant. Mean accumulation factors for moclobemide during the first week were 1.85 for Cmax and 3.0 for AUC. These values were higher than predicted from single-dose characteristics. There was a marked reduction in the variability of AUC and clearance (C1/F) values at steady-state compared with the first dose. Minimum plasma concentrations of the 2 metabolites, Ro 12-5637 and Ro 12-8095, were relatively stable throughout dosing. The exact mechanism of the decrease in systemic and oral clearance of moclobemide with time during multiple oral dosing is not known at present. Either moclobemide inhibits its own clearance or moclobemide metabolism is inhibited by one or more of its metabolites. The findings indicate that, if dosage needs to be adjusted during treatment with moclobemide, the changes should be made carefully and at intervals of not less than 1 week.
Abstract: Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half-life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min-1 kg-1). Propoxyphene significantly prolonged alprazolam half-life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min-1 kg-1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half-life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min-1 kg-1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N-demethylation, and has no apparent influence on lorazepam conjugation.
Abstract: The absorption and disposition kinetics of moclobemide (Ro 11-1163), a new reversible and preferential monoamine oxidase-A enzyme inhibitor, were examined in 12 normal male subjects. An intravenous infusion was administered before and after a 15-day multiple oral dosing regimen (100 mg t.i.d.). Plasma concentration-time data were obtained after each intravenous infusion, after the first oral dose, during two dosing intervals at steady state, and before the second daily dose on several days. The disposition values (percent coefficient of variation in parentheses) after the first and second intravenous infusions, respectively, were: clearance, 39.4 (15%) and 29.1 (12%) L/hr; elimination half-life, 1.60 (15%) and 2.00 (18%) hours; and volume of distribution at steady state, 84.3 (11%) and 80.7 (15%) L. The absolute oral bioavailability increased from 0.56 after the first oral dose to 0.86 and 0.90 after the first and second weeks of administration, respectively. The reduced metabolic, presumably hepatic, clearance may be the result of self-inhibition or metabolite inhibition of moclobemide clearance.
Abstract: Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: No Abstract available
Abstract: 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.
Abstract: No Abstract available
Abstract: No Abstract available
Abstract: No Abstract available
Abstract: There has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious pressor effects. Furthermore, the current drugs are far more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined. Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order). Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug. Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and pressor amine drugs); the so-called 'cheese effect' is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxication per se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.
Abstract: The metabolic fate of moclobemide (Ro 11-1163), a new reversible and selective inhibitor of monoamine oxidase type A (MAO-A), has been assessed in a pilot study in 2 debrisoquine poor metabolizers (PM) and 4 extensive metabolizers (EM) after multiple oral dosings of moclobemide with and without co-medication of dextromethorphan. Absorption and disposition parameters were not different between PM and EM. Concurrent application of dextromethorphan, a selective substrate of CYP2D6, did not affect the pharmacokinetics of moclobemide. These results indicate that the cytochromal isoenzyme CYP2D6 does not play a major role in the metabolic degradation of moclobemide. Limited CYP2D6 activities because of a genetic defect or co-medications with CYP2D6 substrates should therefore not give rise to elevated moclobemide blood levels.
Abstract: No Abstract available
Abstract: OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.
Abstract: BACKGROUND: Moclobemide, an antidepressant with selective monoamine oxidase-A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study. METHODS: The effect of omeprazole on the pharmacokinetics of moclobemide was studied in 16 healthy volunteers. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study II, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. RESULTS: The inhibition of moclobemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor metabolizers, no remarkable changes in the pharmacokinetic parameters were observed. CONCLUSION: Our results show that CYP2C19 is an important enzyme in the elimination of moclobemide and that it is extensively inhibited by omeprazole in extensive metabolizers, but not in poor metabolizers.
Abstract: BACKGROUND: Several medications have been found to prolong the QT interval in overdose. This can predispose to torsade de pointes-type ventricular tachycardia. AIMS: To analyse the effects of moclobemide deliberate self-poisoning on the length of both QT and corrected QT (QTc) intervals. METHODS: Electrocardiograms (ECG) of all patients presenting to a regional toxicology service with moclobemide ingestion were reviewed. Cases where a cardiotoxic agent was coingested were excluded. QT and QTc parameters were compared with a comparison group of patients ingesting paracetamol or benzodiazepines. RESULTS: Of 75 patients where ECG were available, the median ingested dose was 4.5 g (interquartile range (IQR): 2.4-7.5; range: 0.6-18 g) and the median age was 34 years (IQR: 26-44). The mean QT interval was 415 ms (standard deviation (SD): 51 ms) with a mean QTc of 459 ms (SD: 44 ms), and were prolonged compared with the comparison group. Twelve female patients had a QTc > 500 ms and in seven of these causality was established based on a pre- or post-ECG with a QTc < 500 ms. Only 10% of the moclobemide cases had a heart rate (HR) > 100 beats per minute, making overcorrection of HR by Bazett's formula an unlikely cause of the findings. No cardiac arrythmias were observed other than one case of first-degree heart block. CONCLUSIONS: Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done on all moclobemide deliberate self-poisonings. Continuous cardiac monitoring for what is otherwise a relatively benign overdose would appear to be an inappropriate use of resources but can be considered in patients with a QTc > 500 ms or with known risks for QT prolongation.
Abstract: The present study investigates the kinetic disposition with focus on the racemization, glucuronidation capacity and the transplacental transfer of lorazepam in term parturients during labor. The study was conducted on 10 healthy parturients aged 18-37 years with a gestational age of 36-40.1 weeks, treated with a single oral dose of 2 mg racemic lorazepam 2-9 h before delivery. Maternal venous blood and urine samples were obtained over a 0-48 h interval and the umbilical cord sample was obtained immediately after clamping. Lorazepam enantiomers were determined in plasma and urine samples by LC-MS/MS using a Chiralcel OD-R column. In vitro racemization of lorazepam required the calculation of the pharmacokinetic parameters as isomeric mixtures. The data were fitted to two-compartment model and the pharmacokinetic parameters are reported as means (95% CI): t(1/2a) 3.2h (2.6-3.7 h), K(a) 0.23 h(-1) (0.19-0.28 h(-1)), t(1/2) 10.4h (9.4-11.3h), beta 0.068 h(-1) (0.061-0.075h(-1)), AUC(0-infinity) 175.3(ngh)/ml (145.7-204.8(ngh)/ml), Cl/F 2.6 ml/(minkg) (2.3-2.9 ml/(minkg)), Vd/F178.8l (146.5-211.1l), Fel 0.3% (0.1-0.5%), and Cl(R) 0.010 ml/(minkg) (0.005-0.015 ml/(minkg)). Placental transfer of lorazepam evaluated as the ratio of vein umbilical/maternal vein plasma concentrations, obtained as an isomeric mixture, was 0.73 (0.52-0.94). Pregnancy changes the pharmacokinetics of lorazepam, with an increase in the apparent distribution volume, an increase in apparent oral clearance, and a reduction of elimination half-life. The increase in oral clearance may indicate an increase in glucuronidation capacity, with a possible reduction in the plasma concentrations of drugs depending on glucuronidation capacity as the major metabolic pathway.
Abstract: Cases of catatonia in patients with renal failure have been rarely reported. In this report, we describe two renal-insufficient patients with catatonia who had a good response to intramuscular lorazepam whereby the catatonic symptoms were relieved. Case 1 involved a patient with end-stage renal disease and severe pneumonia related respiratory failure. He responded well to intramuscular lorazepam (total dose, 4 mg) whereby the catatonia was elieved. Case 2 involved a patient with alcoholic liver cirrhosis and rhabdomyolysis-related acute renal failure. He showed great improvement with intramuscular lorazepam (2 mg) whereby the catatonia was subsequently relieved. This report demonstrates that intramuscular lorazepam is safe, effective and rapid in relieving catatonia associated with renal function impairment. Neither of the patients had a recurrence of catatonia during a period of 6- months follow-up. In conclusion, intramuscular lorazepam may play an important role in the treatment of catatonia associated with renal insufficiency.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd.
Abstract: Our recent paper demonstrated the ability to predict in vivo clearance of flavin-containing monooxygenase (FMO) drug substrates using in vitro human hepatocyte and human liver microsomal intrinsic clearance with standard scaling approaches. In this paper, we apply a physiologically based pharmacokinetic (PBPK) modeling and simulation approach (M&S) to predict the clearance, area under the curve (AUC), andvalues together with the plasma profile of a range of drugs from the original study. The human physiologic parameters for FMO, such as enzyme abundance in liver, kidney, and gut, were derived from in vitro data and clinical pharmacogenetics studies. The drugs investigated include itopride, benzydamine, tozasertib, tamoxifen, moclobemide, imipramine, clozapine, ranitidine, and olanzapine. The fraction metabolized by FMO for these drugs ranged from 21% to 96%. The developed PBPK models were verified with data from multiple clinical studies. An attempt was made to estimate the scaling factor for recombinant FMO (rFMO) using a parameter estimation approach and automated sensitivity analysis within the PBPK platform. Simulated oral clearance using in vitro hepatocyte data and associated extrahepatic FMO data predicts the observed in vivo plasma concentration profile reasonably well and predicts the AUC for all of the FMO substrates within 2-fold of the observed clinical data; seven of the nine compounds fell within 2-fold when human liver microsomal data were used. rFMO overpredicted the AUC by approximately 2.5-fold for three of the nine compounds. Applying a calculated intersystem extrapolation scalar or tissue-specific scalar for the rFMO data resulted in better prediction of clinical data. The PBPK M&S results from this study demonstrate that human hepatocytes and human liver microsomes can be used along with our standard scaling approaches to predict human in vivo pharmacokinetic parameters for FMO substrates.