Frank Larsen

Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans

The steady-state pharmacokinetics in serum and urine of the enantiomers of citalopram and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), were investigated after multiple doses of rac-citalopram for 21 consecutive days (40 mg per day) to healthy human subjects who were extensive metabolisers of sparteine and mephenytoin. Comparable pharmacokinetic variability was noted for (+)-(S)-, (-)-(R)- and rac-citalopram. Enantiomeric (S/R) serum concentration ratios for citalopram were always less than unity and were constant during the steady-state dosing interval. A modest, but statistically significant, stereoselectivity in the disposition of citalopram and its two main metabolites was observed. Serum levels of the (+)-(S)-enantiomers of citalopram, DCT, and DDCT throughout the steady-state dosing interval investigated were 37 +/- 6%, 42 +/- 3% and 32 +/- 3%, respectively, of their total racemic serum concentrations. The (+)-(S)-enantiomers of citalopram, DCT, and DDCT were eliminated faster than their antipodes. For (-)-(R)- and (+)-(S)-citalopram, respectively, the serum t1/2 averaged 47 +/- 11 and 35 +/- 4 h and AUCss averaged 4,193 +/- 1,118 h.nmol/l and 2,562 +/- 1,190 h.nmol/l. The observed enantiospecificities were apparently more related to clearance, rather than to distributional mechanisms.

The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects

The pharmacokinetics of escitalopram (S‐citalopram) and its principal metabolite, S‐demethylcitalopram (S‐DCT), were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion of escitalopram, the mean systemic clearance and volume of distribution were 31 L/h and 1100 L, respectively. After oral administration of single or multiple doses, the absorption was relatively fast, with the maximum observed plasma or serum concentration (Cmax) attained after 3 to 4 hours. The mean half‐lives were 27 and 33 hours, respectively; steady state was attained within 10 days. The area under the plasma or serum concentration‐time curve from time zero to 24 hours and Cmax was both linear and proportional to the dose. The apparent volume of distribution was around 20 L/kg. Comparison of the systemic and oral clearance implied a high absolute bioavailability. There was no evidence of interconversion from S‐citalopram to R‐citalopram either in plasma or in urine. Concurrent intake of food had no effect on the pharmacokinetics of escitalopram or its metabolite. All treatments were well tolerated.

Identification of Cytochrome P450 Isoforms Involved in the Metabolism of Paroxetine and Estimation of Their Importance for Human Paroxetine Metabolism Using a Population-Based Simulator

We identify here for the first time the low-affinity cytochrome P450 (P450) isoforms that metabolize paroxetine, using cDNA-expressed human P450s measuring substrate depletion and paroxetine-catechol (product) formation by liquid chromatography-tandem mass spectrometry. CYP1A2, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were identified as paroxetine-catechol-forming P450 isoforms, and CYP2C19 and CYP2D6 were identified as metabolizing P450 isoforms by substrate depletion. Michaelis-Menten constants Km and Vmax were determined by product formation and substrate depletion. Using selective inhibitory studies and a relative activity factor approach for pooled and single-donor human liver microsomes, we confirmed involvement of the identified P450 isoforms for paroxetine-catechol formation at 1 and 20 μM paroxetine. In addition, we used the population-based simulator Simcyp to estimate the importance of the identified paroxetine-metabolizing P450 isoforms for human metabolism, taking mechanism-based inhibition into account. The amount of active hepatic CYP2D6 and CYP3A4 (not inactivated by mechanism-based inhibition) was also estimated by Simcyp. For extensive and poor metabolizers of CYP2D6, Simcyp-estimated pharmacokinetic profiles were in good agreement with those reported in published in vivo studies. Considering the kinetic parameters, inhibition results, relative activity factor calculations, and Simcyp simulations, CYP2D6 (high affinity) and CYP3A4 (low affinity) are most likely to be the major contributors to paroxetine metabolism in humans. For some individuals CYP1A2 could be of importance for paroxetine metabolism, whereas the importance of CYP2C19 and CYP3A5 is probably limited.

The pharmacokinetics of escitalopram in patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of escitalopram was determined by means of nonlinear mixed effect modeling, considering both the Child-Pugh classification (and its components) and cytochrome P450 2C19 (CYP2C19) activity. Twenty-four subjects were grouped according to their Child-Pugh score as healthy, with mild hepatic impairment or with moderate hepatic impairment. The subjects were administered a single oral dose of escitalopram 20 mg, and blood was sampled up to 168 hours after dosage. The serum concentration of escitalopram was determined and the pharmacokinetics assessed by nonlinear mixed effect modeling. The CYP2C19 activity was measured from the urinary excretion ratio of S/R-mephenytoin. All subjects tolerated the treatment well, and no serious adverse events were reported. Predicted mean area under the curve from zero to infinity (AUCinf) values were 51% and 69% higher for patients with mild and moderate hepatic impairment (Child-Pugh classification), respectively, compared with healthy subjects. The best-fitting model showed an influence of CYP2C19 activity on clearance and body weight on the volume of distribution for escitalopram. CYP2C19 activity is a better predictor of escitalopram clearance than is Child-Pugh classification.

Interaction between fed gastric media (Ensure Plus) and different hypromellose based caffeine controlled release tablets; comparison and mechanistic study of caffeine release in fed and fasted media versus water using the USP dissolution apparatus 3

The aim of the study was to investigate caffeine release in fed and fasted state media from three controlled release matrix tablets containing different HPMC viscosity grades. The biorelevant in vitro dissolution methods utilize the USP 3 dissolution apparatus and biorelevant media to simulate fed and fasted gastro-intestinal dissolution conditions. The effect of tablet reciprocation rate (dip speed) in dissolution media (10 and 15 dips per minute) and media (water, fed and fasted) on caffeine release rate from - and erosion rate of - 100, 4000 and 15,000 mPa s HPMC viscosity tablets was investigated using factorial designed experiments. Furthermore, the mechanism of release in Ensure Plus(®), a nutrition drink similar in composition to the FDA standard meal, was investigated by studying tablet swelling using texture analysis. Altering dip speed has negligible effect on release and erosion rates. Using fasted media instead of water slightly decreases caffeine release from 100 and 4000 mPa s HPMC viscosity tablets as well as erosion rates, while 15,000 mPa s tablets remain unaffected. Fed compared to fasted media decreases caffeine release rate, and the food effect is greater for the 100 mPa s viscosity tablets compared to the 4000 and 15,000 mPa s viscosity tablets. The investigation using texture analysis indicates that Ensure Plus(®) becomes rate-limiting for caffeine release from HPMC tablets by forming a hydrophobic barrier around the tablets. The barrier decreases tablet water permeation, which decreases erosion rate in 100 mPa s viscosity tablets, swelling in 15,000 mPa s viscosity tablets and caffeine release from both tablets. This observed interaction between Ensure Plus(®) and the HPMC tablets may translate into decreased drug release rate in the fed stomach, which may decrease the amount of drug available for absorption in the small intestine and thus reduce systemic drug exposure and maximum plasma concentration.

Lack of effect of citalopram on the steady-state pharmacokinetics of carbamazepine in healthy male subjects

Carbamazepine, a drug used in the treatment of seizure disorders, and citalopram, a highly selective serotonin reuptake inhibitor used for the treatment of depression and other psychiatric disorders, are both metabolized predominantly by the cytochrome P4503A4 isozyme. In this study, the effect of subchronic administration of citalopram on the steady-state pharmacokinetics of carbamazepine was evaluated in 12 healthy male subjects. Carbamazepine was administered orally twice daily as a 100-mg dose from days 1 to 3, as a 200-mg dose twice a day from days 4 to 6, and as a 400-mg dose once a day from days 7 to 35. Citalopram, 40 mg, administered once daily, was added to the carbamazepine-dosing regimen on days 22 to 35. The steady-state plasma concentration profiles of carbamazepine and its active metabolite, carbamazepine 10,11-epoxide, on day 35 (in the presence of steady-state levels of citalopram) were compared to the corresponding carbamazepine and epoxide metabolite profiles on day 21 (in the absence of citalopram). No significant differences were found between mean steady-state values for maximal drug concentration, area under the curve, or time of maximal concentration values for carbamazepine and its epoxide metabolite before and after the addition of citalopram to the daily carbamazepine dosing regimen (p > 0.05). These results suggest that the use of citalopram in patients stabilized on carbamazepine should not produce clinically significant changes in carbamazepine plasma concentrations.

Effect of citalopram on plasma levels of oral theophylline.

BACKGROUND Citalopram and theophylline may be prescribed together to treat patients with depression and asthmatic disease. Because theophylline has a low therapeutic index, small changes in plasma levels may result in therapeutic failure or adverse effects. Both citalopram and theophylline are metabolized by cytochrome P450 (CYP) isozymes. Theophylline is metabolized by CYP1A2; however, the extent to which citalopram interacts with this isozyme in vivo is not known. OBJECTIVE This study was conducted to investigate whether citalopram alters plasma levels of oral theophylline. METHODS In an open-label, multiple-dose study, healthy nonsmoking volunteers 18 to 45 years of age were administered a single oral dose of theophylline (300 mg) on day 1. Beginning on day 3, citalopram 40 mg was administered daily through day 24 to achieve steady-state plasma levels. On day 23 a single oral dose of theophylline 300 mg was coadministered with citalopram 40 mg. Fasting plasma levels of theophylline were measured on day 1 (in the absence of citalopram) and on day 23 (in the presence of steady-state plasma concentrations of citalopram) periodically for 36 hours. RESULTS Thirteen subjects (8 men and 5 women) participated; all completed the study. One subject was not included in the pharmacokinetic calculations. Citalopram treatment had no effect on the pharmacokinetic characteristics of theophylline. CONCLUSIONS Citalopram dosing to steady state did not inhibit or induce the metabolism of theophylline in this population of healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with citalopram.

Risk assessment of accidental nortriptyline poisoning: The importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator

It is not possible to make a prospective clinical study that reveals the importance of the nortriptyline metabolising cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) in relation to attaining potential toxic nortriptyline concentrations with a possibly fatal outcome. Therefore to study this we have applied the population based pharmacokinetic simulator Simcyp. The objective was to estimate how important CYP2C19 and CYP2D6 phenotype status, hepatic activity of CYP3A4, body weight, CYP2D6 phenotype dose adjustment, and drug-drug interactions are with regard to accidental poisoning in a virtual population receiving a daily dose of 100mg nortriptyline. Accidental poisoning is here defined as intake of a normal dose which because of slow metabolism may lead to potentially toxic concentrations. The input parameters values for Simcyp were based on average literature in vitro and in vivo data. The Simcyp simulations of nortriptyline pharmacokinetics reflected reported clinical concentration-time profiles, therapeutic drug monitoring data, and the consequence of CYP2D6 poor metaboliser (PM) and ultrarapid metaboliser status. Of the investigated factors, the simulations indicate that having CYP2D6 PM status is a major risk factor for attaining high concentrations and thereby possibly becoming poisoned by nortriptyline. Of the CYP2D6 PM subjects 16% would attain plasma concentrations exceeding the toxic limit. Individuals with the combination of CYP2D6 PM status and 10% of the average liver CYP3A4 expression had a 90% risk of becoming poisoned. The results point towards the combination of low CYP3A4 activity and CYP2D6 PM status of major importance for attaining possibly toxic nortriptyline concentrations. In a forensic toxicological context, the results indicate that both the activity of CYP3A4, information on possible drug-drug interactions, and the genotype of CYP2D6 are needed in order to elucidate whether an individual might have been accidentally poisoned because of slow metabolism. In a clinical context, the simulations suggest that precise individual dose adjustment of nortriptyline requires information regarding the activity of both CYP3A4 and CYP2D6. This underlines the value of therapeutic drug monitoring for nortriptyline. Population based pharmacokinetic simulations are considered useful tools for risk assessment in clinical and forensic toxicology.

Multiple Oral Administration of a Ketoprofen–Dextran Ester Prodrug in Pigs: Assessment of Gastrointestinal Unavailability by Deconvolution

Deconvolution has been applied to estimate the in vivo dissolution/ release process of ketoprofen from a ketoprofen–dextran ester pro-drug in pigs. The prodrug was given to three pigs at intervals of 12 hr and in seven doses corresponding to 4 mg ketoprofen/kg body weight. Frequent blood sampling was carried out at the first, third, and seventh intervals. Plasma steady-state concentrations of ketoprofen following the prodrug administration were between 2 and 4 µg/ml. The reference consisted of a single p.o. dose of parent ketoprofen (4 mg/kg body weight). For each pig the response following the multiple dosing was deconvolved with the reference response using an algebraic deconvolution procedure adopted from the literature. The obtained cumulated in vivo dissolution/release profiles revealed similar release rates for the three pigs and similar extents of release (59, 70, and 65%). The mean in vivo dissolution/release times (MDT) were calculated to be 5.4, 6.1, and 5.7 hr, respectively. In conclusion, following administration of the dextran prodrug the plasma concentration curves and the dissolution/release profiles are uniform, with small interindividual variations.

Lack of citalopram effect on oral digoxin pharmacokinetics

The effect of chronic administration of citalopram on the single oral dose pharmacokinetics of digoxin was evaluated in 11 healthy adult subjects in an open, one‐way crossover study. Subjects received 1 mg digoxin on day 1. Serial blood samples and total urine were collected over 192 hours, followed by an 11‐day washout period. On days 22 through 50, subjects received 40 mg citalopram once daily. On day 43, a single dose of1 mg digoxin was coadministered; again, serial blood samples and total urine were collected over 192 hours after the digoxin dose. There were no statistically significant differences in any of the digoxin pharmacokinetic parameters (AUC→,∞’ AUC→ Cmax’ tmax’ t1/2’CL/F CL/renal’ and Ae→∞, and the 90% confidence intervals for treatment differences for the parameters (except for tmax) were all within 80% to 125%. Concomitant digoxin administration did not significantly affect citalopram pharmacokinetics. The treatment was well tolerated by all subjects; no serious adverse events and no clinically significant ECG changes were observed. These data suggest that it is unlikely that concomitantly administered citalopram would have any significant effect on serum digoxin concentrations in patients who are receiving chronic digoxin therapy.