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DRUG INTERACTIONS

Effects of Hypericum perforatum on Ivabradine Pharmacokinetics in Healthy Volunteers: An Open-Label, Pharmacokinetic Interaction Clinical Trial

A. Portolés, MD, PhD, A. Terleira, MD, PhD, A. Calvo, MD, I. Martínez and G. Resplandy, MD

From the Clinical Pharmacology Studies Unit, Clinical Pharmacology Service, Hospital Clínico San Carlos, Madrid, Spain (Dr Portolés, Dr Terleira, Dr Calvo); Laboratorios Servier, Madrid, Spain (Ms Martínez); and the Cardiovascular Division, Institut de Recherches Internationales Servier, Curbevoie Cedex, France (Dr Resplandy).

Address for reprints: A. Portolés, MD, PhD, Clinical Pharmacology Studies Unit, Clinical Pharmacology Service, Hospital Clínico San Carlos, c/Prof. Martín Lagos s/n, 28040 Madrid, Spain; e-mail: aportoles.hcsc{at}salud.madrid.org.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The effects of the CYP3A4 inducer, Hypericum perforatum, on the pharmacokinetics of a single oral dose of ivabradine were assessed. An open-label, 2-period, nonrandomized, phase-I, pharmacokinetic interaction design was used. Twelve healthy volunteers received a single oral dose of ivabradine (10 mg) followed by H perforatum (300 mg orally, 3 times a day) for 14 days, combining the last dose with another single dose of ivabradine. Pharmacokinetic data for ivabradine (S16257 [GenBank] ) and its main active metabolite (S18982) prior to and after the administration of H perforatum were analyzed. After repeated administration of H perforatum, highest observed concentration in plasma (Cmax) and area under the concentration-time curve (AUC) were significantly decreased for ivabradine (32.7 ± 16.6 vs 15.4 ± 7.0 ng/mL, P < .01; 114 ± 39.1 vs 43.7 ± 12.0 ng·h/mL, P < .01, respectively), and for S18982 (Cmax, 6.8 ± 3.7 vs 5.1 ± 2.0 ng/mL, P < .05; AUC, 56.2 ± 23.4 vs 38.3 ± 25.1 ng·h/mL, P < .01). Tendencies toward shorter time to Cmax and lower apparent terminal half-life values were found. Pharmacokinetic results are consistent with an induction of ivabradine metabolism by H perforatum.

Key Words: Pharmacokinetics • interaction • ivabradine • Hypericum perforatum • induction • healthy volunteers • clinical trial

Ivabradine (S16257 [GenBank] ) is a novel heart rate–lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Its activity provides pure heart rate reduction at rest and during exercise, which improves myocardial oxygen balance and increases coronary perfusion, without any relevant influence on conduction, contractility, ventricular repolarization or blood pressure.1,2 The anti-ischemic efficacy and the safety of ivabradine have been demonstrated in patients with stable angina pectoris.3,4 Mild and transient visual symptoms, mainly phosphene-like events, have been reported and were generally well tolerated.

The metabolic clearance of ivabradine accounts for about 80% of its total clearance, the other 20% corresponds to a renal clearance. Only CYP3A4 is involved in ivabradine's metabolism, so numerous potential interactions can arise with CYP3A4 inhibitors and inducers. Its main metabolite, the N-desmethylated S18982, has been shown to block If in a similar way and is also a CYP3A4 substrate.5

The extract of St John's wort (Hypericum perforatum) is an herbal product widely used for treatment of depression and anxiety disorders, without medical control, because it can be purchased over the counter in Western countries. It contains potent inducers (after at least 14 days of treatment) of intestinal and hepatic CYP3A4 and intestinal P-glycoprotein.6-8 The present study was designed to explore the potential interaction between ivabradine and H perforatum.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Six male and 6 female healthy volunteers were enrolled after having met inclusion criteria and passed exclusion criteria. Key inclusion criteria included age between 18 and 40 years, 12-lead electrocardiogram (ECG) within normal standards (QTc interval, ≤450 ms [male subjects]; ≤470 ms [female subjects]), a body mass index below or equal to 30 kg/m2 and normal hematology and biochemistry blood and urine analyses. Only subjects with a heart rate (at rest) ≥50 beats per minutes (bpm) were included. A negative result for the quick test for ß-human chorionic gonadotrophin (ß-HCG) and an effective contraception method during the study were also compulsory for female subjects.

Key exclusion criteria included personal or family history of long QT syndrome, acute or chronic disease, and regular use of medication. Further exclusion criteria were hypersensitivity or photosensitivity to any drug, smoking, intention to donate blood or to participate in another study in the following months, or any clinically relevant abnormalities, including vital signs and blood and urinary analyses.

Subjects received no medication for 2 weeks prior to inclusion in the study (4 weeks in the case of CYP3A4 inducers or inhibitors). Subjects were also free from stimulants (eg, coffee and tea), nicotine, and nonpharmacologic liver inducers or inhibitors, and strenuous physical exercise was to be avoided on the 3 days before inclusion in the study.

The study was not confirmatory in nature but had the explorative aim to investigate the effect of H perforatum on the pharmacokinetic, pharmacodynamic, and safety parameters of ivabradine. The primary objective of the study was to assess the effect of H perforatum on the pharmacokinetics of ivabradine and S18982. Taking into account the moderate bioavailability (40%) and the relatively low variability of ivabradine kinetics (about 30% in terms of intersubject AUC), a sample of 12 subjects was considered enough to derive reliable information.

The study was performed according to the rules for Good Clinical Practice (International Conference on Harmonisation) and was authorized by the Ethics Committee of the Hospital Clínico San Carlos (HCSC) and by the AEMPS (Spanish agency on medicines and sanitary products). The ethics principles of the Declaration of Helsinki and its further revisions were observed, with written informed consent given by each subject after protocol approval.

Study Drugs
Ivabradine (10-mg tablets) was to be taken orally with a standard breakfast, as a single dose, whereas H perforatum (Jarsin, 300-mg tablets) was to be taken 3 times a day, 1 hour before meals. Both treatments were supplied by Servier Laboratories (Madrid, Spain).

Design
An open, 2-period, nonrandomized, phase I, pharmacokinetic interaction monocenter design was used. Because the variables were pharmacokinetic parameters, it was considered unnecessary to use a blind design. Considering the exploratory nature of the study, the analyses were essentially descriptive.

Subjects were selected 1 to 15 days before the start of the treatment (day –15 to day –1).

A single dose of ivabradine (10 mg) was administered orally on day 1. Then, starting at 24 hours after this dose, the subjects received repeated administration of H perforatum (300 mg 3 times a day) during 14 days (days 2 to 15). On day 16, they received a single coadministration of ivabradine (10 mg) and H perforatum (300 mg).

Blood sampling for pharmacokinetic monitoring of ivabradine and metabolite in plasma was collected on day 1 and day 16, prior to the administration of ivabradine, and at 9 time points up to 24 hours at 0.5, 1, 1.5, 3, 4, 6, 8, 12, and 24 hours. Blood sampling to verify H perforatum compliance was collected on days 5, 10, and 16 (3 hours after morning dose).

In an attempt to evaluate CYP3A4 induction, ratios of 6[ß]-hydroxycortisol to cortisol were determined from 24-hour urine collection after ivabradine administration.

Safety regarding 12-lead ECG parameters at rest (PR, QRS, RR, and QT intervals; QTc; ST segment; rhythm; or other abnormalities) and blood pressure were recorded during inclusion period, prior to each administration of ivabradine, and at 1 and 24 hours after. Safety measurements also included adverse events and other vital signs, which were recorded throughout the study, and chemistry/hematology/urinary analyses, recorded at inclusion period and after completing treatment.

Pharmacodynamics (heart rate at rest) was evaluated as a secondary objective at inclusion period, prior to each ivabradine administration and 1 and 24 hours after.

Subjects were admitted to the unit approximately 24 hours before each administration of ivabradine (day 0 and day 15).

Assay
The assay for S16257 [GenBank] and S18982 had been previously validated by ADME Bioanalyses. Plasma samples (1 mL) were stored at –20°C until assayed by a liquid-solid extraction on Cyano cartridges, followed by specific high-performance liquid chromatography (HPLC) analysis using a Nova-Pak C8 column (Waters Corp, Milford, Mass) with fluorescence detection ({lambda}exc: 283 nm, {lambda}em: 315 nm). S16070, an ivabradine derivative, was used as internal standard. Mobile phase consisted of 80% phosphate buffer at pH 3.0 and 20% acetonitrile. The method was linear from 1.0 to 40.0 ng/mL. The calibration range for ivabradine and S18982 was 1.00 to 200 ng/mL. The limit of quantification for both parent compound and metabolite was 1.00 ng/mL. Intra- and interrun precision and accuracy were within the predefined acceptable range (≤15% and ≤20% for the lowest quantification level). The specificity of the method for S16257 [GenBank] and S18982 was checked regarding H perforatum.

The assay for hypericin was developed by ADME Bioanalyses and validated during this study. This method was adapted from a previously described method9 and consisted of a liquid-liquid extraction, followed by specific HPLC using a Lichrospher 60 column with fluorescence detection. Intra- and interrun precision and accuracy were within the predefined acceptable range (≤15% and ≤20% for the lowest quantification level).

Calculations of concentrations were performed by a least square linear regression model using a 1/C2 weighting, with Excel 5.0 (Microsoft Corp, Redmond, Wash) and Millenium (Waters Corp) software.

Data Analyses
A database was created for data management and analyses on demographic, safety, and activity using a proprietary clinical data management system developed by IDDI (Brussels, Belgium). The data were stored in Paradox (release 4.5, Borland Software Corp, Cupertino, Calif) and could be automatically transferred to SAS System for Windows (release 8.02, SAS Institute, Cary, NC) data sets at any time. All description and asymptotic inferential analyses were performed using SAS System. The type I error {alpha} was set at 5% for all statistical tests.

Pharmacokinetic Analysis
Data for concentration in plasma (C) versus time (t) for both ivabradine (S16257 [GenBank] ) and S18982 were analyzed by noncompartmental methods at the HCSC. The pharmacokinetics of the compounds was characterized, as appropriate, using the WinNonlin Pro software (release 3.1; Pharsight Corp, Mountain View, Calif). The highest observed concentration in plasma and the corresponding sampling time were defined as Cmax and tmax, respectively. The elimination rate constant ({lambda}z) was estimated by means of linear regression analysis of the log-linear part of the time concentration profile, and t1/2 was defined as the apparent terminal half-life, calculated as (ln2)/{lambda}z. The area under the concentration-time curve (AUC) was estimated by use of the trapezoidal rule from time zero to 12 hours (AUC12) and 24 hours (AUC24), up to the last measurable concentration (AUClast) and with extrapolation to infinity (AUCinf). The S18982 to S16257 [GenBank] AUCinf ratio and the apparent total clearance (CL/F) for S16257 [GenBank] were also calculated.

Descriptive statistics (mean, standard deviation, median, range) for Cmax, tmax, AUC12, AUC24, AUClast, AUCinf, t1/2 of S16257 [GenBank] and S18982, S16257 [GenBank] CL/F, and S18982 to S16257 [GenBank] AUCinf ratio were performed using the WinNonlin Pro (release 3.1; Pharsight Corp). Statistical analyses of pharmacokinetic parameters were performed using the software TRYARCUS (StatsSirect Ltd, Cheshire, UK). Comparison between ivabradine alone (I) and ivabradine + H perforatum (I+H) of ln-transformed values for AUC (AUC12, AUC24, AUClast, AUCinf) and Cmax were determined using the paired-data Student t test. The 95% confidence interval of the ratio (I+H)/I for these parameters was calculated, and its statistical significance was assessed. The a priori level of significance was P = .05.

Given the discrete and nonparametric nature of tmax, the comparison between (I) and (I+H) for tmax was performed using the Wilcoxon signed rank test.

Activity and Safety Analysis
Descriptive statistics (mean, standard deviation, and range) for heart rate changes were performed. A Wilcoxon signed rank test was performed for the comparison between (I) and (I+H).

Descriptive statistics for 12-lead ECG parameters, blood pressure, adverse events, treatment-emergent adverse events, biochemistry/hematology/urinary parameters, and concomitant treatments were provided. Qualitative variables were described by number and percentage of subjects, whereas quantitative variables were described as mean, standard deviation, median, and range.

The mean changes from baseline in QT, QTc, QRS, PR, and RR intervals were compared using the Wilcoxon signed rank test.

No descriptive statistics were performed for adverse events.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The 12 subjects evaluated were between 19 and 28 years old (mean ± SD, 22.7 ± 2.7 years) and their body mass index was between 18.6 and 29.8 kg/m2 (mean ± SD, 23.3 ± 3 kg/m2).

Pharmacokinetic parameters for ivabradine and S18982 before and after repeated administration of H perforatum are described in Table I. Mean plasma concentration-time profiles are displayed in Figure 1.


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  		Table I Pharmacokinetic Parameters of Ivabradine and Main Active Metabolite (S18982) After Single Oral Administration of Ivabradine 10 mg Alone or Coadministered With Hypericum perforatum 300 mg After Repeated Administration of Hypericum perforatum 300 mg 3 Times a Day

 

Figure 1
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  		Figure 1. Mean plasma concentrations of ivabradine (top) and S18982 (bottom) versus time before and after single oral administration of ivabradine 10 mg alone or coadministered with Hypericum perforatum 300 mg after repeated administration of H perforatum 300 mg 3 times a day.

 

Cmax and AUC (AUC12, AUC24, AUClast, AUCinf) values for ivabradine and S18982 were significantly lower after the repeated administration of H perforatum. The concentrations of S18982 were much lower than were ivabradine's concentrations. There was a clear though nonstatistically significant decrease in tmax for both ivabradine and S18982 after the administration of H perforatum (Table I), and t1/2 values were also lower (though not statistically tested).

A statistically significant increase in S18982/S16257 AUCinf ratio was evidenced after repeated administration of H perforatum (difference between ratios, 0.33; 95% confidence interval, 0.06-0.59; P = .02. Thus, the induction of CYP3A4 led to an increase in the metabolite/parent-drug ratio and when combined with the decrease in S18982 concentration, shows that CYP3A4 is probably the pathway for both S16257 [GenBank] and S18982 elimination.

Hypericin plasma concentrations (compliance evaluation) are shown in Table II. Hypericin concentrations were homogeneous among subjects and indicate a high treatment compliance, especially considering that for some subjects the concentration obtained was very close to the lower limit of quantification (5 ng/mL). The morning dose of H perforatum was taken at the unit on days 2, 5, and 10.


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  		Table II Individual Plasma Concentrations of Hypericin (ng/mL) on Day 5, Day 10, and Day 16

 

Heart rate data are shown in Table III. No statistically significant difference from baseline heart rate was evidenced 1 hour after the administration of ivabradine, between both treatment periods [–0.8 ± 11.1 bpm (I) vs 4.8 ± 6.4 bpm (I+H); P = .0957], whereas a statistically significant increase was detected 24 hours after administration of ivabradine between the 2 periods [–1.9 ± 11.7 bpm (I) vs 4.5 ± 10.8 bpm (I+H]; P = .0366).


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  		Table III Evolution Over Time of Mean Heart Rate After Single Oral Administration of Ivabradine 10 mg Alone or Coadministered With Hypericum perforatum 300 mg After Repeated Administration of Hypericum perforatum 300 mg 3 Times a Day

 

No statistically significant difference was evidenced in the urinary 6[ß]-hydroxycortisol to cortisol ratio after repeated administration of H perforatum.

Twelve subjects were enrolled, and all of them completed the study. A high compliance was achieved with H perforatum. One subject missed 1 morning dose of H perforatum (of 42 doses for every subject), and another missed 2 morning doses.

Ivabradine and H perforatum, given alone or in combination, were well tolerated by all subjects participating in the study. Mild gastrointestinal symptoms (4 subjects) and 1 cephalea were reported during the repeated administration of H perforatum. No adverse event was found to be related to the administration of ivabradine. No visual symptoms were reported. No clinically relevant change was observed on laboratory, blood pressure, and ECG parameters.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
The herbal preparation H perforatum (St John's wort) has become a popular self-managed alternative medicinal product used as an antidepressant therapy, generally without medical control. It contains potent inducers (hyperforin and hypericin) of hepatic CYP3A4,6-8 and because ivabradine is a CYP3A4 substrate, the in vivo confirmation of this potential interaction was considered highly relevant, particularly considering that its main active metabolite is metabolized in a similar fashion.

No randomization was performed as the sequence of treatments was the same for all subjects. Because the variables were pharmacokinetic parameters, it was considered unnecessary to use a blind design. Considering the exploratory nature of the study, the analyses were essentially descriptive.

The primary objective of this study was to explore the effects of H perforatum on ivabradine pharmacokinetic parameters. Concomitant administration of H perforatum, resulted in significant decreases in AUC, Cmax, and tmax for ivabradine and its main active metabolite, S18982, in healthy volunteers. An increase in the S18982/S16257 AUCinf ratio was also evidenced. It is likely that this interaction is explained mainly by the enhancement of the CYP3A4 activity. These findings would support the major role of CYP3A4 in ivabradine (and S18982) metabolism and H perforatum's ability to induce CYP3A4.

The urinary 6[ß]-hydroxycortisol to cortisol ratio was used in an attempt to evaluate the in vivo CYP3A4 activity. However, no differences could be detected, which could be explained by a high intersubject variability, and by the fact that CYP is a nonspecific pathway for cortisol metabolization.10

Although no pharmacodynamic effect was evidenced, a decrease in ivabradine heart rate–lowering effect would have been consistent with the pharmacokinetic interaction described. Lack of results in this regard might be due to the design of the study, because pharmacodynamics evaluation was not the primary objective (maximal heart rate–lowering effect of ivabradine is generally observed ~4 hours after drug administration, whereas heart rate measurements were performed 1 and 24 hours after). No safety concerns regarding adverse events, blood pressure, laboratory, or ECG parameters rose during the study.

In conclusion, analysis of ivabradine and its main active metabolite (S18982) plasma concentrations in healthy volunteers treated with H perforatum for 14 days, revealed a pharmacokinetic interaction. Modulation of CYP3A4 could be the underlying mechanism of this interaction, and although no pharmacodynamic effects were evidenced, the potential consequences of this interaction should be elucidated. Because H perforatum is available without medical control and consumers generally expect no risks, patients' and physicians' awareness of possible interactions between CYP3A4 substrates and H perforatum is essential.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
We thank all the medical, nursing, and administrative personnel of the Clinical Pharmacology Study Unit, Hospital Clínico San Carlos, for their enthusiastic cooperation and their dedication to this project.

This study was financed by Laboratorios Servier through a contract managed by Universidad Complutense de Madrid.

DOI: 10.1177/0091270006291623


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Vilaine JP, Thollon C, Villeneuve N. Procoralan, a new selective I(f) current inhibitor. Eur Heart J. 2003;5(suppl G): G26-G35.

2. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16): 1757-1765.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Tardif JC, Ford I, Tendenra M, Fox K. Anti-anginal and anti-ischaemic effects of the If current inhibitor ivabradine versus atenolol in stable angina: a 4-month randomised, double-blind, multicenter trial. Eur Heart J. 2003;24(suppl abst): 20.

4. Borer JS, Fox KP, Lerebours G. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107: 817-823.[Abstract/Free Full Text]

5. Procorolan [summary of product characteristics]. Neuilly sur Seine, France: Les Laboratoires Servier; 2005.

6. Di Carlo G, Borrelli F, Ernst E, Izzo AA. St John's wort: prozac from the plant kingdom. Trends Pharmacol Sci. 2001;22: 292-297.[CrossRef][Medline] [Order article via Infotrieve]

7. Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH. St John's wort: effect on CYP3A4 activity. Clin Pharmacol Ther. 2000;67: 451-457.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

8. Dürr D, Stieger B, Kullak-Ublick GA, et al. St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther. 2000;68: 598-604.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Bauer S, Stormer E, Graubaum HJ, Roots I. Determination of hyperforin, hypericin and pseudohypericin in plasma using high-performance liquid chromatography analysis with fluorescence and ultraviolet detection. J Chromatogr B Biomed Sci Appl. 2001;765: 29-35.[CrossRef][Medline] [Order article via Infotrieve]

10. Galteau MM, Shamsa F. Urinary 6ß-hydrocortisol: a validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur J Clin Pharmacol. 2003;59: 713-733.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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