Clin Drug Investig DOI 10.1007/s40261-014-0205-2
ORIGINAL RESEARCH ARTICLE
Pharmacokinetic Interaction Study of Ticagrelor and Cyclosporine in Healthy Volunteers Renli Teng • Mirjana Kujacic • Judith Hsia
Ó Springer International Publishing Switzerland 2014
Abstract Background and Objective Patients with acute coronary syndrome and certain co-morbidities may receive ticagrelor, a reversibly binding P2Y12 receptor antagonist, and cyclosporine, a commonly used immunosuppressant drug. This study assessed the potential pharmacokinetic drug– drug interaction between ticagrelor and cyclosporine. Methods In this single-centre, open-label, three-treatment, three-period crossover study (NCT01504906), healthy volunteers (n = 26) randomly received each of three treatments: cyclosporine (600 mg single oral dose) plus ticagrelor (180 mg single oral dose); cyclosporine alone; ticagrelor alone. Treatments were separated by a washout period of C14 days. Plasma concentrations of ticagrelor and its active metabolite (AR-C124910XX) and blood concentrations of cyclosporine were analyzed, and pharmacokinetic parameters were calculated. Safety and tolerability were assessed. Results Compared with ticagrelor alone, the geometric least squares mean (LSM) ratio (90 % confidence interval [CI]) for the ticagrelor area under the plasma concentration–time curve from time zero to infinity (AUC?) was 2.83 (2.63–3.06), and the maximum plasma concentration (Cmax) was 2.30 (2.06–2.58), in the presence of cyclosporine. Co-administration of cyclosporine with ticagrelor significantly increased AR-C124910XX AUC? (1.33 [1.23–1.42]) and decreased Cmax (0.85 [0.76–0.94]). R. Teng (&) J. Hsia Clinical Pharmacology, AstraZeneca LP, FOC W1-677, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA e-mail: [email protected] M. Kujacic AstraZeneca, Mo¨lndal, Sweden
Ticagrelor had no effect on cyclosporine pharmacokinetic parameters, as the 90 % CIs of the LSM ratios were all within the 0.80–1.25 no-effect range. Co-administration of ticagrelor and cyclosporine was generally well tolerated. Conclusion Co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite and had no effect on cyclosporine pharmacokinetic parameters. The magnitude of cyclosporine’s effect on ticagrelor pharmacokinetics does not warrant dose adjustment of ticagrelor.
Key Points Co-administration of single-dose cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite; no effect on cyclosporine pharmacokinetic parameters was observed. The changes in ticagrelor pharmacokinetic parameters observed with co-administration of cyclosporine are unlikely to be of sufficient magnitude to require a modification of the ticagrelor dose.
1 Introduction Ticagrelor, a cyclopentyltriazolopyrimidine oral antiplatelet agent, is a reversibly binding P2Y12 receptor antagonist [1]. In the phase III PLATelet inhibition and patient Outcomes (PLATO) trial, the rate of the primary composite
R. Teng et al.
endpoint of myocardial infarction, stroke or death from vascular causes at 12 months was significantly lower in patients with acute coronary syndrome (ACS) treated with ticagrelor plus aspirin than in those treated with clopidogrel plus aspirin (9.8 vs 11.7 %; p \ 0.001) [2]. Pharmacokinetic studies have shown that ticagrelor is rapidly absorbed after oral administration and displays linear and predictable pharmacokinetic characteristics [3– 6]. Following twice daily administration, accumulation ratios are approximately 1.4–1.8 for ticagrelor and 2.1–2.6 for AR-C124910XX [7]. Ticagrelor is pharmacologically active and does not require metabolic activation to exert its antiplatelet effects. In-vitro studies have demonstrated that ticagrelor is metabolized to an active metabolite, ARC124910XX, via cytochrome P450 (CYP) 3A enzymes [8]. Ticagrelor and AR-C124910XX have similar potency [9], and exposure to AR-C124910XX is approximately 40 % of that to ticagrelor [6]. In vitro studies have also shown that ticagrelor is a weak inhibitor and activator of CYP3A [8], as well as a substrate and weak inhibitor of P-glycoprotein [10]. In drug–drug interaction studies with CYP3A substrates, ticagrelor acted as a weak CYP3A activator with midazolam [11] and as a weak CYP3A inhibitor with simvastatin and atorvastatin [12]. In a study utilizing the model P-glycoprotein substrate digoxin, ticagrelor acted as a weak inhibitor of intestinal P-glycoprotein [13]. The immunosuppressant drug cyclosporine is used to prevent transplant rejection [14] and to treat certain chronic inflammatory diseases such as psoriasis [15] and rheumatoid arthritis [16]. Cyclosporine is a substrate and weak inhibitor of CYP3A4 and a potent inhibitor of P-glycoprotein and other drug transporters [17, 18]. Patients with ACS have a wide variety of co-morbidities and often require multiple drugs for disease management [19, 20]. Therefore, in clinical practice, antiplatelet agents may be given to patients who are also receiving cyclosporine. For example, the risk of cardiovascular events in kidney transplant recipients is markedly higher than in the general population, with one study reporting an incidence of myocardial infarction of 8.7 % at 36 months after transplantation [21]. Patients with psoriasis or rheumatoid arthritis are also at increased risk of morbidity and death due to cardiovascular disease [22, 23]. A recent metaanalysis of cohort studies suggested that psoriasis increases the risk of myocardial infarction independently of conventional cardiovascular risk factors [24]. As ticagrelor and cyclosporine may be co-administered in patients with ACS and certain co-morbidities, and since both drugs modulate the activities of CYP3A and P-glycoprotein, a drug–drug interaction study was conducted in healthy volunteers. The primary objectives of this study were to investigate the effect of cyclosporine on the pharmacokinetics of ticagrelor and the effect of ticagrelor
on cyclosporine pharmacokinetic parameters. The safety and tolerability of ticagrelor and cyclosporine co-administration was also assessed.
2 Methods 2.1 Sample Size Based on a previous study (AstraZeneca, data on file), the intra-subject coefficients of variation (CVs) for the area under the plasma concentration–time curve from time zero to infinity (AUC?) and the maximum plasma concentration (Cmax) of ticagrelor and AR-C124910XX were estimated to be B19 %. Assuming an intra-subject variability of 19 %, two one-sided tests (alpha level = 0.05; true ratio = 1.0) demonstrated that a sample size of 18 volunteers would provide a statistical power of 90 % and that the 90 % confidence intervals (CIs) for the geometric least squares mean (LSM) ratios for ticagrelor AUC? and Cmax (ticagrelor ? cyclosporine/ticagrelor alone) would be contained within a pre-specified no-effect range of 0.80–1.25. 2.2 Study Population To exclude the possible effects of female sex hormones on CYP3A expression [25], only male volunteers were recruited. Key inclusion criteria included healthy males aged 18–45 years, a body mass index (BMI) of 18–30 kg/ m2, and weight C50 and B100 kg. Key exclusion criteria were a history or presence of any clinically significant disease including gastrointestinal, hepatic, renal or psychiatric disease; a history of diseases that could alter bleeding propensity; recent intake of drugs with enzymeinducing properties (including over-the-counter medication such as antacids and analgesics [other than paracetamol], herbal remedies) and products containing grapefruit, Seville oranges or poppy seeds. All volunteers gave written informed consent. The final study protocol was approved by an institutional review board (Midlands Independent Review Board, Overland Park, KS, USA) and the study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Conference on Harmonization/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on bioethics. 2.3 Study Design and Treatments This trial was a single-centre, open-label, randomized, three-treatment, three-period crossover study
Ticagrelor and Cyclosporine Drug–Drug Interaction Study
(NCT01504906; D5130C00074). Since no time-dependent changes in pharmacokinetics were seen over the course of multiple administrations during the clinical development of ticagrelor (and the mean accumulation ratio at 90 mg twice daily was approximately 1.8 for ticagrelor) a 180 mg single dose would have provided exposure to ticagrelor and AR-C124910XX higher than that following multiple 90 mg twice daily administrations. Therefore, a single dose of 180 mg was chosen for the current study because this not only resulted in a simple study design but also maximized the potential impact of ticagrelor on cyclosporine. Cyclosporine may present a safety hazard when given over a longer period to healthy volunteers at exposures required to discern P-glycoprotein inhibition. Therefore a single dose of 600 mg was selected for the present study. Volunteers were screened within 28 days of the study start. On day 1 of the first treatment visit, volunteers were randomized to one of six treatment sequences: ABC; ACB; BAC; BCA; CAB; CBA. Treatment A was a single oral dose of cyclosporine (NeoralÒ; Novartis Pharmaceuticals, East Hanover, NJ, USA: 600 mg) plus a single oral dose of ticagrelor (BrilintaTM; AstraZeneca, Wilmington, NC, USA: 180 mg), treatment B was a single dose of cyclosporine (600 mg) and treatment C was a single dose of ticagrelor (180 mg). Volunteers were admitted to the study centre on day -1 of each treatment visit. On day 1 of each treatment visit, volunteers took the appropriate drug(s) with 240 mL of water after an overnight fast of C8 h, which continued until 4 h post-dose. Volunteers were discharged on day 3 of each treatment visit. Treatments were separated by a washout period of C14 days to minimize the risk of any carry-over between administrations. A follow-up visit was held 7–10 days after discharge from the final treatment visit. Volunteers were provided with standardized meals and drinks during the treatment visits. Caffeine-containing drinks were permitted during the residential part of the study only as a part of the standardized meals. Alcohol and energy drinks containing taurine or glucuronolactone were not permitted from 72 h before each admission, while resident in the study centre and for 72 h before follow-up. Grapefruit-, Seville orange- or poppy seed-containing products were not permitted from 7 days before admission for the first treatment visit until discharge from the final treatment visit. Use of tobacco, nicotine-containing products and drugs of abuse were not permitted throughout the study. Consumption of prescribed and non-prescribed medications (apart from occasional use of paracetamol and saline nasal spray) was not permitted for at least 2 weeks prior to the first administration of study treatment until follow-up.
2.4 Pharmacokinetic Sampling and Analytical Methods During each treatment visit, venous blood samples for analyses of ticagrelor, AR-C124910XX and cyclosporine were collected at 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 h post-dose. Plasma concentrations of ticagrelor and AR-C124910XX [26], and whole-blood concentrations of cyclosporine, were determined using fully validated liquid chromatography with tandem mass spectrometry bioanalytical methods. Lower limits of quantification were 1 and 2.5 ng/mL for ticagrelor and AR-C124910XX, respectively [26], and 20.0 ng/mL for cyclosporine. The assay method for cyclosporine was validated in the range of 20–4,000 ng/mL and provided accurate and reproducible results, with the defined limits of accuracy (standard deviation \20 %) and precision (coefficient of variation B12.1 %) over the validated range. 2.5 Safety and Tolerability The safety and tolerability of ticagrelor and cyclosporine when given alone or in combination were assessed by monitoring adverse events (AEs), standard clinical laboratory parameters (clinical biochemistry, urinalysis, hematology), physical examinations, vital signs and 12-lead electrocardiograms (ECGs). 2.6 Data Analyses Pharmacokinetic parameters were determined using standard non-compartmental methods (WinNonlin Professional 5.2; Pharsight Corporation, Mountain View, CA, USA). Key pharmacokinetic parameters calculated for ticagrelor, ARC124910XX and cyclosporine were AUC?, AUC from time zero to the time of the last measurable plasma/blood concentration (AUClast), Cmax, time to Cmax (tmax) and terminal half-life (t). AUClast values were calculated using the linear trapezoidal rule and AUC? values were obtained using the linear trapezoidal rule up to the last measureable concentration then extrapolated to infinity. t values were calculated as 0.693/kz, where k is the terminal elimination rate constant, which was estimated by least-squares regression analysis of the plasma concentration–time data. Statistical analyses were performed using SASÒ version 9.2 (SAS Institute, Cary, NC, USA) and SigmaPlotÒ version 9.0 (Systat Software, Inc., San Jose, CA, USA). All pharmacokinetic parameters were summarized using descriptive statistics. For statistical comparisons, AUC? and Cmax for ticagrelor, AR-C124910XX and cyclosporine were natural log transformed and analyzed separately using a mixed-effects model with terms for treatment, period and sequence as fixed effects and volunteer-nested-within-
R. Teng et al.
sequence as a random effect. The treatment effect and its corresponding 90 % CIs were back-transformed using anti-logarithms to the original scale and reported as geometric LSM ratios of treatments. The no-effect limits of the 90 % CIs for the geometric LSM ratios were set at 0.80–1.25.
3 Results 3.1 Patient Demographics, Baseline Characteristics and Disposition Twenty-six healthy male volunteers were randomized into the study. Mean ± standard deviation (SD) age was 24 ± 6 years (range 19–43 years). Sixteen volunteers (62 %) were Caucasian and 10 (38 %) were African American. Mean (SD) BMI was 24.4 (3.0) kg/m2. Overall, 20 patients completed the study. Of the six volunteers who discontinued the study, one received all treatments but was subsequently lost to follow-up; the other five volunteers were either lost to follow-up (n = 2) or withdrew because of an AE (n = 1), sponsor decision (n = 1) or volunteer decision (n = 1). Overall, 24 volunteers received ticagrelor plus cyclosporine, 24 received ticagrelor alone and 25 received cyclosporine alone. One volunteer was excluded from the ticagrelor plus cyclosporine pharmacokinetic analyses and another was excluded from the cyclosporine-alone pharmacokinetic analyses (both because of emesis within 1 h of treatment administration). Concomitant medications were used by seven volunteers during the study (paracetamol, ibuprofen, eucalyptus globulus [an essential oil often used for respiratory conditions], menthol and oseltamivir [n = 1]; diphenhydramine [n = 1]; aspirin, paracetamol and diphenhydramine [n = 1]; paracetamol [n = 2]; aspirin, chlorphenamine and phenylpropanolamine [n = 1]; and eucalyptus globulus, menthol and paracetamol [n = 1]). Use of these medications was considered not to affect the study results. 3.2 Effect of Cyclosporine on Ticagrelor and ARC124910XX Pharmacokinetic Parameters Throughout most of the sampling period, plasma concentrations of ticagrelor and AR–C124910XX were higher when ticagrelor and cyclosporine were co-administered compared with ticagrelor alone (Fig. 1). Co-administration of cyclosporine with ticagrelor resulted in statistically significant increases in ticagrelor AUC? and Cmax of 183 and 130 %, respectively (Table 1). Both tmax and t for ticagrelor were unaffected by co-administration with cyclosporine.
Fig. 1 Mean (±standard deviation) plasma concentrations of a ticagrelor and b AR-C124910XX over time following administration of a single 180 mg dose of ticagrelor alone or with a single 600 mg dose of cyclosporine
For AR-C124910XX, there was a statistically significant 33 % increase in AUC? with ticagrelor plus cyclosporine versus ticagrelor alone, while Cmax was significantly decreased by 15 % (Table 1). Both tmax and t for ARC124910XX were comparable in the presence or absence of cyclosporine. 3.3 Effect of Ticagrelor on Cyclosporine Pharmacokinetic Parameters No notable differences between cyclosporine blood concentration–time profiles were observed when cyclosporine was administered alone or with ticagrelor (Fig. 2). Key cyclosporine pharmacokinetic parameters (AUC?, Cmax, tmax and t) were unaffected by co-administration of ticagrelor (Table 2). For cyclosporine AUC? and Cmax, 90 % CIs of the geometric LSM ratios were within the noeffect limits, confirming that ticagrelor had no effect on exposure to cyclosporine. 3.4 Safety and Tolerability Overall, 23/26 volunteers (89 %) reported at least one AE; 15/24 (63 %) with ticagrelor plus cyclosporine, 6/24
Ticagrelor and Cyclosporine Drug–Drug Interaction Study Table 1 Pharmacokinetic parameters of ticagrelor and AR-C124910XX following administration of a single 180 mg dose of ticagrelor alone or with a single 600 mg dose of cyclosporine Parameter
Ticagrelor (n = 24)
Ticagrelor ? cyclosporine (n = 23)
Geometric LSM ratio (90 % CI)a
2.83 (2.63–3.06)
Ticagrelor AUC? (ngh/mL)
6,270 (29)
17,900 (21)
AUClast (ngh/mL)
6,190 (29)
17,600 (20)
Cmax (ng/mL)
1,040 (38)
2,350 (22)
tmax (h)b
2.5 (1–4)
3.0 (1–4)
t (h)
8.0 (13.5)
7.7 (14.8)
AR-C124910XX AUC? (ngh/mL)
3,090 (27)
4,150 (20)
AUClast (ngh/mL)
3,000 (26)
3,940 (20)
356 (27)
295 (31)
Cmax (ng/mL) tmax (h)b t (h)
3 (1–4)
4 (2–6)
9.2 (17.7)
9.9 (21.4)
2.30 (2.06–2.58)
1.33 (1.23–1.42) 0.85 (0.76–0.94)
Values are expressed as geometric mean (coefficient of variation %) unless specified otherwise AUClast area under the plasma concentration–time curve from time zero to the time of the last measurable concentration, AUC? area under the plasma concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum plasma concentration, LSM least squares mean, t terminal half-life, tmax time to maximum plasma concentration a
Geometric LSM ratio of ticagrelor ? cyclosporine/ticagrelor
b
Median (range)
Table 2 Pharmacokinetic parameters of cyclosporine following administration of a single 600 mg dose of cyclosporine alone or with a single 180 mg dose of ticagrelor Parameter
Cyclosporine (n = 24)
Ticagrelor ? cyclosporine (n = 23)
Geometric LSM ratio (90 % CI)a
AUC? (ngh/mL) AUClast (ngh/mL)
11,700 (22) 10,800 (23)
12,600 (16) 12,000 (17)
1.12 (1.06–1.19)
1,700 (23)
1,740 (19)
1.05 (0.99–1.12)
Cmax (ng/mL) tmax (h)b t (h)
2 (1–4)
2 (1–4)
13.1 (34.9)
12.7 (29.1)
Values are expressed as geometric mean (coefficient of variation %) unless specified otherwise AUClast area under the blood concentration–time curve from time zero to the time of the last measurable concentration, AUC? area under the blood concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum blood concentration, LSM, least squares mean, t terminal half-life, tmax time to maximum blood concentration a
Geometric LSM ratio of ticagrelor ? cyclosporine/cyclosporine
b
Median (range)
(25 %) with ticagrelor alone and 17/25 (68 %) with cyclosporine alone. The most common AEs (occurring in C10 % of volunteers with any treatment) were feeling hot (n = 10 [42 %], n = 0, and n = 12 [48 %] for ticagrelor plus cyclosporine, ticagrelor alone, and cyclosporine alone, respectively), nausea (n = 5 [21 %], n = 0, and n = 1 [4 %]) and headache (n = 4 [17 %], n = 1 [4 %], and n = 0). One volunteer who received cyclosporine alone in period 2 experienced dyspnea. All AEs were mild in severity except for one (viral infection in a volunteer treated with cyclosporine alone) which was moderate. One volunteer discontinued during period 2 after experiencing vomiting following administration of cyclosporine alone; the event was considered mild and resolved spontaneously.
There were no serious AEs or deaths. No clinically relevant changes in standard clinical laboratory parameters, physical examinations, vital signs or ECG parameters were observed during the study.
4 Discussion and Conclusion Ticagrelor is a substrate, weak inhibitor and weak activator of CYP3A, and a substrate and weak inhibitor of P-glycoprotein [8, 11–13]. Cyclosporine, a widely used immunosuppressant, is also a substrate and weak inhibitor of CYP3A4, and is a potent inhibitor of P-glycoprotein and other drug transporters [17, 18]. As ticagrelor and
R. Teng et al.
Fig. 2 Mean (±standard deviation) blood concentration of cyclosporine over time following administration of a single 600 mg dose of cyclosporine alone or with a single 180 mg dose of ticagrelor
cyclosporine may be co-administered in patients with ACS and co-morbidities requiring immunosuppressive treatment, the current study assessed the potential drug–drug interactions between these two agents. The present single-dose study demonstrated that, in healthy volunteers, co-administration of cyclosporine increased exposure to ticagrelor (AUC? and Cmax increased by 183 and 130 %, respectively) and ARC124910XX (AUC? increased 33 %) compared with ticagrelor given alone. The Cmax of the active metabolite was decreased by 15 % in the presence of cyclosporine. For both ticagrelor and AR-C124910XX, tmax and t were unaffected by cyclosporine co-administration. Ticagrelor had no effect on the pharmacokinetics of cyclosporine. A single ticagrelor dose of 180 mg was used in the study as this is the recommended loading dose and the highest approved dose of ticagrelor [2]. In general, the pharmacokinetics of single-dose ticagrelor observed in the current study were consistent with other healthy volunteer studies [3, 5, 27]. The selected dose of cyclosporine for this study was 600 mg. Blood concentrations of cyclosporine in the range of 1,000–5,000 ng/mL are sufficient to inhibit P-glycoprotein [18]. Therefore, the cyclosporine dose used in this study was sufficient to investigate the effects of P-glycoprotein inhibition on ticagrelor pharmacokinetic parameters. Cyclosporine is a potent inhibitor of P-glycoprotein, an efflux transporter protein located in the intestinal mucosa, liver and kidney [28, 29]. It is well established that inhibition of P-glycoprotein increases exposure to substrates of this transporter; for example, the P-glycoprotein inhibitors quinidine, verapamil and itraconazole increase the plasma levels of digoxin, which is a model P-glycoprotein substrate [30]. In-vitro studies have indicated that ticagrelor is a substrate of P-glycoprotein [10]. Therefore, it is possible that cyclosporine-mediated inhibition of P-glycoprotein is the main mechanism resulting in increased exposure to
ticagrelor. The increase in AUC? for AR-C124910XX following cyclosporine co-administration is small, which may reflect the increased exposure to ticagrelor, which overcomes the opposing effects on metabolite generation exerted by CYP3A inhibition. In the present study, given that the plasma half-life of ticagrelor was unaffected by coadministration with cyclosporine, it is most likely that the effect of drug interaction is mediated predominantly via P-glycoprotein in the gastrointestinal wall. Other studies have shown that cyclosporine also inhibits other drug transporters, namely organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and OATP2 and breast cancer resistance protein (BCRP) [17, 18, 30], thereby potentially impacting plasma levels of substrates of these transporters. Although it is not yet known whether or not ticagrelor is a substrate for these transporters, the possibility that inhibition of OATP1B1, OATP1B3 or BCRP contributed to the effects of cyclosporine on ticagrelor pharmacokinetic parameters in this study cannot be excluded. While there is an absence of data relating to the effect of ticagrelor on OATP1B1, evidence from other studies may offer insight. Statins are substrates of the OATP1B1 transporter, and OATP1B1 inhibition has been linked with three-fold and five-fold increases in exposure to atorvastatin and simvastatin acid, respectively [31]. In a recent study, co-administration with ticagrelor increased exposure to atorvastatin and simvastatin (AUC? values were increased by 36 and 81 %, respectively) [12]. Given the magnitude of the increases in exposure to atorvastatin and simvastatin with co-administration of ticagrelor, the effect of ticagrelor on the OATP1B1 transporter is not expected to be significant or to have any clinically relevant effect on the exposure to these statins. The present study showed that co-administration of cyclosporine with ticagrelor resulted in increased exposure to ticagrelor and AR-C124910XX in healthy volunteers. As both agents have anti-platelet activity, it is important to consider whether such increases in the presence of cyclosporine may affect the safety of ticagrelor. However, coadministration of ticagrelor and cyclosporine was generally well tolerated in the healthy male volunteers who participated in this study. Only one volunteer discontinued from the study because of an AE (vomiting after administration of cyclosporine alone). All AEs except one were mild in severity, no serious AEs were reported, and the overall AE profile was consistent with that reported in other ticagrelor studies in healthy volunteers [3–6]. Evidence from studies in patients indicates that the magnitude of cyclosporineassociated increases in ticagrelor exposure is unlikely to have a significant impact on patient safety. For example, in patients with atherosclerosis receiving 200 mg ticagrelor twice daily, a near 200 % increase in exposure to both ticagrelor and AR-C124910XX relative to patients
Ticagrelor and Cyclosporine Drug–Drug Interaction Study
receiving ticagrelor 100 mg twice daily was associated with only a slight increase in minor bleeding events [32]. Further, at 4 h post-dose, 100, 200 and 400 mg twice daily ticagrelor doses produced a similar final-extent mean inhibition of platelet aggregation (IPA) of approximately 90–95 % [32]. Similar rates of total bleeding events were also observed in patients with ACS treated with ticagrelor 90 mg twice daily and 180 mg twice daily, despite a 180 % increase in ticagrelor exposure with the latter regimen [33]. Additionally, a 200 % increase in exposure to ticagrelor and AR-C124910XX following a 180 mg dose of ticagrelor would be unlikely to exceed the plasma concentrations observed following administration of the maximum tolerated dose of ticagrelor (900 mg) [4]. Finally, in the present study, the magnitude of increased exposure to ticagrelor following cyclosporine co-administration was comparable to that observed with the moderate CYP3A4 inhibitor diltiazem [27], approximately doubling the AUC? of ticagrelor. These data collectively suggest that increased ticagrelor exposure following concomitant administration with a CYP3A inhibitor would not result in a clinically relevant increase in IPA. Therefore, changes in ticagrelor pharmacokinetic parameters observed with co-administration of cyclosporine are unlikely to be of sufficient magnitude to require modification of the ticagrelor dose. Although cyclosporine is a substrate of CYP3A [17, 18, 30], the pharmacokinetics of cyclosporine were not affected by co-administration of ticagrelor, which is consistent with previous findings that ticagrelor is only a weak CYP3A inhibitor [11]. A limitation of this study is that a single high dose of cyclosporine was used in an all-male population; therefore, it is not possible to fully evaluate the potential inhibition effect on CYP3A by ticagrelor. In addition, cyclosporine is a lifelong treatment for patients who have undergone transplantation, and therefore a multiple-dose study that reflects real life is needed to confirm the findings of the current assessment. Nonetheless, this study provides important evidence for clinicians regarding co-administration of ticagrelor and cyclosporine. In conclusion, co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its metabolite and there was no effect on cyclosporine pharmacokinetics. Ticagrelor and cyclosporine were generally well tolerated in this male healthy volunteer study population and these findings contribute to the comprehensive body of information on the pharmacokinetic, safety and tolerability profile of ticagrelor. Acknowledgments All authors are employees of AstraZeneca, who funded this study. The authors thank the principal investigator, Dr. K Craven (Quintiles Phase I Unit, Overland Park, KS, USA) and her team. Colleagues at Clinical Pharmacology & DMPK, and those at York Bioanalytical Solutions, are acknowledged for their contribution to the pharmacokinetic analyses. Medical assistance was provided by
Glenn Carlson (AstraZeneca, Wilmington, DE, USA). Statistical support was provided by Jack Jenkins (Quintiles Phase I Unit). We also thank Rick Flemming and Jackie Phillipson (Gardiner-Caldwell Communications) who provided medical writing support funded by AstraZeneca.
References 1. Husted S. Evaluating the risk-benefit profile of the direct-acting P2Y(12) inhibitor ticagrelor in acute coronary syndromes. Postgrad Med. 2011;123(6):79–90. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57. 3. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol. 2010;70(1):65–77. 4. Teng R, Butler K. Safety, tolerability, pharmacokinetics and pharmacodynamics of high single ascending doses of ticagrelor in healthy volunteers. Int J Clin Pharmacol Ther. 2013;51(10):795–806. 5. Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol. 2010;66(5):487–96. 6. Teng R, Oliver S, Hayes M, et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010;38(5):1514–21. 7. Teng R, Butler K. Comparison of the pharmacokinetics, pharmacodynamics and tolerability of single and multiple doses of ticagrelor in healthy Japanese and Caucasian volunteers. Int J Clin Pharmacol Ther. 2014 [Epub ahead of print]. 8. Zhou D, Andersson TB, Grimm SW. In vitro evaluation of potential drug–drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction and differential kinetics. Drug Metab Dispos. 2011;39(4):703–10. 9. European Medicines Agency assessment report: ticagrelor (procedure no. EMEA/H/C/1241). http://www.ema.europa.eu/docs/en_ GB/document_library/EPAR_-_Public_assessment_report/human/ 001241/WC500100492.pdf. Accessed 10 April 2014. 10. Summary of product characteristics: Brilique. http://www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001241/WC500100494.pdf. Accessed 10 April 2014. 11. Teng R, Butler K. The effect of ticagrelor on the metabolism of midazolam in healthy volunteers. Clin Ther. 2013;35(7):1025–37. 12. 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(9):477–87. 13. Teng R, Butler K. A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers. Eur J Clin Pharmacol. 2013;69(10):1801–8. 14. Colombo D, Ammirati E. Cyclosporine in transplantation—a history of converging timelines. J Biol Regul Homeost Agents. 2011;25(4):493–504. 15. Dehesa L, Abuchar A, Nuno-Gonazalez A, Vitiello M, Kerdel FA. The use of cyclosporine in dermatology. J Drugs Dermatol. 2012;11(8):979–87. 16. Gremese E, Ferraccioli GF. Benefit/risk of cyclosporine in rheumatoid arthritis. Clin Exp Rheumatol. 2004;22(5 Suppl 35):S101–7. 17. Kusuhara H, Sugiyama Y. Drug–drug interactions involving the membrane transport process. In: Rodrigues AD, editor. Drug– drug interactions. New York: Marcel Dekker; 2001. p. 123–88.
R. Teng et al. 18. Krishna R, Bergman A, Larson P, et al. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol. 2007;47(2):165–74. 19. Kumar A, Cannon CP. Acute coronary syndromes: diagnosis and management. Mayo Clin Proc. 2009;84(10):917–38. 20. Taneva E, Bogdanova V, Shtereva N. Acute coronary syndrome, comorbidity, and mortality in geriatric patients. Ann N Y Acad Sci. 2004;1019:106–10. 21. Kasiske BL, Maclean JR, Snyder JJ. Acute myocardial infarction and kidney transplantation. J Am Soc Nephrol. 2006;17(3):900–7. 22. Boehncke WH, Boehncke S. Cardiovascular mortality in psoriasis and psoriatic arthritis: epidemiology, pathomechanisms, therapeutic implications, and perspectives. Curr Rheumatol Rep. 2012;14(4):343–8. 23. Charles-Schoeman C. Cardiovascular disease and rheumatoid arthritis: an update. Curr Rheumatol Rep. 2012;14(5):455–62. 24. Xu T, Zhang YH. Association of psoriasis with stroke and myocardial infarction: meta-analysis of cohort studies. Br J Dermatol. 2012;167(6):1345–50. 25. Sakuma T, Kawasaki Y, Jarukamjorn K, Nemoto N. Sex differences of drug-metabolizing enzyme: female predominant expression of human and mouse cytochrome P450 3A isoforms. J Health Sci. 2009;55(3):325–37. 26. Sille´n H, Cook M, Davis P. Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B. 2010;878(25):2299–306. 27. Teng R, Butler K. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers. J Drug Assess. 2013;2:30–9.
28. von Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivisto KT. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004;75(3):172–83. 29. Glaeser H. Importance of P-glycoprotein for drug–drug interactions. Handb Exp Pharmacol. 2011;201:285–97. 30. FDA. Guidance for industry. Drug interaction studies—study design, data analysis, implications for dosing, and labelling recommendations. Draft guidance. Food and Drug Administration, February 2012. http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/ucm292362.pdf. Accessed 06 Feb 2014. 31. Elsby R, Hilgendorf C, Fenner K. Understanding the critical disposition pathway of statins to assess drug–drug interaction risk during drug development: it’s just about OATP1B1. Clin Pharmacol Ther. 2012;95(5):584–98. 32. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27(9):1038–47. 33. Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007;50(19):1852–6.
ORIGINAL RESEARCH ARTICLE
Pharmacokinetic Interaction Study of Ticagrelor and Cyclosporine in Healthy Volunteers Renli Teng • Mirjana Kujacic • Judith Hsia
Ó Springer International Publishing Switzerland 2014
Abstract Background and Objective Patients with acute coronary syndrome and certain co-morbidities may receive ticagrelor, a reversibly binding P2Y12 receptor antagonist, and cyclosporine, a commonly used immunosuppressant drug. This study assessed the potential pharmacokinetic drug– drug interaction between ticagrelor and cyclosporine. Methods In this single-centre, open-label, three-treatment, three-period crossover study (NCT01504906), healthy volunteers (n = 26) randomly received each of three treatments: cyclosporine (600 mg single oral dose) plus ticagrelor (180 mg single oral dose); cyclosporine alone; ticagrelor alone. Treatments were separated by a washout period of C14 days. Plasma concentrations of ticagrelor and its active metabolite (AR-C124910XX) and blood concentrations of cyclosporine were analyzed, and pharmacokinetic parameters were calculated. Safety and tolerability were assessed. Results Compared with ticagrelor alone, the geometric least squares mean (LSM) ratio (90 % confidence interval [CI]) for the ticagrelor area under the plasma concentration–time curve from time zero to infinity (AUC?) was 2.83 (2.63–3.06), and the maximum plasma concentration (Cmax) was 2.30 (2.06–2.58), in the presence of cyclosporine. Co-administration of cyclosporine with ticagrelor significantly increased AR-C124910XX AUC? (1.33 [1.23–1.42]) and decreased Cmax (0.85 [0.76–0.94]). R. Teng (&) J. Hsia Clinical Pharmacology, AstraZeneca LP, FOC W1-677, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA e-mail: [email protected] M. Kujacic AstraZeneca, Mo¨lndal, Sweden
Ticagrelor had no effect on cyclosporine pharmacokinetic parameters, as the 90 % CIs of the LSM ratios were all within the 0.80–1.25 no-effect range. Co-administration of ticagrelor and cyclosporine was generally well tolerated. Conclusion Co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite and had no effect on cyclosporine pharmacokinetic parameters. The magnitude of cyclosporine’s effect on ticagrelor pharmacokinetics does not warrant dose adjustment of ticagrelor.
Key Points Co-administration of single-dose cyclosporine with ticagrelor increased exposure to ticagrelor and its active metabolite; no effect on cyclosporine pharmacokinetic parameters was observed. The changes in ticagrelor pharmacokinetic parameters observed with co-administration of cyclosporine are unlikely to be of sufficient magnitude to require a modification of the ticagrelor dose.
1 Introduction Ticagrelor, a cyclopentyltriazolopyrimidine oral antiplatelet agent, is a reversibly binding P2Y12 receptor antagonist [1]. In the phase III PLATelet inhibition and patient Outcomes (PLATO) trial, the rate of the primary composite
R. Teng et al.
endpoint of myocardial infarction, stroke or death from vascular causes at 12 months was significantly lower in patients with acute coronary syndrome (ACS) treated with ticagrelor plus aspirin than in those treated with clopidogrel plus aspirin (9.8 vs 11.7 %; p \ 0.001) [2]. Pharmacokinetic studies have shown that ticagrelor is rapidly absorbed after oral administration and displays linear and predictable pharmacokinetic characteristics [3– 6]. Following twice daily administration, accumulation ratios are approximately 1.4–1.8 for ticagrelor and 2.1–2.6 for AR-C124910XX [7]. Ticagrelor is pharmacologically active and does not require metabolic activation to exert its antiplatelet effects. In-vitro studies have demonstrated that ticagrelor is metabolized to an active metabolite, ARC124910XX, via cytochrome P450 (CYP) 3A enzymes [8]. Ticagrelor and AR-C124910XX have similar potency [9], and exposure to AR-C124910XX is approximately 40 % of that to ticagrelor [6]. In vitro studies have also shown that ticagrelor is a weak inhibitor and activator of CYP3A [8], as well as a substrate and weak inhibitor of P-glycoprotein [10]. In drug–drug interaction studies with CYP3A substrates, ticagrelor acted as a weak CYP3A activator with midazolam [11] and as a weak CYP3A inhibitor with simvastatin and atorvastatin [12]. In a study utilizing the model P-glycoprotein substrate digoxin, ticagrelor acted as a weak inhibitor of intestinal P-glycoprotein [13]. The immunosuppressant drug cyclosporine is used to prevent transplant rejection [14] and to treat certain chronic inflammatory diseases such as psoriasis [15] and rheumatoid arthritis [16]. Cyclosporine is a substrate and weak inhibitor of CYP3A4 and a potent inhibitor of P-glycoprotein and other drug transporters [17, 18]. Patients with ACS have a wide variety of co-morbidities and often require multiple drugs for disease management [19, 20]. Therefore, in clinical practice, antiplatelet agents may be given to patients who are also receiving cyclosporine. For example, the risk of cardiovascular events in kidney transplant recipients is markedly higher than in the general population, with one study reporting an incidence of myocardial infarction of 8.7 % at 36 months after transplantation [21]. Patients with psoriasis or rheumatoid arthritis are also at increased risk of morbidity and death due to cardiovascular disease [22, 23]. A recent metaanalysis of cohort studies suggested that psoriasis increases the risk of myocardial infarction independently of conventional cardiovascular risk factors [24]. As ticagrelor and cyclosporine may be co-administered in patients with ACS and certain co-morbidities, and since both drugs modulate the activities of CYP3A and P-glycoprotein, a drug–drug interaction study was conducted in healthy volunteers. The primary objectives of this study were to investigate the effect of cyclosporine on the pharmacokinetics of ticagrelor and the effect of ticagrelor
on cyclosporine pharmacokinetic parameters. The safety and tolerability of ticagrelor and cyclosporine co-administration was also assessed.
2 Methods 2.1 Sample Size Based on a previous study (AstraZeneca, data on file), the intra-subject coefficients of variation (CVs) for the area under the plasma concentration–time curve from time zero to infinity (AUC?) and the maximum plasma concentration (Cmax) of ticagrelor and AR-C124910XX were estimated to be B19 %. Assuming an intra-subject variability of 19 %, two one-sided tests (alpha level = 0.05; true ratio = 1.0) demonstrated that a sample size of 18 volunteers would provide a statistical power of 90 % and that the 90 % confidence intervals (CIs) for the geometric least squares mean (LSM) ratios for ticagrelor AUC? and Cmax (ticagrelor ? cyclosporine/ticagrelor alone) would be contained within a pre-specified no-effect range of 0.80–1.25. 2.2 Study Population To exclude the possible effects of female sex hormones on CYP3A expression [25], only male volunteers were recruited. Key inclusion criteria included healthy males aged 18–45 years, a body mass index (BMI) of 18–30 kg/ m2, and weight C50 and B100 kg. Key exclusion criteria were a history or presence of any clinically significant disease including gastrointestinal, hepatic, renal or psychiatric disease; a history of diseases that could alter bleeding propensity; recent intake of drugs with enzymeinducing properties (including over-the-counter medication such as antacids and analgesics [other than paracetamol], herbal remedies) and products containing grapefruit, Seville oranges or poppy seeds. All volunteers gave written informed consent. The final study protocol was approved by an institutional review board (Midlands Independent Review Board, Overland Park, KS, USA) and the study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Conference on Harmonization/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on bioethics. 2.3 Study Design and Treatments This trial was a single-centre, open-label, randomized, three-treatment, three-period crossover study
Ticagrelor and Cyclosporine Drug–Drug Interaction Study
(NCT01504906; D5130C00074). Since no time-dependent changes in pharmacokinetics were seen over the course of multiple administrations during the clinical development of ticagrelor (and the mean accumulation ratio at 90 mg twice daily was approximately 1.8 for ticagrelor) a 180 mg single dose would have provided exposure to ticagrelor and AR-C124910XX higher than that following multiple 90 mg twice daily administrations. Therefore, a single dose of 180 mg was chosen for the current study because this not only resulted in a simple study design but also maximized the potential impact of ticagrelor on cyclosporine. Cyclosporine may present a safety hazard when given over a longer period to healthy volunteers at exposures required to discern P-glycoprotein inhibition. Therefore a single dose of 600 mg was selected for the present study. Volunteers were screened within 28 days of the study start. On day 1 of the first treatment visit, volunteers were randomized to one of six treatment sequences: ABC; ACB; BAC; BCA; CAB; CBA. Treatment A was a single oral dose of cyclosporine (NeoralÒ; Novartis Pharmaceuticals, East Hanover, NJ, USA: 600 mg) plus a single oral dose of ticagrelor (BrilintaTM; AstraZeneca, Wilmington, NC, USA: 180 mg), treatment B was a single dose of cyclosporine (600 mg) and treatment C was a single dose of ticagrelor (180 mg). Volunteers were admitted to the study centre on day -1 of each treatment visit. On day 1 of each treatment visit, volunteers took the appropriate drug(s) with 240 mL of water after an overnight fast of C8 h, which continued until 4 h post-dose. Volunteers were discharged on day 3 of each treatment visit. Treatments were separated by a washout period of C14 days to minimize the risk of any carry-over between administrations. A follow-up visit was held 7–10 days after discharge from the final treatment visit. Volunteers were provided with standardized meals and drinks during the treatment visits. Caffeine-containing drinks were permitted during the residential part of the study only as a part of the standardized meals. Alcohol and energy drinks containing taurine or glucuronolactone were not permitted from 72 h before each admission, while resident in the study centre and for 72 h before follow-up. Grapefruit-, Seville orange- or poppy seed-containing products were not permitted from 7 days before admission for the first treatment visit until discharge from the final treatment visit. Use of tobacco, nicotine-containing products and drugs of abuse were not permitted throughout the study. Consumption of prescribed and non-prescribed medications (apart from occasional use of paracetamol and saline nasal spray) was not permitted for at least 2 weeks prior to the first administration of study treatment until follow-up.
2.4 Pharmacokinetic Sampling and Analytical Methods During each treatment visit, venous blood samples for analyses of ticagrelor, AR-C124910XX and cyclosporine were collected at 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 h post-dose. Plasma concentrations of ticagrelor and AR-C124910XX [26], and whole-blood concentrations of cyclosporine, were determined using fully validated liquid chromatography with tandem mass spectrometry bioanalytical methods. Lower limits of quantification were 1 and 2.5 ng/mL for ticagrelor and AR-C124910XX, respectively [26], and 20.0 ng/mL for cyclosporine. The assay method for cyclosporine was validated in the range of 20–4,000 ng/mL and provided accurate and reproducible results, with the defined limits of accuracy (standard deviation \20 %) and precision (coefficient of variation B12.1 %) over the validated range. 2.5 Safety and Tolerability The safety and tolerability of ticagrelor and cyclosporine when given alone or in combination were assessed by monitoring adverse events (AEs), standard clinical laboratory parameters (clinical biochemistry, urinalysis, hematology), physical examinations, vital signs and 12-lead electrocardiograms (ECGs). 2.6 Data Analyses Pharmacokinetic parameters were determined using standard non-compartmental methods (WinNonlin Professional 5.2; Pharsight Corporation, Mountain View, CA, USA). Key pharmacokinetic parameters calculated for ticagrelor, ARC124910XX and cyclosporine were AUC?, AUC from time zero to the time of the last measurable plasma/blood concentration (AUClast), Cmax, time to Cmax (tmax) and terminal half-life (t). AUClast values were calculated using the linear trapezoidal rule and AUC? values were obtained using the linear trapezoidal rule up to the last measureable concentration then extrapolated to infinity. t values were calculated as 0.693/kz, where k is the terminal elimination rate constant, which was estimated by least-squares regression analysis of the plasma concentration–time data. Statistical analyses were performed using SASÒ version 9.2 (SAS Institute, Cary, NC, USA) and SigmaPlotÒ version 9.0 (Systat Software, Inc., San Jose, CA, USA). All pharmacokinetic parameters were summarized using descriptive statistics. For statistical comparisons, AUC? and Cmax for ticagrelor, AR-C124910XX and cyclosporine were natural log transformed and analyzed separately using a mixed-effects model with terms for treatment, period and sequence as fixed effects and volunteer-nested-within-
R. Teng et al.
sequence as a random effect. The treatment effect and its corresponding 90 % CIs were back-transformed using anti-logarithms to the original scale and reported as geometric LSM ratios of treatments. The no-effect limits of the 90 % CIs for the geometric LSM ratios were set at 0.80–1.25.
3 Results 3.1 Patient Demographics, Baseline Characteristics and Disposition Twenty-six healthy male volunteers were randomized into the study. Mean ± standard deviation (SD) age was 24 ± 6 years (range 19–43 years). Sixteen volunteers (62 %) were Caucasian and 10 (38 %) were African American. Mean (SD) BMI was 24.4 (3.0) kg/m2. Overall, 20 patients completed the study. Of the six volunteers who discontinued the study, one received all treatments but was subsequently lost to follow-up; the other five volunteers were either lost to follow-up (n = 2) or withdrew because of an AE (n = 1), sponsor decision (n = 1) or volunteer decision (n = 1). Overall, 24 volunteers received ticagrelor plus cyclosporine, 24 received ticagrelor alone and 25 received cyclosporine alone. One volunteer was excluded from the ticagrelor plus cyclosporine pharmacokinetic analyses and another was excluded from the cyclosporine-alone pharmacokinetic analyses (both because of emesis within 1 h of treatment administration). Concomitant medications were used by seven volunteers during the study (paracetamol, ibuprofen, eucalyptus globulus [an essential oil often used for respiratory conditions], menthol and oseltamivir [n = 1]; diphenhydramine [n = 1]; aspirin, paracetamol and diphenhydramine [n = 1]; paracetamol [n = 2]; aspirin, chlorphenamine and phenylpropanolamine [n = 1]; and eucalyptus globulus, menthol and paracetamol [n = 1]). Use of these medications was considered not to affect the study results. 3.2 Effect of Cyclosporine on Ticagrelor and ARC124910XX Pharmacokinetic Parameters Throughout most of the sampling period, plasma concentrations of ticagrelor and AR–C124910XX were higher when ticagrelor and cyclosporine were co-administered compared with ticagrelor alone (Fig. 1). Co-administration of cyclosporine with ticagrelor resulted in statistically significant increases in ticagrelor AUC? and Cmax of 183 and 130 %, respectively (Table 1). Both tmax and t for ticagrelor were unaffected by co-administration with cyclosporine.
Fig. 1 Mean (±standard deviation) plasma concentrations of a ticagrelor and b AR-C124910XX over time following administration of a single 180 mg dose of ticagrelor alone or with a single 600 mg dose of cyclosporine
For AR-C124910XX, there was a statistically significant 33 % increase in AUC? with ticagrelor plus cyclosporine versus ticagrelor alone, while Cmax was significantly decreased by 15 % (Table 1). Both tmax and t for ARC124910XX were comparable in the presence or absence of cyclosporine. 3.3 Effect of Ticagrelor on Cyclosporine Pharmacokinetic Parameters No notable differences between cyclosporine blood concentration–time profiles were observed when cyclosporine was administered alone or with ticagrelor (Fig. 2). Key cyclosporine pharmacokinetic parameters (AUC?, Cmax, tmax and t) were unaffected by co-administration of ticagrelor (Table 2). For cyclosporine AUC? and Cmax, 90 % CIs of the geometric LSM ratios were within the noeffect limits, confirming that ticagrelor had no effect on exposure to cyclosporine. 3.4 Safety and Tolerability Overall, 23/26 volunteers (89 %) reported at least one AE; 15/24 (63 %) with ticagrelor plus cyclosporine, 6/24
Ticagrelor and Cyclosporine Drug–Drug Interaction Study Table 1 Pharmacokinetic parameters of ticagrelor and AR-C124910XX following administration of a single 180 mg dose of ticagrelor alone or with a single 600 mg dose of cyclosporine Parameter
Ticagrelor (n = 24)
Ticagrelor ? cyclosporine (n = 23)
Geometric LSM ratio (90 % CI)a
2.83 (2.63–3.06)
Ticagrelor AUC? (ngh/mL)
6,270 (29)
17,900 (21)
AUClast (ngh/mL)
6,190 (29)
17,600 (20)
Cmax (ng/mL)
1,040 (38)
2,350 (22)
tmax (h)b
2.5 (1–4)
3.0 (1–4)
t (h)
8.0 (13.5)
7.7 (14.8)
AR-C124910XX AUC? (ngh/mL)
3,090 (27)
4,150 (20)
AUClast (ngh/mL)
3,000 (26)
3,940 (20)
356 (27)
295 (31)
Cmax (ng/mL) tmax (h)b t (h)
3 (1–4)
4 (2–6)
9.2 (17.7)
9.9 (21.4)
2.30 (2.06–2.58)
1.33 (1.23–1.42) 0.85 (0.76–0.94)
Values are expressed as geometric mean (coefficient of variation %) unless specified otherwise AUClast area under the plasma concentration–time curve from time zero to the time of the last measurable concentration, AUC? area under the plasma concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum plasma concentration, LSM least squares mean, t terminal half-life, tmax time to maximum plasma concentration a
Geometric LSM ratio of ticagrelor ? cyclosporine/ticagrelor
b
Median (range)
Table 2 Pharmacokinetic parameters of cyclosporine following administration of a single 600 mg dose of cyclosporine alone or with a single 180 mg dose of ticagrelor Parameter
Cyclosporine (n = 24)
Ticagrelor ? cyclosporine (n = 23)
Geometric LSM ratio (90 % CI)a
AUC? (ngh/mL) AUClast (ngh/mL)
11,700 (22) 10,800 (23)
12,600 (16) 12,000 (17)
1.12 (1.06–1.19)
1,700 (23)
1,740 (19)
1.05 (0.99–1.12)
Cmax (ng/mL) tmax (h)b t (h)
2 (1–4)
2 (1–4)
13.1 (34.9)
12.7 (29.1)
Values are expressed as geometric mean (coefficient of variation %) unless specified otherwise AUClast area under the blood concentration–time curve from time zero to the time of the last measurable concentration, AUC? area under the blood concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum blood concentration, LSM, least squares mean, t terminal half-life, tmax time to maximum blood concentration a
Geometric LSM ratio of ticagrelor ? cyclosporine/cyclosporine
b
Median (range)
(25 %) with ticagrelor alone and 17/25 (68 %) with cyclosporine alone. The most common AEs (occurring in C10 % of volunteers with any treatment) were feeling hot (n = 10 [42 %], n = 0, and n = 12 [48 %] for ticagrelor plus cyclosporine, ticagrelor alone, and cyclosporine alone, respectively), nausea (n = 5 [21 %], n = 0, and n = 1 [4 %]) and headache (n = 4 [17 %], n = 1 [4 %], and n = 0). One volunteer who received cyclosporine alone in period 2 experienced dyspnea. All AEs were mild in severity except for one (viral infection in a volunteer treated with cyclosporine alone) which was moderate. One volunteer discontinued during period 2 after experiencing vomiting following administration of cyclosporine alone; the event was considered mild and resolved spontaneously.
There were no serious AEs or deaths. No clinically relevant changes in standard clinical laboratory parameters, physical examinations, vital signs or ECG parameters were observed during the study.
4 Discussion and Conclusion Ticagrelor is a substrate, weak inhibitor and weak activator of CYP3A, and a substrate and weak inhibitor of P-glycoprotein [8, 11–13]. Cyclosporine, a widely used immunosuppressant, is also a substrate and weak inhibitor of CYP3A4, and is a potent inhibitor of P-glycoprotein and other drug transporters [17, 18]. As ticagrelor and
R. Teng et al.
Fig. 2 Mean (±standard deviation) blood concentration of cyclosporine over time following administration of a single 600 mg dose of cyclosporine alone or with a single 180 mg dose of ticagrelor
cyclosporine may be co-administered in patients with ACS and co-morbidities requiring immunosuppressive treatment, the current study assessed the potential drug–drug interactions between these two agents. The present single-dose study demonstrated that, in healthy volunteers, co-administration of cyclosporine increased exposure to ticagrelor (AUC? and Cmax increased by 183 and 130 %, respectively) and ARC124910XX (AUC? increased 33 %) compared with ticagrelor given alone. The Cmax of the active metabolite was decreased by 15 % in the presence of cyclosporine. For both ticagrelor and AR-C124910XX, tmax and t were unaffected by cyclosporine co-administration. Ticagrelor had no effect on the pharmacokinetics of cyclosporine. A single ticagrelor dose of 180 mg was used in the study as this is the recommended loading dose and the highest approved dose of ticagrelor [2]. In general, the pharmacokinetics of single-dose ticagrelor observed in the current study were consistent with other healthy volunteer studies [3, 5, 27]. The selected dose of cyclosporine for this study was 600 mg. Blood concentrations of cyclosporine in the range of 1,000–5,000 ng/mL are sufficient to inhibit P-glycoprotein [18]. Therefore, the cyclosporine dose used in this study was sufficient to investigate the effects of P-glycoprotein inhibition on ticagrelor pharmacokinetic parameters. Cyclosporine is a potent inhibitor of P-glycoprotein, an efflux transporter protein located in the intestinal mucosa, liver and kidney [28, 29]. It is well established that inhibition of P-glycoprotein increases exposure to substrates of this transporter; for example, the P-glycoprotein inhibitors quinidine, verapamil and itraconazole increase the plasma levels of digoxin, which is a model P-glycoprotein substrate [30]. In-vitro studies have indicated that ticagrelor is a substrate of P-glycoprotein [10]. Therefore, it is possible that cyclosporine-mediated inhibition of P-glycoprotein is the main mechanism resulting in increased exposure to
ticagrelor. The increase in AUC? for AR-C124910XX following cyclosporine co-administration is small, which may reflect the increased exposure to ticagrelor, which overcomes the opposing effects on metabolite generation exerted by CYP3A inhibition. In the present study, given that the plasma half-life of ticagrelor was unaffected by coadministration with cyclosporine, it is most likely that the effect of drug interaction is mediated predominantly via P-glycoprotein in the gastrointestinal wall. Other studies have shown that cyclosporine also inhibits other drug transporters, namely organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and OATP2 and breast cancer resistance protein (BCRP) [17, 18, 30], thereby potentially impacting plasma levels of substrates of these transporters. Although it is not yet known whether or not ticagrelor is a substrate for these transporters, the possibility that inhibition of OATP1B1, OATP1B3 or BCRP contributed to the effects of cyclosporine on ticagrelor pharmacokinetic parameters in this study cannot be excluded. While there is an absence of data relating to the effect of ticagrelor on OATP1B1, evidence from other studies may offer insight. Statins are substrates of the OATP1B1 transporter, and OATP1B1 inhibition has been linked with three-fold and five-fold increases in exposure to atorvastatin and simvastatin acid, respectively [31]. In a recent study, co-administration with ticagrelor increased exposure to atorvastatin and simvastatin (AUC? values were increased by 36 and 81 %, respectively) [12]. Given the magnitude of the increases in exposure to atorvastatin and simvastatin with co-administration of ticagrelor, the effect of ticagrelor on the OATP1B1 transporter is not expected to be significant or to have any clinically relevant effect on the exposure to these statins. The present study showed that co-administration of cyclosporine with ticagrelor resulted in increased exposure to ticagrelor and AR-C124910XX in healthy volunteers. As both agents have anti-platelet activity, it is important to consider whether such increases in the presence of cyclosporine may affect the safety of ticagrelor. However, coadministration of ticagrelor and cyclosporine was generally well tolerated in the healthy male volunteers who participated in this study. Only one volunteer discontinued from the study because of an AE (vomiting after administration of cyclosporine alone). All AEs except one were mild in severity, no serious AEs were reported, and the overall AE profile was consistent with that reported in other ticagrelor studies in healthy volunteers [3–6]. Evidence from studies in patients indicates that the magnitude of cyclosporineassociated increases in ticagrelor exposure is unlikely to have a significant impact on patient safety. For example, in patients with atherosclerosis receiving 200 mg ticagrelor twice daily, a near 200 % increase in exposure to both ticagrelor and AR-C124910XX relative to patients
Ticagrelor and Cyclosporine Drug–Drug Interaction Study
receiving ticagrelor 100 mg twice daily was associated with only a slight increase in minor bleeding events [32]. Further, at 4 h post-dose, 100, 200 and 400 mg twice daily ticagrelor doses produced a similar final-extent mean inhibition of platelet aggregation (IPA) of approximately 90–95 % [32]. Similar rates of total bleeding events were also observed in patients with ACS treated with ticagrelor 90 mg twice daily and 180 mg twice daily, despite a 180 % increase in ticagrelor exposure with the latter regimen [33]. Additionally, a 200 % increase in exposure to ticagrelor and AR-C124910XX following a 180 mg dose of ticagrelor would be unlikely to exceed the plasma concentrations observed following administration of the maximum tolerated dose of ticagrelor (900 mg) [4]. Finally, in the present study, the magnitude of increased exposure to ticagrelor following cyclosporine co-administration was comparable to that observed with the moderate CYP3A4 inhibitor diltiazem [27], approximately doubling the AUC? of ticagrelor. These data collectively suggest that increased ticagrelor exposure following concomitant administration with a CYP3A inhibitor would not result in a clinically relevant increase in IPA. Therefore, changes in ticagrelor pharmacokinetic parameters observed with co-administration of cyclosporine are unlikely to be of sufficient magnitude to require modification of the ticagrelor dose. Although cyclosporine is a substrate of CYP3A [17, 18, 30], the pharmacokinetics of cyclosporine were not affected by co-administration of ticagrelor, which is consistent with previous findings that ticagrelor is only a weak CYP3A inhibitor [11]. A limitation of this study is that a single high dose of cyclosporine was used in an all-male population; therefore, it is not possible to fully evaluate the potential inhibition effect on CYP3A by ticagrelor. In addition, cyclosporine is a lifelong treatment for patients who have undergone transplantation, and therefore a multiple-dose study that reflects real life is needed to confirm the findings of the current assessment. Nonetheless, this study provides important evidence for clinicians regarding co-administration of ticagrelor and cyclosporine. In conclusion, co-administration of cyclosporine with ticagrelor increased exposure to ticagrelor and its metabolite and there was no effect on cyclosporine pharmacokinetics. Ticagrelor and cyclosporine were generally well tolerated in this male healthy volunteer study population and these findings contribute to the comprehensive body of information on the pharmacokinetic, safety and tolerability profile of ticagrelor. Acknowledgments All authors are employees of AstraZeneca, who funded this study. The authors thank the principal investigator, Dr. K Craven (Quintiles Phase I Unit, Overland Park, KS, USA) and her team. Colleagues at Clinical Pharmacology & DMPK, and those at York Bioanalytical Solutions, are acknowledged for their contribution to the pharmacokinetic analyses. Medical assistance was provided by
Glenn Carlson (AstraZeneca, Wilmington, DE, USA). Statistical support was provided by Jack Jenkins (Quintiles Phase I Unit). We also thank Rick Flemming and Jackie Phillipson (Gardiner-Caldwell Communications) who provided medical writing support funded by AstraZeneca.
References 1. Husted S. Evaluating the risk-benefit profile of the direct-acting P2Y(12) inhibitor ticagrelor in acute coronary syndromes. Postgrad Med. 2011;123(6):79–90. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57. 3. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol. 2010;70(1):65–77. 4. Teng R, Butler K. Safety, tolerability, pharmacokinetics and pharmacodynamics of high single ascending doses of ticagrelor in healthy volunteers. Int J Clin Pharmacol Ther. 2013;51(10):795–806. 5. Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol. 2010;66(5):487–96. 6. Teng R, Oliver S, Hayes M, et al. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos. 2010;38(5):1514–21. 7. Teng R, Butler K. Comparison of the pharmacokinetics, pharmacodynamics and tolerability of single and multiple doses of ticagrelor in healthy Japanese and Caucasian volunteers. Int J Clin Pharmacol Ther. 2014 [Epub ahead of print]. 8. Zhou D, Andersson TB, Grimm SW. In vitro evaluation of potential drug–drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction and differential kinetics. Drug Metab Dispos. 2011;39(4):703–10. 9. European Medicines Agency assessment report: ticagrelor (procedure no. EMEA/H/C/1241). http://www.ema.europa.eu/docs/en_ GB/document_library/EPAR_-_Public_assessment_report/human/ 001241/WC500100492.pdf. Accessed 10 April 2014. 10. Summary of product characteristics: Brilique. http://www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001241/WC500100494.pdf. Accessed 10 April 2014. 11. Teng R, Butler K. The effect of ticagrelor on the metabolism of midazolam in healthy volunteers. Clin Ther. 2013;35(7):1025–37. 12. 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(9):477–87. 13. Teng R, Butler K. A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers. Eur J Clin Pharmacol. 2013;69(10):1801–8. 14. Colombo D, Ammirati E. Cyclosporine in transplantation—a history of converging timelines. J Biol Regul Homeost Agents. 2011;25(4):493–504. 15. Dehesa L, Abuchar A, Nuno-Gonazalez A, Vitiello M, Kerdel FA. The use of cyclosporine in dermatology. J Drugs Dermatol. 2012;11(8):979–87. 16. Gremese E, Ferraccioli GF. Benefit/risk of cyclosporine in rheumatoid arthritis. Clin Exp Rheumatol. 2004;22(5 Suppl 35):S101–7. 17. Kusuhara H, Sugiyama Y. Drug–drug interactions involving the membrane transport process. In: Rodrigues AD, editor. Drug– drug interactions. New York: Marcel Dekker; 2001. p. 123–88.
R. Teng et al. 18. Krishna R, Bergman A, Larson P, et al. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol. 2007;47(2):165–74. 19. Kumar A, Cannon CP. Acute coronary syndromes: diagnosis and management. Mayo Clin Proc. 2009;84(10):917–38. 20. Taneva E, Bogdanova V, Shtereva N. Acute coronary syndrome, comorbidity, and mortality in geriatric patients. Ann N Y Acad Sci. 2004;1019:106–10. 21. Kasiske BL, Maclean JR, Snyder JJ. Acute myocardial infarction and kidney transplantation. J Am Soc Nephrol. 2006;17(3):900–7. 22. Boehncke WH, Boehncke S. Cardiovascular mortality in psoriasis and psoriatic arthritis: epidemiology, pathomechanisms, therapeutic implications, and perspectives. Curr Rheumatol Rep. 2012;14(4):343–8. 23. Charles-Schoeman C. Cardiovascular disease and rheumatoid arthritis: an update. Curr Rheumatol Rep. 2012;14(5):455–62. 24. Xu T, Zhang YH. Association of psoriasis with stroke and myocardial infarction: meta-analysis of cohort studies. Br J Dermatol. 2012;167(6):1345–50. 25. Sakuma T, Kawasaki Y, Jarukamjorn K, Nemoto N. Sex differences of drug-metabolizing enzyme: female predominant expression of human and mouse cytochrome P450 3A isoforms. J Health Sci. 2009;55(3):325–37. 26. Sille´n H, Cook M, Davis P. Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B. 2010;878(25):2299–306. 27. Teng R, Butler K. Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers. J Drug Assess. 2013;2:30–9.
28. von Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivisto KT. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004;75(3):172–83. 29. Glaeser H. Importance of P-glycoprotein for drug–drug interactions. Handb Exp Pharmacol. 2011;201:285–97. 30. FDA. Guidance for industry. Drug interaction studies—study design, data analysis, implications for dosing, and labelling recommendations. Draft guidance. Food and Drug Administration, February 2012. http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/ucm292362.pdf. Accessed 06 Feb 2014. 31. Elsby R, Hilgendorf C, Fenner K. Understanding the critical disposition pathway of statins to assess drug–drug interaction risk during drug development: it’s just about OATP1B1. Clin Pharmacol Ther. 2012;95(5):584–98. 32. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27(9):1038–47. 33. Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007;50(19):1852–6.
