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Evaluation of the Pharmacokinetic Interaction Between Ticagrelor and Venlafaxine, a Cytochrome P-450 2D6 Substrate, in Healthy Subjects
Clinical Therapeutics/Volume 36, Number 9, 2014
Evaluation of the Pharmacokinetic Interaction Between Ticagrelor and Venlafaxine, a Cytochrome P-450 2D6 Substrate, in Healthy Subjects Renli Teng, PhD1; Mirjana Kujacic, MD, PhD2; and Judith Hsia, MD1 1
AstraZeneca LP, Wilmington, Delaware; and 2AstraZeneca, Mo¨lndal, Sweden
ABSTRACT Purpose: Ticagrelor is a reversibly binding P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor has been shown in vitro to be a weak inhibitor of cytochrome P-450 (CYP) 2D6, a clinically important enzyme for the metabolism of many drugs. This study assessed the effects of coadministration of ticagrelor on the pharmacokinetics of the CYP2D6 substrate venlafaxine. The impact of venlafaxine on ticagrelor pharmacokinetic parameters was also investigated. Methods: Healthy subjects (N ¼ 22) received a single 180-mg oral dose of ticagrelor on days 1 and 9 and oral doses of venlafaxine on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). Plasma concentrations of ticagrelor, venlafaxine, and their metabolites (AR-C124910XX and O-desmethylvenlafaxine [ODV], respectively) were quantified for pharmacokinetic analyses. Safety and tolerability were assessed throughout the study. Findings: Overall, 19 of 25 subjects were male; 14 were white, 10 were black, and 1 was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m2. Ticagrelor had no effect on overall exposure to venlafaxine, as assessed by the AUC0–τ (geometric least squares mean ratio, 110.32 ng · h/mL [90% CI, 106.27–114.52]). Venlafaxine Cmax was increased by 22% in the presence of ticagrelor (121.83 ng/mL [90% CI, 111.80–132.75]). ODV AUC0–τ and Cmax were unaffected by coadministration with ticagrelor (98.71 ng · h/mL [90% CI, 96.61–100.85] and 101.44 ng/mL [90% CI, 98.34–104.65], respectively). Venlafaxine had no effect on the Cmax or AUC0–1 of ticagrelor (96.54 ng/mL [90% CI, 85.03–109.61] and 89.67 ng · h/mL [90% CI, 82.78–97.14]) or ARC124910XX (106.39 ng/mL [90% CI, 96.10–117.78] and 106.32 ng · h/mL [90% CI, 97.28–116.21],
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respectively). Ticagrelor and venlafaxine were well tolerated whether given alone or in combination. Implications: Ticagrelor had no clinically relevant effect on the plasma levels of venlafaxine and its CYP2D6-generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the pharmacokinetics of ticagrelor. (Clin Ther. 2014;36:1217– 1225) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: CYP2D6, drug–drug interaction, pharmacokinetics, ticagrelor, venlafaxine.
INTRODUCTION Ticagrelor is a reversibly binding P2Y12 receptor antagonist1 that is used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). The randomized, Phase III PLATO (PLATelet inhibition and patient Outcomes) trial demonstrated that ticagrelor plus aspirin was associated with a significant reduction in the rate of the primary composite endpoint of myocardial infarction, stroke, and death from vascular causes at 12 months in patients admitted to the hospital with ACS compared with the use of clopidogrel plus aspirin (9.8% vs 11.7%; P o 0.001).2 Rates of major bleeding were not significantly different between ticagrelor and clopidogrel (11.6% vs 11.2%; P ¼ 0.43); ticagrelor was associated, however, with a significant increase in the rate of major bleeding not related to coronary artery Accepted for publication June 23, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.06.024 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics bypass grafting (4.5% vs 3.8%; P ¼ 0.03). The dose of ticagrelor used clinically is 180 mg as a loading dose, followed by a 90-mg BID maintenance dose, with an aspirin dose of 75 to 100 mg.3 Ticagrelor is rapidly absorbed after oral administration and displays linear and predictable pharmacokinetics.4–7 Although ticagrelor does not require metabolic activation to exert its pharmacodynamic effects, it is metabolized by cytochrome P-450 (CYP) 3A4 and CYP3A5 to AR-C124910XX, a metabolite that also inhibits platelet aggregation and is present in the plasma at a concentration 30% that of ticagrelor.7–9 CYP3A4 and CYP3A5 are also the enzymes predominantly responsible for generation of ARC133913XX, the inactive ticagrelor metabolite.9 Patients with ACS are often prescribed multiple medications, a fact that reflects both the increased cardiovascular risk faced by these patients as well as the high prevalence of comorbid disease.10,11 Ticagrelor’s pharmacokinetic interaction with major human CYP isoenzymes has been assessed in vitro8 and in several drug–drug interaction studies.12–14 CYP2D6 metabolizes many clinically important drugs, including various antidepressants, antiarrhythmic agents, and β-adrenoceptor antagonists.15 The CYP inhibition profile of ticagrelor found in vitro indicates that it is a weak inhibitor of CYP2D6 activity with a drug concentration causing 50% inhibition of the desired activity (IC50) of 27 μM; therefore, as a competitive inhibitor, Ki is IC50/2 (or 13.5 mM). The average plasma concentration of ticagrelor after a 90-mg dose is 1000 ng/mL or 2.0 mM.4 The inhibitor concentration ratio versus its Ki value is 0.15, suggesting a low potential for CYP2D6 inhibition in vivo. Ticagrelor is also a weak inhibitor and activator of CYP3A.9 In drug–drug interaction studies with CYP3A substrates, ticagrelor acted as a weak CYP3A activator with midazolam13 and as a weak CYP3A inhibitor with simvastatin and atorvastatin.12 Between 20% and 40% of patients admitted to hospital with ACS events experience depression.16,17 Serotonin-selective and serotonin-noradrenaline reuptake inhibitors (SSRIs and SNRIs, respectively) are commonly used antidepressants. It is well recognized that serotonin has a key role in platelet function.18 Thus, it is not surprising that SSRIs have been shown to decrease adenosine diphosphate–induced platelet aggregation.19 Moreover, new-generation SSRIs and SNRIs have been associated with an increased risk of
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gastrointestinal and other bleeding complications,20,21 as well as ischemic and hemorrhagic stroke.20 Given the potential of a drug–drug interaction between ticagrelor and CYP2D6 substrates, a clinical pharmacology study was conducted to assess the effects of ticagrelor on the metabolism of the SNRI, venlafaxine, a CYP2D6 substrate.22 In vitro studies indicate that venlafaxine is metabolized to O-desmethylvenlafaxine (ODV) and a less active molecule, Ndesmethylvenlafaxine, by CYP2D6 and CYP3A4, respectively.23,24 However, CYP3A4 is typically a minor pathway compared with CYP2D6 in the metabolism of venlafaxine; therefore, the potential for a clinically significant drug interaction between agents that inhibit CYP3A4-mediated metabolism and venlafaxine is low.25 The primary objectives of the present interaction study were: (1) to assess the effect of ticagrelor on the pharmacokinetic parameters of venlafaxine and ODV; and (2) to assess the effect of venlafaxine on the pharmacokinetic parameters of ticagrelor and ARC124910XX. Secondary objectives were to assess the safety and tolerability of ticagrelor and venlafaxine when given alone or in combination.
SUBJECTS AND METHODS Sample Size In a previous study, 18 healthy subjects received oral venlafaxine (75 mg BID).26 The intersubject % CV for Cmax and AUC0–24 in that study were 29% and 39%, respectively. Based on these calculations of variability, a two 1-sided testing procedure (α level ¼ 0.05; true ratio ¼ 1) was used to estimate that a sample size of 18 subjects would provide a statistical power of 90% and that the 90% CIs for the geometric least squares mean (LSM) ratios for venlafaxine Cmax and AUC during the dosing interval (AUC0–τ) (ticagrelor þ venlafaxine/venlafaxine) would be contained within the prespecified no-effect range of 0.80 to 1.25.
Study Population Key inclusion criteria included: healthy men and women of childbearing and non–childbearing potential; age 18 to 45 years; weight 50 to 100 kg; and body mass index 18 to 30 kg/m2. Women of childbearing potential were to be nonpregnant and were required to use contraception. Key exclusion criteria were: history of any disorder that could alter the
Volume 36 Number 9
R. Teng et al. propensity for bleeding; history of any vascular abnormality; history of severe hemorrhage, hematemesis, melena, hemoptysis, severe epistaxis, severe thrombocytopenia, intracranial hemorrhage, or rectal bleeding within the past year; use of enzyme-inducing drugs within 3 weeks of the start of the study; and consumption of products containing grapefruit, Seville orange, or poppy seed within 1 week of study start. The final study protocol was approved by the Midlands Institutional Review Board (Overland Park, Kansas). The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation/Good Clinical Practice Guideline, and applicable regulatory requirements; AstraZeneca’s policy on bioethics was also followed. All subjects provided written informed consent before enrollment.
Study Design and Treatments This was a single-center, open-label, 1-sequence crossover study (AstraZeneca study identifier, D5130C00073; NCT01350921). Because no time-dependent changes in pharmacokinetics were seen over the course of multiple administrations during the clinical development of ticagrelor (and mean accumulation ratios in white subjects were 1.5–1.6 for ticagrelor and 2.1–2.6 for ARC124910XX),27 a 180-mg single dose would have provided exposure to ticagrelor and AR-C124910XX higher than that after administration of multiple 90-mg BID doses. Therefore, a single dose of 180 mg was chosen for the present study because this not only resulted in a simple study design but also maximized the potential impact of ticagrelor on venlafaxine. Eligible subjects were enrolled after a screening visit up to 4 weeks before day 1 of the study. Subjects were required to stay at the clinical research unit from day –1 until day 12 and to attend a follow-up visit 7 to 10 days after discharge. A single 180-mg oral dose of ticagrelor was administered on days 1 and 9. Oral doses of venlafaxine were administered in the morning and the evening on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). On day 9, the morning dose of venlafaxine was coadministered with ticagrelor. Study medication was taken with 240 mL of water. On days 1, 8, and 9, subjects fasted overnight (Z10 hours) and until 4 hours after the morning dose. Restricted activities during the study included: consumption of alcohol-, taurine-, glucuronolactone- or caffeine-containing drinks; consumption of grapefruit-,
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Seville orange–, or poppy seed–containing products; use of tobacco or nicotine-containing products; use of noninvestigator-approved prescribed or over-thecounter medications; surgery; and strenuous exercise.
Pharmacokinetic Sampling and Analytical Methods Blood samples for the determination of plasma concentrations of ticagrelor and AR-C124910XX were collected at 0 hour (predose) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, and 48 hours after ticagrelor dosing on days 1 and 9. For analysis of venlafaxine and ODV, blood samples were collected before the morning dose on days 6 and 7 and before the morning dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the morning dose on days 8 and 9. Blood samples (2 mL each) were collected into plastic lithium heparin Vacuette tubes (Greiner Bio-One, Monroe, North Carolina) at the defined time points. The samples were immediately frozen upright at –201C or below until assay. Samples were analyzed within 3 months of collection, well within the known period of stability. Plasma concentrations of ticagrelor, ARC124910XX,28 venlafaxine, and ODV (AstraZeneca, data on file) were determined by using fully validated reversed-phase liquid chromatography–MS/MS bioanalytical methods. Lower limits of quantitation were 1 ng/mL and 2.5 ng/mL for ticagrelor and ARC124910XX, respectively,28 and 0.1 ng/mL for venlafaxine and ODV (AstraZeneca, data on file). Accuracy and precision values were within an acceptable limit of r15%.
Safety and Tolerability Assessments Safety and tolerability of ticagrelor and venlafaxine when given alone and in combination were evaluated throughout the study by assessment of adverse events (AEs), clinical laboratory parameters (clinical chemistry, hematology, and urinalysis), physical examinations, 12-lead ECGs, and vital signs. The Columbia– Suicide Severity Rating Scale29 was used on days –1 and 12 to assess for potential suicidal ideation due to the use of venlafaxine.
Data Analyses Pharmacokinetic parameters were calculated by standard noncompartmental methods using WinNonlin Professional 5.2 (Pharsight Corporation, Mountain View, California). Actual blood collection times were
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Clinical Therapeutics used for pharmacokinetic parameter calculations, and nominal times were used for graphic presentation. Data collected after morning administration of venlafaxine on days 8 and 9 were used to calculate the following pharmacokinetic parameters for venlafaxine and ODV: Cmax, AUC0–τ, and Tmax. Data collected after ticagrelor administration on days 1 and 9 were used to calculate the following pharmacokinetic parameters for ticagrelor and AR-C124910XX: Cmax, AUC0–1, Tmax, and t½. AUC0–τ was calculated by using the trapezoidal
rule, and AUC0–1 was obtained by using the trapezoidal rule with extrapolation to infinity. Values for ticagrelor and AR-C124910XX t½ were calculated as 0.693/λz, where λ is the terminal-phase elimination rate constant, estimated by least squares regression analysis of the plasma concentration–time data obtained over the terminal log-linear phase. Statistical analyses of pharmacokinetic data were performed by using SAS version 9.2 (SAS Institute, Inc, Cary, North Carolina). AUC0–τ, AUC0–1, and
500
Venlafaxine Ticagrelor + venlafaxine
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0 0
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Figure 1. Mean (SD) plasma concentrations of (A) venlafaxine and (B) O-desmethylvenlafaxine over time after administration of venlafaxine (75 mg BID) alone or with a single dose of ticagrelor (180 mg).
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R. Teng et al. Cmax values were log-transformed and analyzed by using a mixed-effects model with treatment as a fixed effect and subjects as a random effect. Geometric LSM ratios (ticagrelor þ venlafaxine/venlafaxine alone or ticagrelor þ venlafaxine/ticagrelor alone) and 90% CIs were obtained by antilogarithm transformation of the LSM estimates and confidence limits for differences in the means of these log-transformed parameters. The prespecified no-effect limits of the 90% CIs were 0.80 to 1.25.
RESULTS Demographic and Baseline Characteristics A total of 25 subjects were treated. Three subjects withdrew from the study before day 8 for personal reasons, and 1 subject was lost to follow-up after the completion of treatment. Overall, 19 (76%) of 25 subjects were male; 14 (56%) were white, 10 (40%) were black, and 1 (4%) was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m2. Concomitant medications were used by 5 subjects during the study for the treatment of AEs (paracetamol for headache; ciprofloxacin and hydrocodone/paracetamol for right pyelonephritis; ondansetron for emesis and nausea; and hydrocortisone cream for tape-induced dermatitis). All concomitant medication use was
considered unlikely to have a major effect on the pharmacokinetic analyses.
Pharmacokinetics Venlafaxine and ODV Pharmacokinetic Parameters With and Without Ticagrelor The steady-state plasma concentrations of venlafaxine were achieved in all subjects by day 6. Plasma concentration–time profiles of venlafaxine and ODV at steady-state were similar whether venlafaxine was administered alone or in combination with ticagrelor. However, venlafaxine plasma concentrations at 1 hour were slightly higher in the presence of ticagrelor (Figure 1). Venlafaxine Cmax was 22% higher in the presence of ticagrelor compared with venlafaxine alone, with the upper boundary of the 90% CIs of the geometric LSM ratio lying marginally outside the noeffect limits (Table I). For venlafaxine AUC0–τ, the 90% CIs of the geometric LSM ratio were contained within the no-effect limits. Tmax of venlafaxine was similar in the presence and absence of ticagrelor. ODV Cmax and AUC0–τ were not affected by coadministration of ticagrelor, with the 90% CIs of the geometric LSM ratios for these parameters falling within the no-effect limits. ODV Tmax was also unaffected by ticagrelor (Table I).
Table I. Pharmacokinetic parameters of venlafaxine and O-desmethylvenlafaxine (ODV) after administration of venlafaxine (75 mg BID) alone or with a single dose of ticagrelor (180 mg). Parameter Venlafaxine Cmax, ng/mL† AUC0–τ, ng h/mL† Tmax, h‡ ODV Cmax, ng/mL† AUC0–τ, ng h/mL† Tmax, h‡
Venlafaxine (n ¼ 22)
Ticagrelor þ Venlafaxine (n ¼ 22)
Geometric LSM Ratio* (90% CI)
164.5 (128.2–211.1) 943.1 (694.9–1280) 1.0 (0.98–4.0)
200.4 (156.2–257.2) 1040 (766.6–1412) 1.0 (1.0–2.0)
121.83 (111.80–132.75) 110.32 (106.27–114.52) —
264.2 (214.9–324.8) 2536 (2100–3063) 2.0 (1.0–6.0)
268.0 (218–329.5) 2504 (2073–3023) 2.0 (1.0–4.0)
101.44 (98.34–104.65) 98.71 (96.61–100.85) —
Geometric least squares mean (LSM) ratio of ticagrelor þ venlafaxine/venlafaxine, in which the treatment effect and its corresponding 90% CIs were retransformed by using antilogarithms to its original scale and reported as ratio of treatments (ticagrelor þ venlafaxine/venlafaxine) in percentages. † Geometric LSM (geometric LSM 95% CI). ‡ Median (range). *
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Ticagrelor and AR-C124910XX Pharmacokinetic Parameters With and Without Venlafaxine
Safety and Tolerability Study treatments were generally well tolerated. No severe or serious AEs occurred, and no AEs led to discontinuations. Overall, 21 (84%) of 25 subjects reported at least 1 AE; 5 (20%) subjects reported an AE during treatment with ticagrelor alone, 18 (75%) during treatment with venlafaxine alone, and 10 (45%) during treatment with ticagrelor plus venlafaxine. The most common AEs were nausea (which affected 2 [8%], 12 [50%], and 2 [9%] subjects during treatment with ticagrelor alone, venlafaxine
Coadministration of venlafaxine had no effect on the pharmacokinetics of ticagrelor and AR-C124910XX (Figure 2, Table II). Absorption of ticagrelor and generation of the active metabolite were rapid in the absence and presence of venlafaxine. For both ticagrelor and AR-C124910XX, the 90% CIs of the geometric LSM ratios for Cmax and AUC0–1 were within the no-effects limits. The t½ values for ticagrelor and AR-C124910XX were similar in the presence and absence of venlafaxine.
1500 Ticagrelor Mean [ticagrelor] (ng/mL)
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Figure 2. Mean (SD) plasma concentrations of (A) ticagrelor and (B) AR-C124910XX over time after administration of a single dose of ticagrelor (180 mg) alone or with venlafaxine (75 mg BID).
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Table II. Pharmacokinetic parameters of ticagrelor and AR-C124910XX after administration of a single dose of ticagrelor (180 mg) alone or with venlafaxine (75 mg BID). Parameter Ticagrelor Cmax, ng/mL† AUC0–1, ng h/mL† Tmax, h‡ t½ , h § AR-C124910XX Cmax, ng/mL† AUC0–1, ng h/mL† Tmax, h‡ t½ , h §
Ticagrelor (n ¼ 25)
Ticagrelor þ Venlafaxine (n ¼ 22)
Geometric LSM Ratio* (90% CI)
1153 6352 2.0 7.74
(1015–1311) (5670–7115) (1.0–3.0) (12.9)
1113 5696 2.0 8.35
(972.1–1275) (5065–6405) (1.0–4.0) (22.2)
96.54 (85.03–109.61) 89.67 (82.78–97.14) — —
393.8 3118 2.0 8.85
(346.0–448.3) (2787–3489) (1.0–4.0) (16.0)
419.0 3316 2.5 8.92
(366.1–479.5) (2949–3727) (1.98–4.0) (17.4)
106.39 (96.10–117.78) 106.32 (97.28–116.21) — —
Geometric least squares mean (LSM) ratio of ticagrelor þ venlafaxine/ticagrelor, in which the treatment effect and its corresponding 90% CIs were retransformed by using antilogarithms to its original scale and reported as ratio of treatments (ticagrelor þ venlafaxine/ticagrelor) in percentages. † Geometric LSM (geometric LSM 95% CI). ‡ Median (range). § Geometric mean (%CV). *
alone, and ticagrelor plus venlafaxine, respectively); decreased appetite (0, 9 [38%], and 0); headache (1 [4%], 3 [13%], and 1 [5%]); vomiting (0, 3 [13%], and 0); and mydriasis (0, 3 [13%], and 0). All AEs, except 3, were mild in intensity. Two subjects experienced moderate nausea shortly after administration of venlafaxine; both of these events resolved within 3 hours and were considered related to venlafaxine treatment. Another subject experienced moderate neuropraxia 2 to 3 days after administration of venlafaxine; this event was not considered related to treatment. No clinically relevant changes in clinical laboratory parameters, physical examinations, ECGs, vital signs, or Columbia–Suicide Severity Rating Scale scores were observed during the study.
DISCUSSION This study showed that ticagrelor had no clinically relevant effect on CYP2D6-mediated metabolism of venlafaxine. Single-dose administration of ticagrelor 180 mg, the dose used as the initial loading dose in clinical practice, had no effect on steady-state exposure to ODV, as measured by using Cmax and AUC0–τ. Similarly, ticagrelor had no effect on overall exposure
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to the parent compound, as assessed by AUC0–1. However, a small increase (22%) in venlafaxine Cmax was observed. The effects of ticagrelor on Cmax may have been due to inhibition of CYP3A4-mediated metabolism of venlafaxine to the minor metabolite N-desmethylvenlafaxine, as ticagrelor is known to be a weak inhibitor of CYP3A4.9,12,13 Venlafaxine had no effect on the single-dose pharmacokinetics of ticagrelor in the present study. Overall, the pharmacokinetic profile of ticagrelor we observed, including a Tmax in the region of 2 hours and t½ of 8 hours, was consistent with that reported in previous studies in healthy subjects and patients with ACS.4–6,8 The lack of effect of ticagrelor on the pharmacokinetics of venlafaxine and ODV in the present study contrasts with in vitro evidence suggesting that ticagrelor is an inhibitor of CYP2D6.9 It appears, therefore, that the inhibitory effects of ticagrelor on this enzyme are not of sufficient magnitude to be clinically relevant. CYP2D6 is a clinically important enzyme that, while accounting for no more than 5% of total CYP in the liver, is estimated to be involved in the metabolism of approximately one quarter of currently available drugs.15,30 Substrates of CYP2D6
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Clinical Therapeutics potentially prescribed alongside ticagrelor in clinical practice include metoprolol, propranolol, and carvedilol, agents that, due to their role as β-blockers, are commonly used in patients with ACS.10,31 Other commonly used drugs that are metabolized by CYP2D6 include various antidepressants, antiemetics, antipsychotics, and opioids.15,30 Interindividual variation in the CYP2D6 gene means that some individuals may have little or no CYP2D6 enzymatic activity (“poor metabolizers”), whereas others may be considered intermediate, extensive, or ultrarapid metabolizers.15,30 One of the major apparent influences on CYP2D6 phenotype is race; for example, 7% to 10% of white European subjects are thought to be poor metabolizers compared with r1% of individuals from East Asia.15 All subjects participating in the present study were able to metabolize venlafaxine to ODV and therefore demonstrated adequate CYP2D6 function. Ticagrelor and venlafaxine were generally well tolerated in this study, whether given alone or in combination. No serious AEs were reported, and no AEs led to discontinuation from the study. Most AEs that occurred during the study were gastrointestinal in nature, a finding consistent with the known adverse effect profile of venlafaxine.32
CONCLUSIONS Ticagrelor had no clinically relevant effect on the pharmacokinetics of venlafaxine and its CYP2D6generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the single-dose pharmacokinetics of ticagrelor.
ACKNOWLEDGMENTS The study was sponsored by AstraZeneca. Rick Flemming and David Evans of Gardiner Caldwell Communications provided medical writing support funded by AstraZeneca. The authors thank the principal investigator, Dr. K. Craven (Quintiles Phase I Services), and the clinical research staff who conducted the study. All authors contributed to the design and conduct of the study, statistical analyses, and data interpretation. Authors contributed equally to the drafting and editing of the paper and approval of its final contents.
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CONFLICTS OF INTEREST All the authors are current employees of AstraZeneca.
REFERENCES
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Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60:645–681. Teng R, Mitchell PD, Butler KA. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. Eur J Clin Pharmacol. 2013;69:477–487. Teng R, Butler K. The effect of ticagrelor on the metabolism of midazolam in healthy volunteers. Clin Ther. 2013;35:1025–1037. Teng R, Butler K. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers. J Drug Asses. 2013;2:30–39. Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet. 2012;27:55–67. Lesperance F, Frasure-Smith N, Juneau M, et al. Depression and 1-year prognosis in unstable angina. Arch Intern Med. 2000;160:1354–1360. Grace SL, Abbey SE, Kapral MK, et al. Effect of depression on fiveyear mortality after an acute coronary syndrome. Am J Cardiol. 2005;96:1179–1185. Jedlitschky G, Greinacher A, Kroemer HK. Transporters in human platelets: physiologic function and impact for pharmacotherapy. Blood. 2012;119:3394–3402. Tseng YL, Chiang ML, Lane HY, et al. Selective serotonin reuptake inhibitors reduce P2Y12 receptormediated amplification of platelet aggregation. Thromb Res. 2013;131: 325–332. Castro VM, Gallagher PJ, Clements CC, et al. Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants. BMJ Open. 2012;2:e000544. Targownik LE, Bolton JM, Metge CJ, et al. Selective serotonin reuptake inhibitors are associated with a
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22.
23.
24.
25.
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27.
modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol. 2009;104:1475–1482. Otton SV, Ball SE, Cheung SW, et al. Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol. 1996;41:149–156. Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and Ndemethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology. 1999;20:480–490. Venlafaxine prescribing information. http://www.drugs.com/pro/venlafax ine.html. Accessed May 16, 2014. Spina E, Trifirò G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs. 2012;26:39–67. Troy SM, Parker VD, Fruncillo RJ, et al. The pharmacokinetics of venlafaxine when given in a twicedaily regimen. J Clin Pharmacol. 1995;35:404–409. Teng R, Butler K. Pharmacokinetics, pharmacodynamics, and
28.
29.
30.
31.
32.
tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers. Int J Clin Pharmacol Ther. 2014;52:478–491. Sillén H, Cook M, Davis P. Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878: 2299–2306. Columbia University Medical Center (CUMC). Columbia–Suicide Severity Rating Scale (C-SSRS). http://www. cssrs.columbia.edu/index.html. Accessed March 20, 2014. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet. 2009;48:689–723. Shin J, Johnson JA. Pharmacogenetics of beta-blockers. Pharmacotherapy. 2007;27:874–877. Rudolph RL, Derivan AT. The safety and tolerability of venlafaxine hydrochloride: analysis of the clinical trials database. J Clin Psychopharmacol. 1996;16(3 Suppl. 2): 54S–59S.
Address correspondence to: Renli Teng, PhD. Clinical Pharmacology, AstraZeneca LP, FOC W1-677, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437. E-mail: [email protected]
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Evaluation of the Pharmacokinetic Interaction Between Ticagrelor and Venlafaxine, a Cytochrome P-450 2D6 Substrate, in Healthy Subjects Renli Teng, PhD1; Mirjana Kujacic, MD, PhD2; and Judith Hsia, MD1 1
AstraZeneca LP, Wilmington, Delaware; and 2AstraZeneca, Mo¨lndal, Sweden
ABSTRACT Purpose: Ticagrelor is a reversibly binding P2Y12 receptor antagonist used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor has been shown in vitro to be a weak inhibitor of cytochrome P-450 (CYP) 2D6, a clinically important enzyme for the metabolism of many drugs. This study assessed the effects of coadministration of ticagrelor on the pharmacokinetics of the CYP2D6 substrate venlafaxine. The impact of venlafaxine on ticagrelor pharmacokinetic parameters was also investigated. Methods: Healthy subjects (N ¼ 22) received a single 180-mg oral dose of ticagrelor on days 1 and 9 and oral doses of venlafaxine on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). Plasma concentrations of ticagrelor, venlafaxine, and their metabolites (AR-C124910XX and O-desmethylvenlafaxine [ODV], respectively) were quantified for pharmacokinetic analyses. Safety and tolerability were assessed throughout the study. Findings: Overall, 19 of 25 subjects were male; 14 were white, 10 were black, and 1 was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m2. Ticagrelor had no effect on overall exposure to venlafaxine, as assessed by the AUC0–τ (geometric least squares mean ratio, 110.32 ng · h/mL [90% CI, 106.27–114.52]). Venlafaxine Cmax was increased by 22% in the presence of ticagrelor (121.83 ng/mL [90% CI, 111.80–132.75]). ODV AUC0–τ and Cmax were unaffected by coadministration with ticagrelor (98.71 ng · h/mL [90% CI, 96.61–100.85] and 101.44 ng/mL [90% CI, 98.34–104.65], respectively). Venlafaxine had no effect on the Cmax or AUC0–1 of ticagrelor (96.54 ng/mL [90% CI, 85.03–109.61] and 89.67 ng · h/mL [90% CI, 82.78–97.14]) or ARC124910XX (106.39 ng/mL [90% CI, 96.10–117.78] and 106.32 ng · h/mL [90% CI, 97.28–116.21],
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respectively). Ticagrelor and venlafaxine were well tolerated whether given alone or in combination. Implications: Ticagrelor had no clinically relevant effect on the plasma levels of venlafaxine and its CYP2D6-generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the pharmacokinetics of ticagrelor. (Clin Ther. 2014;36:1217– 1225) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: CYP2D6, drug–drug interaction, pharmacokinetics, ticagrelor, venlafaxine.
INTRODUCTION Ticagrelor is a reversibly binding P2Y12 receptor antagonist1 that is used clinically for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS). The randomized, Phase III PLATO (PLATelet inhibition and patient Outcomes) trial demonstrated that ticagrelor plus aspirin was associated with a significant reduction in the rate of the primary composite endpoint of myocardial infarction, stroke, and death from vascular causes at 12 months in patients admitted to the hospital with ACS compared with the use of clopidogrel plus aspirin (9.8% vs 11.7%; P o 0.001).2 Rates of major bleeding were not significantly different between ticagrelor and clopidogrel (11.6% vs 11.2%; P ¼ 0.43); ticagrelor was associated, however, with a significant increase in the rate of major bleeding not related to coronary artery Accepted for publication June 23, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.06.024 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics bypass grafting (4.5% vs 3.8%; P ¼ 0.03). The dose of ticagrelor used clinically is 180 mg as a loading dose, followed by a 90-mg BID maintenance dose, with an aspirin dose of 75 to 100 mg.3 Ticagrelor is rapidly absorbed after oral administration and displays linear and predictable pharmacokinetics.4–7 Although ticagrelor does not require metabolic activation to exert its pharmacodynamic effects, it is metabolized by cytochrome P-450 (CYP) 3A4 and CYP3A5 to AR-C124910XX, a metabolite that also inhibits platelet aggregation and is present in the plasma at a concentration 30% that of ticagrelor.7–9 CYP3A4 and CYP3A5 are also the enzymes predominantly responsible for generation of ARC133913XX, the inactive ticagrelor metabolite.9 Patients with ACS are often prescribed multiple medications, a fact that reflects both the increased cardiovascular risk faced by these patients as well as the high prevalence of comorbid disease.10,11 Ticagrelor’s pharmacokinetic interaction with major human CYP isoenzymes has been assessed in vitro8 and in several drug–drug interaction studies.12–14 CYP2D6 metabolizes many clinically important drugs, including various antidepressants, antiarrhythmic agents, and β-adrenoceptor antagonists.15 The CYP inhibition profile of ticagrelor found in vitro indicates that it is a weak inhibitor of CYP2D6 activity with a drug concentration causing 50% inhibition of the desired activity (IC50) of 27 μM; therefore, as a competitive inhibitor, Ki is IC50/2 (or 13.5 mM). The average plasma concentration of ticagrelor after a 90-mg dose is 1000 ng/mL or 2.0 mM.4 The inhibitor concentration ratio versus its Ki value is 0.15, suggesting a low potential for CYP2D6 inhibition in vivo. Ticagrelor is also a weak inhibitor and activator of CYP3A.9 In drug–drug interaction studies with CYP3A substrates, ticagrelor acted as a weak CYP3A activator with midazolam13 and as a weak CYP3A inhibitor with simvastatin and atorvastatin.12 Between 20% and 40% of patients admitted to hospital with ACS events experience depression.16,17 Serotonin-selective and serotonin-noradrenaline reuptake inhibitors (SSRIs and SNRIs, respectively) are commonly used antidepressants. It is well recognized that serotonin has a key role in platelet function.18 Thus, it is not surprising that SSRIs have been shown to decrease adenosine diphosphate–induced platelet aggregation.19 Moreover, new-generation SSRIs and SNRIs have been associated with an increased risk of
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gastrointestinal and other bleeding complications,20,21 as well as ischemic and hemorrhagic stroke.20 Given the potential of a drug–drug interaction between ticagrelor and CYP2D6 substrates, a clinical pharmacology study was conducted to assess the effects of ticagrelor on the metabolism of the SNRI, venlafaxine, a CYP2D6 substrate.22 In vitro studies indicate that venlafaxine is metabolized to O-desmethylvenlafaxine (ODV) and a less active molecule, Ndesmethylvenlafaxine, by CYP2D6 and CYP3A4, respectively.23,24 However, CYP3A4 is typically a minor pathway compared with CYP2D6 in the metabolism of venlafaxine; therefore, the potential for a clinically significant drug interaction between agents that inhibit CYP3A4-mediated metabolism and venlafaxine is low.25 The primary objectives of the present interaction study were: (1) to assess the effect of ticagrelor on the pharmacokinetic parameters of venlafaxine and ODV; and (2) to assess the effect of venlafaxine on the pharmacokinetic parameters of ticagrelor and ARC124910XX. Secondary objectives were to assess the safety and tolerability of ticagrelor and venlafaxine when given alone or in combination.
SUBJECTS AND METHODS Sample Size In a previous study, 18 healthy subjects received oral venlafaxine (75 mg BID).26 The intersubject % CV for Cmax and AUC0–24 in that study were 29% and 39%, respectively. Based on these calculations of variability, a two 1-sided testing procedure (α level ¼ 0.05; true ratio ¼ 1) was used to estimate that a sample size of 18 subjects would provide a statistical power of 90% and that the 90% CIs for the geometric least squares mean (LSM) ratios for venlafaxine Cmax and AUC during the dosing interval (AUC0–τ) (ticagrelor þ venlafaxine/venlafaxine) would be contained within the prespecified no-effect range of 0.80 to 1.25.
Study Population Key inclusion criteria included: healthy men and women of childbearing and non–childbearing potential; age 18 to 45 years; weight 50 to 100 kg; and body mass index 18 to 30 kg/m2. Women of childbearing potential were to be nonpregnant and were required to use contraception. Key exclusion criteria were: history of any disorder that could alter the
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R. Teng et al. propensity for bleeding; history of any vascular abnormality; history of severe hemorrhage, hematemesis, melena, hemoptysis, severe epistaxis, severe thrombocytopenia, intracranial hemorrhage, or rectal bleeding within the past year; use of enzyme-inducing drugs within 3 weeks of the start of the study; and consumption of products containing grapefruit, Seville orange, or poppy seed within 1 week of study start. The final study protocol was approved by the Midlands Institutional Review Board (Overland Park, Kansas). The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation/Good Clinical Practice Guideline, and applicable regulatory requirements; AstraZeneca’s policy on bioethics was also followed. All subjects provided written informed consent before enrollment.
Study Design and Treatments This was a single-center, open-label, 1-sequence crossover study (AstraZeneca study identifier, D5130C00073; NCT01350921). Because no time-dependent changes in pharmacokinetics were seen over the course of multiple administrations during the clinical development of ticagrelor (and mean accumulation ratios in white subjects were 1.5–1.6 for ticagrelor and 2.1–2.6 for ARC124910XX),27 a 180-mg single dose would have provided exposure to ticagrelor and AR-C124910XX higher than that after administration of multiple 90-mg BID doses. Therefore, a single dose of 180 mg was chosen for the present study because this not only resulted in a simple study design but also maximized the potential impact of ticagrelor on venlafaxine. Eligible subjects were enrolled after a screening visit up to 4 weeks before day 1 of the study. Subjects were required to stay at the clinical research unit from day –1 until day 12 and to attend a follow-up visit 7 to 10 days after discharge. A single 180-mg oral dose of ticagrelor was administered on days 1 and 9. Oral doses of venlafaxine were administered in the morning and the evening on day 4 (37.5 mg BID) and days 5 through 10 (75 mg BID). On day 9, the morning dose of venlafaxine was coadministered with ticagrelor. Study medication was taken with 240 mL of water. On days 1, 8, and 9, subjects fasted overnight (Z10 hours) and until 4 hours after the morning dose. Restricted activities during the study included: consumption of alcohol-, taurine-, glucuronolactone- or caffeine-containing drinks; consumption of grapefruit-,
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Seville orange–, or poppy seed–containing products; use of tobacco or nicotine-containing products; use of noninvestigator-approved prescribed or over-thecounter medications; surgery; and strenuous exercise.
Pharmacokinetic Sampling and Analytical Methods Blood samples for the determination of plasma concentrations of ticagrelor and AR-C124910XX were collected at 0 hour (predose) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, and 48 hours after ticagrelor dosing on days 1 and 9. For analysis of venlafaxine and ODV, blood samples were collected before the morning dose on days 6 and 7 and before the morning dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the morning dose on days 8 and 9. Blood samples (2 mL each) were collected into plastic lithium heparin Vacuette tubes (Greiner Bio-One, Monroe, North Carolina) at the defined time points. The samples were immediately frozen upright at –201C or below until assay. Samples were analyzed within 3 months of collection, well within the known period of stability. Plasma concentrations of ticagrelor, ARC124910XX,28 venlafaxine, and ODV (AstraZeneca, data on file) were determined by using fully validated reversed-phase liquid chromatography–MS/MS bioanalytical methods. Lower limits of quantitation were 1 ng/mL and 2.5 ng/mL for ticagrelor and ARC124910XX, respectively,28 and 0.1 ng/mL for venlafaxine and ODV (AstraZeneca, data on file). Accuracy and precision values were within an acceptable limit of r15%.
Safety and Tolerability Assessments Safety and tolerability of ticagrelor and venlafaxine when given alone and in combination were evaluated throughout the study by assessment of adverse events (AEs), clinical laboratory parameters (clinical chemistry, hematology, and urinalysis), physical examinations, 12-lead ECGs, and vital signs. The Columbia– Suicide Severity Rating Scale29 was used on days –1 and 12 to assess for potential suicidal ideation due to the use of venlafaxine.
Data Analyses Pharmacokinetic parameters were calculated by standard noncompartmental methods using WinNonlin Professional 5.2 (Pharsight Corporation, Mountain View, California). Actual blood collection times were
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Clinical Therapeutics used for pharmacokinetic parameter calculations, and nominal times were used for graphic presentation. Data collected after morning administration of venlafaxine on days 8 and 9 were used to calculate the following pharmacokinetic parameters for venlafaxine and ODV: Cmax, AUC0–τ, and Tmax. Data collected after ticagrelor administration on days 1 and 9 were used to calculate the following pharmacokinetic parameters for ticagrelor and AR-C124910XX: Cmax, AUC0–1, Tmax, and t½. AUC0–τ was calculated by using the trapezoidal
rule, and AUC0–1 was obtained by using the trapezoidal rule with extrapolation to infinity. Values for ticagrelor and AR-C124910XX t½ were calculated as 0.693/λz, where λ is the terminal-phase elimination rate constant, estimated by least squares regression analysis of the plasma concentration–time data obtained over the terminal log-linear phase. Statistical analyses of pharmacokinetic data were performed by using SAS version 9.2 (SAS Institute, Inc, Cary, North Carolina). AUC0–τ, AUC0–1, and
500
Venlafaxine Ticagrelor + venlafaxine
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300
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Figure 1. Mean (SD) plasma concentrations of (A) venlafaxine and (B) O-desmethylvenlafaxine over time after administration of venlafaxine (75 mg BID) alone or with a single dose of ticagrelor (180 mg).
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R. Teng et al. Cmax values were log-transformed and analyzed by using a mixed-effects model with treatment as a fixed effect and subjects as a random effect. Geometric LSM ratios (ticagrelor þ venlafaxine/venlafaxine alone or ticagrelor þ venlafaxine/ticagrelor alone) and 90% CIs were obtained by antilogarithm transformation of the LSM estimates and confidence limits for differences in the means of these log-transformed parameters. The prespecified no-effect limits of the 90% CIs were 0.80 to 1.25.
RESULTS Demographic and Baseline Characteristics A total of 25 subjects were treated. Three subjects withdrew from the study before day 8 for personal reasons, and 1 subject was lost to follow-up after the completion of treatment. Overall, 19 (76%) of 25 subjects were male; 14 (56%) were white, 10 (40%) were black, and 1 (4%) was Asian. Mean (SD) age was 26 (6) years, and mean (SD) body mass index was 24.3 (2.9) kg/m2. Concomitant medications were used by 5 subjects during the study for the treatment of AEs (paracetamol for headache; ciprofloxacin and hydrocodone/paracetamol for right pyelonephritis; ondansetron for emesis and nausea; and hydrocortisone cream for tape-induced dermatitis). All concomitant medication use was
considered unlikely to have a major effect on the pharmacokinetic analyses.
Pharmacokinetics Venlafaxine and ODV Pharmacokinetic Parameters With and Without Ticagrelor The steady-state plasma concentrations of venlafaxine were achieved in all subjects by day 6. Plasma concentration–time profiles of venlafaxine and ODV at steady-state were similar whether venlafaxine was administered alone or in combination with ticagrelor. However, venlafaxine plasma concentrations at 1 hour were slightly higher in the presence of ticagrelor (Figure 1). Venlafaxine Cmax was 22% higher in the presence of ticagrelor compared with venlafaxine alone, with the upper boundary of the 90% CIs of the geometric LSM ratio lying marginally outside the noeffect limits (Table I). For venlafaxine AUC0–τ, the 90% CIs of the geometric LSM ratio were contained within the no-effect limits. Tmax of venlafaxine was similar in the presence and absence of ticagrelor. ODV Cmax and AUC0–τ were not affected by coadministration of ticagrelor, with the 90% CIs of the geometric LSM ratios for these parameters falling within the no-effect limits. ODV Tmax was also unaffected by ticagrelor (Table I).
Table I. Pharmacokinetic parameters of venlafaxine and O-desmethylvenlafaxine (ODV) after administration of venlafaxine (75 mg BID) alone or with a single dose of ticagrelor (180 mg). Parameter Venlafaxine Cmax, ng/mL† AUC0–τ, ng h/mL† Tmax, h‡ ODV Cmax, ng/mL† AUC0–τ, ng h/mL† Tmax, h‡
Venlafaxine (n ¼ 22)
Ticagrelor þ Venlafaxine (n ¼ 22)
Geometric LSM Ratio* (90% CI)
164.5 (128.2–211.1) 943.1 (694.9–1280) 1.0 (0.98–4.0)
200.4 (156.2–257.2) 1040 (766.6–1412) 1.0 (1.0–2.0)
121.83 (111.80–132.75) 110.32 (106.27–114.52) —
264.2 (214.9–324.8) 2536 (2100–3063) 2.0 (1.0–6.0)
268.0 (218–329.5) 2504 (2073–3023) 2.0 (1.0–4.0)
101.44 (98.34–104.65) 98.71 (96.61–100.85) —
Geometric least squares mean (LSM) ratio of ticagrelor þ venlafaxine/venlafaxine, in which the treatment effect and its corresponding 90% CIs were retransformed by using antilogarithms to its original scale and reported as ratio of treatments (ticagrelor þ venlafaxine/venlafaxine) in percentages. † Geometric LSM (geometric LSM 95% CI). ‡ Median (range). *
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Ticagrelor and AR-C124910XX Pharmacokinetic Parameters With and Without Venlafaxine
Safety and Tolerability Study treatments were generally well tolerated. No severe or serious AEs occurred, and no AEs led to discontinuations. Overall, 21 (84%) of 25 subjects reported at least 1 AE; 5 (20%) subjects reported an AE during treatment with ticagrelor alone, 18 (75%) during treatment with venlafaxine alone, and 10 (45%) during treatment with ticagrelor plus venlafaxine. The most common AEs were nausea (which affected 2 [8%], 12 [50%], and 2 [9%] subjects during treatment with ticagrelor alone, venlafaxine
Coadministration of venlafaxine had no effect on the pharmacokinetics of ticagrelor and AR-C124910XX (Figure 2, Table II). Absorption of ticagrelor and generation of the active metabolite were rapid in the absence and presence of venlafaxine. For both ticagrelor and AR-C124910XX, the 90% CIs of the geometric LSM ratios for Cmax and AUC0–1 were within the no-effects limits. The t½ values for ticagrelor and AR-C124910XX were similar in the presence and absence of venlafaxine.
1500 Ticagrelor Mean [ticagrelor] (ng/mL)
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Figure 2. Mean (SD) plasma concentrations of (A) ticagrelor and (B) AR-C124910XX over time after administration of a single dose of ticagrelor (180 mg) alone or with venlafaxine (75 mg BID).
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Table II. Pharmacokinetic parameters of ticagrelor and AR-C124910XX after administration of a single dose of ticagrelor (180 mg) alone or with venlafaxine (75 mg BID). Parameter Ticagrelor Cmax, ng/mL† AUC0–1, ng h/mL† Tmax, h‡ t½ , h § AR-C124910XX Cmax, ng/mL† AUC0–1, ng h/mL† Tmax, h‡ t½ , h §
Ticagrelor (n ¼ 25)
Ticagrelor þ Venlafaxine (n ¼ 22)
Geometric LSM Ratio* (90% CI)
1153 6352 2.0 7.74
(1015–1311) (5670–7115) (1.0–3.0) (12.9)
1113 5696 2.0 8.35
(972.1–1275) (5065–6405) (1.0–4.0) (22.2)
96.54 (85.03–109.61) 89.67 (82.78–97.14) — —
393.8 3118 2.0 8.85
(346.0–448.3) (2787–3489) (1.0–4.0) (16.0)
419.0 3316 2.5 8.92
(366.1–479.5) (2949–3727) (1.98–4.0) (17.4)
106.39 (96.10–117.78) 106.32 (97.28–116.21) — —
Geometric least squares mean (LSM) ratio of ticagrelor þ venlafaxine/ticagrelor, in which the treatment effect and its corresponding 90% CIs were retransformed by using antilogarithms to its original scale and reported as ratio of treatments (ticagrelor þ venlafaxine/ticagrelor) in percentages. † Geometric LSM (geometric LSM 95% CI). ‡ Median (range). § Geometric mean (%CV). *
alone, and ticagrelor plus venlafaxine, respectively); decreased appetite (0, 9 [38%], and 0); headache (1 [4%], 3 [13%], and 1 [5%]); vomiting (0, 3 [13%], and 0); and mydriasis (0, 3 [13%], and 0). All AEs, except 3, were mild in intensity. Two subjects experienced moderate nausea shortly after administration of venlafaxine; both of these events resolved within 3 hours and were considered related to venlafaxine treatment. Another subject experienced moderate neuropraxia 2 to 3 days after administration of venlafaxine; this event was not considered related to treatment. No clinically relevant changes in clinical laboratory parameters, physical examinations, ECGs, vital signs, or Columbia–Suicide Severity Rating Scale scores were observed during the study.
DISCUSSION This study showed that ticagrelor had no clinically relevant effect on CYP2D6-mediated metabolism of venlafaxine. Single-dose administration of ticagrelor 180 mg, the dose used as the initial loading dose in clinical practice, had no effect on steady-state exposure to ODV, as measured by using Cmax and AUC0–τ. Similarly, ticagrelor had no effect on overall exposure
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to the parent compound, as assessed by AUC0–1. However, a small increase (22%) in venlafaxine Cmax was observed. The effects of ticagrelor on Cmax may have been due to inhibition of CYP3A4-mediated metabolism of venlafaxine to the minor metabolite N-desmethylvenlafaxine, as ticagrelor is known to be a weak inhibitor of CYP3A4.9,12,13 Venlafaxine had no effect on the single-dose pharmacokinetics of ticagrelor in the present study. Overall, the pharmacokinetic profile of ticagrelor we observed, including a Tmax in the region of 2 hours and t½ of 8 hours, was consistent with that reported in previous studies in healthy subjects and patients with ACS.4–6,8 The lack of effect of ticagrelor on the pharmacokinetics of venlafaxine and ODV in the present study contrasts with in vitro evidence suggesting that ticagrelor is an inhibitor of CYP2D6.9 It appears, therefore, that the inhibitory effects of ticagrelor on this enzyme are not of sufficient magnitude to be clinically relevant. CYP2D6 is a clinically important enzyme that, while accounting for no more than 5% of total CYP in the liver, is estimated to be involved in the metabolism of approximately one quarter of currently available drugs.15,30 Substrates of CYP2D6
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Clinical Therapeutics potentially prescribed alongside ticagrelor in clinical practice include metoprolol, propranolol, and carvedilol, agents that, due to their role as β-blockers, are commonly used in patients with ACS.10,31 Other commonly used drugs that are metabolized by CYP2D6 include various antidepressants, antiemetics, antipsychotics, and opioids.15,30 Interindividual variation in the CYP2D6 gene means that some individuals may have little or no CYP2D6 enzymatic activity (“poor metabolizers”), whereas others may be considered intermediate, extensive, or ultrarapid metabolizers.15,30 One of the major apparent influences on CYP2D6 phenotype is race; for example, 7% to 10% of white European subjects are thought to be poor metabolizers compared with r1% of individuals from East Asia.15 All subjects participating in the present study were able to metabolize venlafaxine to ODV and therefore demonstrated adequate CYP2D6 function. Ticagrelor and venlafaxine were generally well tolerated in this study, whether given alone or in combination. No serious AEs were reported, and no AEs led to discontinuation from the study. Most AEs that occurred during the study were gastrointestinal in nature, a finding consistent with the known adverse effect profile of venlafaxine.32
CONCLUSIONS Ticagrelor had no clinically relevant effect on the pharmacokinetics of venlafaxine and its CYP2D6generated active metabolite, ODV. On the basis of these data, ticagrelor is not expected to affect CYP2D6-mediated drug metabolism to a clinically relevant extent. Venlafaxine had no effect on the single-dose pharmacokinetics of ticagrelor.
ACKNOWLEDGMENTS The study was sponsored by AstraZeneca. Rick Flemming and David Evans of Gardiner Caldwell Communications provided medical writing support funded by AstraZeneca. The authors thank the principal investigator, Dr. K. Craven (Quintiles Phase I Services), and the clinical research staff who conducted the study. All authors contributed to the design and conduct of the study, statistical analyses, and data interpretation. Authors contributed equally to the drafting and editing of the paper and approval of its final contents.
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CONFLICTS OF INTEREST All the authors are current employees of AstraZeneca.
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Address correspondence to: Renli Teng, PhD. Clinical Pharmacology, AstraZeneca LP, FOC W1-677, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437. E-mail: [email protected]
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