The effects of moclobemide on the pharmacokinetics of the 5-HT_1B/1D agonist rizatriptan in healthy volunteers

Abstract

Aims

The new 5-HT_1B/1D agonist rizatriptan (MK-0462) has recently been registered for the treatment of migraine. Its primary route of metabolism is via monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor moclobemide may be used in patients with chronic headache syndromes. Hence, this study aimed to investigate the interactions between rizatriptan and moclobemide.

Methods

In a double-blind, randomized, placebo-controlled, two-period cross-over study 12 healthy, young volunteers (six males, six females) were treated with moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a single dose of rizatriptan (10 mg) was administered, and subsequently blood and urine samples were collected for assay of rizatripan and N-monodesmethyl rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of MAO-A inhibition, were also assessed. Supine and standing blood pressure were measured regularly.

Results

Both treatments were well tolerated. During moclobemide, the increase in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persistent decrease in DHPG level (43% on average). When rizatriptan was coadministered with moclobemide, the area under the plasma drug concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fold (90% CI, 1.93–2.47) and 5.3-fold (90% CI, 4.81–5.91), respectively, when compared with placebo. Peak plasma drug concentrations for rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI, 1.11–1.80) and 2.6-fold (90% CI, 2.23–3.14), respectively, and half-lives of both were prolonged.

Conclusions

Moclobemide inhibited the metabolism of rizatriptan and its active N-monodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemide may considerably potentiate rizatriptan action. Concurrent administration of moclobemide and rizatriptan is not recommended.

Introduction

Rizatriptan (MK-0462; Figure 1) is a 5-HT_1B/1D agonist, that has recently been registered for the treatment of migraine [1]. Rizatriptan appears to be efficacious in aborting migraine headache in Phase II trials at doses of 5–40 mg, with 5 and 10 mg doses having been registered. Rizatriptan is almost completely absorbed after oral administration and has a bioavailability of 40–45%. Similar to sumatriptan and zolmitriptan [2–4], the primary route of metabolism of rizatriptan is via monoamine oxidase-A (MAO-A) to the indole-acetic acid derivative. MAO is reportedly capable of catalysing the oxidative deamination of primary, secondary and tertiary amines [5]. Oxidative metabolism via cytochrome P450 appears to be a minor route of metabolism of this compound. Although N-monodesmethyl-rizatriptan (L-706 248) was identified as a minor oxidative metabolite, it has been shown in binding studies to be a slightly more potent 5-HT_1B/1D agonist than rizatriptan. Like rizatriptan, L-706 248 is a substrate for monoamine oxidase metabolism (Merck Research Laboratories, Data on file).

Figure 1.

Structures of rizatriptan (MK-0462), internal standard (L-743 214) and the desmethyl metabolite (L-706 248).

Moclobemide is a MAO inhibitor used for the treatment of depression [6]. It is a reversible inhibitor, selective for MAO-A. Although moclobemide is less likely to interact with other drugs than nonselective MAO inhibitors, it has been reported to interact with tyramine, cimetidine, clomipramine, ephedrine and others [7]. In one study, after administration of tyramine, plasma concentrations of free tyramine following moclobemide increased on average 2.6-fold [8]. Inhibition of MAO-A by moclobemide is directly related to its plasma concentration. Maximum effects, as measured by decreases in plasma concentrations of DHPG (3,4-dihydroxphenylglycol, a circulatory metabolite of noradrenaline), are apparent at moclobemide plasma levels greater than 1000 ng ml⁻¹ [9]. Although monoamine oxidase inhibitors are currently infrequently used for depression, it is possible that some migraineurs could be taking MAO inhibitors chronically. Under these conditions, significant increases in the plasma concentration of 5-HT_1B/1D agonists, like rizatripan, sumatriptan and zolmitriptan, could be unsafe. Thus, it was important to study a possible interaction between moclobemide and rizatriptan.

Methods

Subjects

Twelve young healthy volunteers (six males and six females) were recruited for the study after giving informed consent. The subjects had a mean age of 22 years (range 19–29 years) and were all judged to be healthy from a medical history, physical examination, routine laboratory investigations and electrocardiogram (ECG). Drugs or medications other than occasional paracetamol, but including oral contraceptives, were not allowed. The study was approved by the Medical Ethics Committee of the Leiden University Medical Centre.

Study design and treatments

The study was a double-blind, randomized, placebo-controlled, two-period cross-over study. One treatment schedule (treatment A) consisted of moclobemide (150 mg capsules orally three times daily) for days 1 through 4 and rizatriptan (10 mg tablet orally, single dose) on day 4. The second treatment schedule (treatment B) consisted of placebo moclobemide capsules (orally, three times daily) for days 1 through 4 and rizatriptan (10 mg tablet orally, single dose) on day 4. On day 4 of each period, rizatriptan was administered 1 h after the morning dose of moclobemide/placebo. To complete dosing over the pharmacokinetic study, two additional doses of moclobemide/placebo were given at 4 and 9 h after the rizatriptan dose. Washout time between treatments was at least 14 days. A diet poor in tyramine was adhered to. On study days 1 and 4 standardized meals were taken prior to moclobemide dosing (at 09.00 h, 14.00 h and 19.00 h approximately).

Supine and standing blood pressure and heart rate were recorded frequently from predose until 6 h after the first moclobemide or placebo intake on day 1, and during a 12 h period following rizatriptan dosing on day 4. An ECG was recorded 4 h after rizatriptan dosing.

Within 3 to 5 days after the final dose of study drug each subject underwent a poststudy screen, including physical examination, routine laboratory investigations, assessment of vital signs and ECG.

Sample collection

On day 1, one blood sample for drug assay and two blood samples for DHPG assay (baseline) were collected before administration of moclobemide or placebo. Additional blood samples for drug assay were collected on day 4 before rizatriptan, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 h after rizatriptan dosing. Blood samples for DHPG were also collected on day 4, just prior to the morning dose of moclobemide/placebo and just prior to rizatriptan, and at 1, 2, 3, 4, 5, 6, 10 and 24 h after rizatriptan dosing. The blood was collected in heparinized tubes, kept on ice, centrifuged at 4° C and plasma samples stored at −20° C for later analysis. Urine samples for drug assay were collected predose on days 1 and 4, and at time intervals of 0–6 h, 6–12 h, and 12–24 h after rizatriptan dosing. A portion (20 ml) of each collection was stored at −20° C.

Bioanalytical methods for rizatriptan (MK-0462) and its N-monodesmethyl metabolite (L -706 248)

The plasma and urine assays were based on h.p.l.c. with tandem MS-MS detection [10, 11]. Plasma samples were mixed with an internal standard, the N-diethyl analogue of rizatriptan (L-743 214) prior to analysis. Linear calibration ranges for rizatriptan and the N-monodesmethyl metabolite were 0.5–100 ng ml⁻¹ and 0.2–40.0 ng ml⁻¹, respectively. The coefficient of variation from day-to-day varied from 2.3 to 3.3% over three different concentrations for rizatriptan and from 3.9 to 7.1% for the metabolite. Urine samples were 1:5 diluted prior to assay. Linear calibration curves for rizatriptan and metabolite were 5.0–2500 ng ml⁻¹ and 2–1000 ng ml⁻¹, respectively; the day-to-day coefficient of variation ranged from 3.0 to 5.3% over three concentrations for rizatriptan and from 5.2 to 7.2% for the metabolite.

The assays were specific for rizatriptan, n-monodesmethyl metabolite and internal standard in plasma and urine containing moclobemide. Plasma and urine samples collected on day 4 before administration of rizatriptan were mixed with moclobemide, extracted, and analysed. In the MS-MS mode, channels for the above analytes were clear of any interferences. Quality controls containing rizatriptan and metabolite were prepared using the above matrices. The mean accuracy results for rizatriptan and the metabolite were 92% and 95% in plasma, and 92% and 98% in urine, respectively.

Bioanalytical method for plasma DHPG

The analysis of plasma DHPG comprised h.p.l.c. and electrochemical detection (h.p.l.c.-e.c.d.) and was based on a procedure described by Scheinin et al. [12] with extensive modifications.

An aliquot (1.0 ml) of a plasma sample was mixed with an internal standard, 3,4-dihydroxybenzylamine, and then subjected to aluminium oxide adsorption and organic phase extraction. The analytes were chromatographed using an RP18 precolumn and a Supersphere C₁₈ analytical column, which were coupled to an ESA CouloChem Model 5100 A and an ANTEC amperometric detector. The linear calibration range for DHPG was 0.5–15 nmol l⁻¹. The average recovery of DHPG was 35.8%. The coefficient of variation from day-to-day for DHPG was 1.9%. Neither rizatriptan nor its N-desmethyl metabolite, nor moclobemide interfered with the bioanalytical procedure for DHPG.

Pharmacokinetics

The area under the plasma drug concentration-time profile from time of rizatriptan intake to the last measurable concentration (AUC(0,t)) was calculated using the linear trapezoidal rule. The terminal elimination rate constant (λ_z) was determined by mono-exponential curve-fitting. AUC to infinity (AUC(0,∞) was calculated as the sum of AUC(0,t) and the last measurable concentration divided by λ_z. Plasma half-life (t_1/2) was calculated as (ln 2)/λ_z. The maximum plasma concentration (C_max) over the plasma profile and its corresponding time of occurrence (t_max) were determined by observation. Renal clearance (CL_r) was determined from the amount of drug excreted from time 0–12 h divided by the area under the plasma concentration-time profile from 0 to 12 h. The urinary excretion (U_e) was defined as the amount of rizatriptan in the urine (by assay in mg) divided by the dose, and expressed as a percentage.

Plasma DHPG levels

For DHPG levels on day 4 the area under the plasma curve was calculated from time of moclobemide or placebo intake to 11 h later (AUC (0,11 h)). AUC (0,11 h) was divided by the time interval of blood collection, i.e. 11 h, thus resulting in the average time-weighted plasma concentration (C_avg). C₀ was the DHPG level just prior to the morning moclobemide dose on day 4, which was 1 h prior to rizatriptan intake.

Blood pressure

Diastolic and systolic (supine and standing) blood pressure change from predose baseline on day 4 was calculated for each time point after rizatriptan dosing. The trapezoidal rule was used to calculate the AUC over the intervals 0–2 h, 2–6 h, 0–6 h, 6–12 h and 0–12 h postdose rizatriptan. By subsequently dividing by the interval length, a measure of average response was obtained.

Statistical analysis

Summary measures (pharmacokinetic and pharmacodynamic parameters) are presented as mean±s.d. unless indicated otherwise. Pharmacokinetic parameters were compared using anova with gender, sequence, subject within gender and sequence, period, treatment and gender by treatment in the model. Pharmacokinetic data were log-transformed prior to statistical analysis. Geometric mean ratios are reported with 90% confidence intervals to test for bioequivalence using the two-one-sided approach. Bioequivalence is proven if the 90% confidence interval is contained in the 0.8–1.25 interval.

For blood pressure, treatments were compared using anova on the natural logs of the AUCs with sequence, subject (sequence), period, and treatment as factors in the model. The carryover effect, confounded with the sequence effect, was tested at α=0.10. If no carryover effects were observed, a model with the terms subject, period, and treatment was used to analyse treatment differences at α=0.05.

Results

Tolerance and safety

Both treatments were well tolerated, with headache and asthenia/fatigue being the most frequently occurring clinical adverse events for both treatments. No clinically relevant changes were observed in laboratory safety test outcomes, nor in ECG parameters during either treatment.

Baseline blood pressure was similar for both treatment groups. Mean baseline supine blood pressure was 112±12/60±6 mmHg during placebo/rizatriptan and 113±10/60±6 mmHg during moclobemide/rizatriptan. As expected, supine and standing blood pressures increased slightly when rizatriptan was given during placebo, with increases most apparent during the initial 4 h after dosing. Concomitant moclobemide and rizatriptan intake did not significantly alter blood pressure responses when compared with placebo/rizatriptan treatment, except for the average supine diastolic blood pressure change from baseline over 12 h after rizatriptan (P<0.05), which increased from 3.1±2.1 mmHg during placebo to 4.4±2.5 mmHg during moclobemide.

DHPG

Pharmacokinetic parameters of plasma concentrations of DHPG are summarized in Table 1. Baseline levels of DHPG prior to first dose on day 1 were 6.7±1.2 nmol l⁻¹. Prior to dosing on day 4, DHPG levels at moclobemide steady state were reduced to 72% (90% CI, 65–80) of those during placebo treatment. Following the last administration of moclobemide onday 4, C_avg and AUC(0,11h) were only 57% (90% CI,53–62) of the values following placebo, a 43% reduction.

Table 1.

Mean (±s.d., n = 12) pharmacokinetic parameters of endogenous plasma DHPG levels.

Rizatriptan and N-monodesmethyl metabolite

Mean plasma concentrations of rizatriptan and n-monodesmethyl metabolite (L-706 248) are shown in Figure 2. The concentrations of rizatriptan and the N-monodesmethyl metabolite were greater with moclobemide and, based on the statistical analyses below, the differences between treatments were statistically significant. Plasma concentrations of rizatriptan and the metabolite were similar in males and females (P = 0.322 and 0.625, respectively), as were the effects of moclobemide.

Figure 2.

Mean (±s.d., n = 12) plasma concentration-time profiles of rizatriptan (a) and its metabolite L-706 248 (b) on day 4 following rizatriptan dosing and 4 days pretreatment with moclobemide (•) or placebo (○).

The effects of moclobemide on the pharmacokinetics of rizatriptan are shown in Table 2. Moclobemide increased the mean AUC(0,∞) for rizatriptan 2.2-fold (90% CI, 1.93–2.47). The mean C_max of rizatriptan during the moclobemide phase of the treatment was 1.4-fold greater (90% CI, 1.11–1.80) than during the placebo phase. The t_1/2 and t_max for rizatriptan were also increased significantly (P<0.05) by moclobemide. Moclobemide consistently increased the AUC(0,∞) and t_1/2 of rizatriptan for every subject; this was not the case for C_max and t_max.

Table 2.

Mean (±s.d., n = 12) pharmacokinetic parameters of rizatriptan.

The effects of moclobemide on the pharmacokinetics of the n-monodesmethyl metabolite are presented in Table 3. The effect of moclobemide on the mean values for AUC(0,∞) and C_max was greater than for rizatriptan: AUC(0,∞) increased 5.3-fold (90% CI, 4.81–5.91) while C_max increased 2.6-fold (90% CI, 2.23–3.14). Individual values for AUC(0,∞), C_max, and t_1/2 increased with moclobemide for every subject.

Table 3.

Mean (±s.d., n = 12) pharmacokinetic parameters of the N-desmethyl metabolite.

The effect of moclobemide on the metabolism of rizatriptan was also reflected in the urinary excretion (U_e) of rizatriptan and its metabolite (Tables 2 and 3). In the presence of moclobemide, the mean urinary excretion increased from 10.2% to 19.7% of the dose for rizatriptan and from 1.1% to 5% of the dose for the N-monodesmethyl metabolite. The renal clearance of both compounds did not differ significantly (P≥0.15) between treatments.

When rizatriptan was administered with moclobemide, the average metabolite-to-drug-AUC-ratio increased 2.4-fold (90% CI, 2.25–2.64)(Table 3). The metabolite/ drug ratio for urinary excretion increased 2.5-fold (90% CI, 2.23–2.84) from 0.11 to 0.28.

Discussion

In this study, 150 mg moclobemide taken orally three times a day for 4 days affected the pharmacokinetics of oral rizatriptan and its active metabolite. The integrated plasma concentrations and the amount excreted in the urine almost doubled for rizatriptan and increased by five-fold for the active metabolite. The half-lives were prolonged by 1.4-fold for the drug and doubled for the metabolite, but the renal clearance of both did not appear to change with moclobemide. During moclobemide, plasma and urine levels of rizatriptan increased as a consequence of a reduced metabolism through MAO-A. The disproportionate increases in plasma concentrations of the N-monodesmethyl metabolite presumably resulted from a decreased metabolism of the metabolite by MAO-A. The increased metabolite-drug ratios reflect the pharmacokinetic changes that occur with moclobemide.

The decreases in plasma DHPG levels following moclobemide clearly illustrate the activity of moclobemide as an inhibitor of MAO. The average DHPG concentrations on day 4 were 6.56 nmol l⁻¹ during placebo and 3.75 nmol l⁻¹ during moclobemide, a 43% reduction. At the time of minimal moclobemide concentrations, DHPG levels were decreased by 28%. These data indicate a persistent blockade of MAO-A, albeit inconstant and incomplete. They fit reasonably well with the 26–58% reductions in DHPG levels observed after single doses of 100–300 mg moclobemide [13, 14]. A further blockade of MAO activity may be obtained by combining MAO-A and MAO-B inhibitors, for instance by using moclobemide and selegiline [15], or by using nonselective, irreversible MAO inhibitors [16, 17]. However, MAO-B inhibitors do not affect the plasma concentration of 5HT_1B/1D agonists which are metabolized by MAO-A [2].

Although the concurrent administration of moclobemide and rizatriptan was well tolerated by the healthy subjects in this study, the interaction may have clinical implications. Plasma concentrations of rizatriptan and its metabolite were increased 2.2-and five-fold, respectively. The increase in parent drug concentrations may not be of major concern as single doses of up to 60 mg have been relatively well tolerated [18], and from this respect a 5 mg dose could theoretically be used in combination with moclobemide. However, the metabolite is an approximately two times more potent 5-HT_1B/1D agonist than rizatriptan (Merck, data on file). Based on an increase in metabolite to drug plasma concentration ratio from 0.15 during placebo to 0.36 during moclobemide, there could at worst be a nearly three-fold increase in active 5-HT_1B/1D agonist in the blood. As a consequence, the combination of moclobemide and rizatriptan may increase the risk of adverse events, especially with regard to the cardiovascular system due to increased vasoconstriction. The statistically significant change in supine diastolic blood pressure observed in this study was very small (1.3 mmHg), but it may be an indication of an enhanced risk of undesirable cardiovascular effects. It should be emphasized that moclobemide is a selective (and reversible) MAO-A blocker, being less potent than nonselective MAO blockers. Furthermore, the 43% reduction in plasma DHPG with moclobemide in this study is consistent with clear, but incomplete, MAO-inhibition. Therefore, we would anticipate an irreversible MAO-A inihibitor to have a greater effect on rizatriptan levels than moclobemide. Thus, the concomitant use of rizatriptan and moclobemide is contraindicated, as MAO-A does play an important role in the metabolism of rizatriptan. In this light it is of interest that sumatriptan, another 5-HT_1B/1D agonist, is also contraindicated in patients receiving MAO blockers. However, this contraindication has been criticised because of a lack of supporting adverse clinical data [19, 20].

In conclusion, concurrent administration of moclobemide could enhance the clinical effects of rizatriptan, by increasing plasma concentrations of both rizatriptan and its more potent N-monodesmethyl metabolite. These data support the recommendation to avoid use of rizatriptan in patients receiving concomitant MAO inhibitors.