Eur J Clin Pharmacol (2015) 71:15–23 DOI 10.1007/s00228-014-1767-x
CLINICAL TRIAL
Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist Martine Gehin & Patricia N. Sidharta & Carmela Gnerre & Alexander Treiber & Atef Halabi & Jasper Dingemanse
Received: 12 May 2014 / Accepted: 6 October 2014 / Published online: 18 October 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Setipiprant, a selective oral CRTH2 antagonist, has been investigated for the treatment of allergic rhinitis and asthma. In vitro data showed that setipiprant has a weak induction potential on CYP3A4. An interaction at the hepatic level between setipiprant and CYP3A4 substrates was not expected even at the dosing regimen of 1,000 mg setipiprant b.i.d. due to the high plasma protein binding. However, at this dosing regimen, interactions at the gut level could not be excluded. Methods In this single-center, open-label study, 40 mg of simvastatin was administered orally on Day 1, and then concomitantly with setipiprant on Day 10 following 9 days of setipiprant 1,000 mg b.i.d. to 22 healthy male subjects. Results In the presence of setipiprant, the simvastatin concentration–time profile was similar to that of simvastatin alone. The concentrations of simvastatin were, however, slightly lower, resulting in a 9 % decrease in Cmax (geometric mean ratio (GMR) 0.91, 90 % confidence interval (CI) (0.73, 1.13)) and in a 16 % lower AUC0–∞ (GMR 0.84, 90 % CI (0.72, 0.99)). Exposure to simvastatin acid was similar when comparing simvastatin with or without setipiprant. The GMR and 90 % CI for AUC0–∞ were within the 0.8 to 1.25 limits, Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1767-x) contains supplementary material, which is available to authorized users. M. Gehin (*) : P. N. Sidharta : J. Dingemanse Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland e-mail: [email protected] C. Gnerre : A. Treiber Department of DMPK, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland A. Halabi CRS, Kiel, Germany
whereas those for Cmax were outside (GMR 2.73, 90 % CI (2.11, 3.53)). Moreover, the median tmax of simvastatin acid occurred earlier (1.8 h) when combined compared to 3.0 h when administered alone. Conclusions As setipiprant has little impact on simvastatin pharmacokinetics, it does not modulate CYP3A4 in a clinically relevant manner. Keywords Setipiprant . CRTH2 . CYP3A4 . Drug-drug interaction study . Simvastatin . Simvastatin acid
Introduction CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) is a G-protein-coupled receptor expressed by Th2 lymphocytes, eosinophils, and basophils. The receptor mediates the activation and chemotaxis of these cell types in response to prostaglandin D2 (PGD2), the major prostanoid produced by mast cells [1–4]. Setipiprant (ACT-129968), an orally active, selective antagonist of CRTH2, was developed for the treatment of allergic diseases, such as allergic asthma [5, 6]. Its pharmacokinetic properties have been explored in early phase I studies [7–9]. After single- and multiple-dose administration, setipiprant was rapidly absorbed with a tmax of approximately 3 h, and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2–3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food [7]. Setipiprant is mainly excreted in feces (81.7 %) in the form of the parent drug (50 %) and in smaller amounts as its two main metabolites M7 and M9. The recovered amount of unchanged setipiprant in urine accounted for 3.7 % [9]. Cytochrome P450 (CYP) 3A4, the most abundant isoenzyme in the human liver and intestinal membranes, is
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Period B consisted of 1,000 mg setipiprant twice daily for 8 days (days 2–9). Period C consisted of concomitant administration of a single morning oral dose of 40 mg simvastatin combined with 1,000 mg setipiprant b.i.d. (Day 10). All drug administrations were done under direct medical supervision at the clinical research unit. After discharge on Day 2, the subjects visited the clinical research unit for the morning and evening intake of setipiprant. In the evening of Day 9, the subjects were admitted again to the clinical research unit until day 11. No study drug was administered after Day 10. Medications were taken in the morning after an overnight fast with 240 mL of water, and in the evening 2 h after finishing a light dinner. The interval between intakes of setipiprant was 12±0.5 h. On the morning of Day 10, simvastatin was administered 1 h after setipiprant. The intake of water was ad libitum except for 1 h before and up to 1 h after study drug administration. Setipiprant was administered as four capsules of 250 mg. Simvastatin was administered as one tablet of 40 mg simvastatin (Zocor® forte, Dieckmann Arzneimittel GmbH, Haar, Germany). The administration of simvastatin was followed by an observation period of 24 h.
responsible for the metabolism of approximately 50 % of all marketed drugs [10]. Pre-clinical experiments in human hepatocytes have shown that setipiprant has a weak induction potential on CYP3A4. A concentration of 10 μM setipiprant elicited an effect on CYP3A4 activity and mRNA of about 30 to 50 % of the effect caused by rifampicin at 10 μM. In the entry-into-man study [7], Cmax following setipiprant 1,000 mg b.i.d. at steady state was around 20 μM. This dosing regimen of 1,000 mg b.i.d. was shown to reduce both the allergeninduced late asthmatic response and the associated allergeninduced airway hyperresponsiveness in allergic asthmatics in a proof-of-mechanism study [11]. With the very high plasma protein binding of setipiprant (99.7 %), the resulting maximum free concentration should be around 60 nM. Therefore, a dosing regimen of 1,000 mg b.i.d. is unlikely to reach systemic free drug concentrations of 10 μM. Consequently, an interaction between setipiprant and CYP3A4 substrates is not expected in the liver. However, at 1,000 mg b.i.d., higher concentrations of free drug are present at the site of absorption, and an interaction of setipiprant on CYP3A4 cannot be excluded. Drugs with low bioavailability and high first-pass effect such as simvastatin could be affected [12]. The aim of this study was to evaluate the pharmacokinetic (PK) interaction between setipiprant and a CYP3A4dependent drug, simvastatin, in order to establish the potential clinical relevance of pre-clinical findings. Single oral doses of simvastatin, a CYP3A4 substrate considered as sensitive by the Food and Drug Administration (FDA) for this kind of study [12], was administered both alone and together with setipiprant at steady state to healthy male subjects.
Subjects The aim was to enroll 22 healthy male subjects in the study in order to have at least 18 evaluable subjects completing the study. Healthy males were eligible and enrolled if they were between 18 and 60 years of age with a body mass index (BMI) of 18–30 kg/m2 and in good health, based on a physical examination, 12-lead electrocardiogram (ECG) recordings, vital signs, and standard laboratory tests. Subjects with excessive caffeine consumption, a history of alcoholism or drug abuse, and any contraindication and/or hypersensitivity to simvastatin or to any excipients of the drug formulations, as well as smokers, were excluded. Drinking of alcoholic beverages or xanthine-containing beverages was not permitted from 48 h prior to the first clinic admission until the end-of-study (EOS) visit. No concomitant medication was allowed during the course of this study, except for the treatment of adverse events (AEs). All subjects gave written informed consent. The study was conducted in Germany in accordance with good
Methods Study design This was an open-label, multiple-dose setipiprant and singledose simvastatin phase I study conducted at a single center in Germany (Actelion trial ID: AC-060-103; EudraCT Number: 2010-023527-18). The study consisted of three periods (A, B, and C) (Fig. 1). In total, 22 healthy male subjects were recruited. Period A consisted of a single oral dose of 40 mg simvastatin on Day 1. Fig. 1 Study design. EOS: End of study
Screening
Period A
Period C
Period B
40 mg simvastatin
-21
-3 1
2
3
4
EOS
Follow-up
14 15 16
40
40 mg simvastatin 5
6
7
8
1000 mg setipiprant
9
10 11
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clinical practice and the Declaration of Helsinki and was approved by the local ethics committee (Ethikkommission Schleswig-Holstein) and the Medicines and the Federal Institute for Drugs and Medical Devices of Germany (BfArM). Pharmacokinetics Blood samples, 2.7 and 4 mL, were collected in EDTA tubes for the measurement of simvastatin/simvastatin acid (the active form of simvastatin) and setipiprant (trough samples only), respectively. PK samples were collected immediately prior to and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 h after study drug administration on Day 1, and immediately prior to and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 h after study drug administration on Day 10 to measure simvastatin and simvastatin acid. Morning setipiprant trough samples were collected on Days 3, 5, 7, 8, 9, and 11. For the quantification of setipiprant in plasma, two calibration ranges were validated. The low and high calibration ranges were 1 to 1,000 ng/mL and 20 to 20,000 ng/mL, respectively [7, 8]. Quantification of setipiprant was performed using a liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assay operating in the positive ionization detection mode. The inter-day coefficients of variation (CVs) were below 8.0 and 7.0 % and intra-assay CVs were below 13.7 and 9.8 %, for the low and high calibration range, respectively. The inter-assay accuracy for setipiprant was between 1.0 and 8.8 %. Plasma concentrations of simvastatin and simvastatin acid were determined using a validated LC-MS/MS method. The lower limit of quantification (LOQ) was 0.1 ng/mL for both simvastatin and simvastatin acid [13]. The inter-day CVs were 7.4 and 9.4 % and intra-assay CVs were 12.3 and 5.8 % for simvastatin and simvastatin acid, respectively. The inter-assay accuracy ranged from −5.1 to 0.7 % and from −6.5 to −4.7 % for simvastatin and simvastatin acid, respectively. The PK parameters of simvastatin and simvastatin acid were determined by noncompartmental analysis from the plasma concentration–time data using Phoenix WinNonlin software ver. 6.1 (Pharsight Corp, Mountain View, CA).
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The following PK parameters were summarized for periods A and C: Cmax, AUC0–∞, elimination half-life (t½), and time to reach Cmax (tmax). Trough concentrations were summarized for periods B and C. The differences between the two periods (with [C] and without [A] setipiprant at steady-state) for AUC0–∞, Cmax, and t½ were explored by calculating the ratios of the geometric means and their 90 % CIs with simvastatin alone as reference. Differences between periods for tmax were explored using the median difference and its 90 % CI. All calculations were performed in Statistical Analysis System (SAS®) software, version 9.2 (SAS Institute, Cary, NC, USA).
Results Demographics and baseline characteristics A total of 22 healthy male subjects were enrolled. All of them completed the study without any major deviation to the protocol and were therefore used for the PK analysis set. Subjects were on average 34.7±10.7 (± standard deviation (SD)) years of age (range 21–60 years) and had a mean BMI of 26.2±2.9 (range 20.8–29.8) kg/m2. Twenty-one subjects were White, one was Asian. Pharmacokinetics Trough setipiprant concentrations Visual inspection of the mean morning trough plasma concentrations of setipiprant measured during periods B and C indicated that apparent steady-state conditions were reached on Day 3 (Fig. 2). Mean trough setipiprant concentrations were approximately 1.6 μg/mL and high variability (CV 56–84 %)
Statistical analysis No formal statistical hypothesis was set for this study. Assuming a within-subject CVof 38 % for the area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) of simvastatin based on previously reported data [14, 15], it was estimated that, with a sample size of 18 evaluable subjects, the lower and upper bounds of the 90 % confidence interval (CI) for the true ratio of test (simvastatin plus setipiprant)/reference (simvastatin) would be within ±24 % for AUC0–∞. Therefore, the 90 % CI is approximately (0.81, 1.24) for AUC0–∞ if the ratio was 1.
Fig. 2 Mean trough concentrations of setipiprant (±SE). Setipiprant dosing regimen: 1,000 mg b.i.d. from Day 3 to Day 10 (n=22)
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was observed on all days of measurement. Single-dose administration of simvastatin on Day 10 did not appear to affect the morning trough concentration of setipiprant on Day 11. Effect of setipiprant on the PK of simvastatin and simvastatin acid The mean plasma concentration versus time profiles of simvastatin and simvastatin acid with and without setipiprant at steady state are shown in Fig. 3. A summary of the PK parameters of simvastatin and simvastatin acid and the statistical analysis results is presented in Table 1. In the absence of setipiprant (period A), the plasma concentration–time profile of simvastatin on Day 1 was characterized by a median tmax occurring 1.0 h after drug administration. Between 1 and 8 h after dosing, simvastatin concentrations decreased by approximately 80 %. With respect to simvastatin, concomitant administration of simvastatin with setipiprant resulted in a similar shape of the plasma concentration–time profile although plasma concentrations were slightly lower in the presence of setipiprant. The geometric mean ratios and their 90 % CI for Cmax, AUC0–∞, and t½ are presented in Table 2. The CIs of these parameters were outside the (0.8 to 1.25) interval. tmax remained relatively constant. Analysis of the individual changes in simvastatin exposure due to setipiprant (Fig. 4) showed that the overall decrease in simvastatin AUC0–∞ and Cmax of 16 % and 9 %, respectively, was elicited by approximately 50 % of the subjects. In the absence of setipiprant (period A), the plasma concentration–time profile of simvastatin acid on Day 1 was characterized by a median tmax occurring 3.0 h after drug administration (Fig. 3). Between 1 and 8 h after dosing, simvastatin acid concentrations varied little, i.e., appeared plateau-like. In the presence of setipiprant (treatment C), the shape of the plasma concentration– time profile of simvastatin acid was markedly different when compared to period A with, most notably, a plateau phase at a higher level and of shorter duration. Simvastatin acid appeared more quickly in the systemic circulation (i.e., higher Cmax, shorter tmax). After attainment of Cmax, simvastatin acid plasma concentrations decreased more rapidly during treatment C when compared to treatment A, as evidenced by a shorter t½ (approximately 4.4 vs 5.9 h). Overall, the exposure to simvastatin acid (as based on AUC) was similar when comparing treatments A and C (Table 1). The geometric mean ratio and 90 % CI for AUC0–∞ were within the limits of 0.80 to 1.25 (Table 2), whereas those for Cmax and t½ were not within these limits. This was confirmed by the individual changes in simvastatin acid exposure due to setipiprant as presented in Fig. 4.
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Discussion In order to investigate the CYP3A4 induction potential of setipiprant, a CRTH2 antagonist, we conducted a drug-drug interaction study with single oral doses of simvastatin, which is a sensitive CYP3A4 model substrate. The choice of simvastatin as substrate of CYP3A4 for this study was based on one of Kato’s conclusions in his 2008 review [16]: The effect of a CYP3A4 inducer is inversely proportional to the value of FaFG (fraction absorbed × fraction escaping the gut clearance). Based on the FaFG values obtained for midazolam (0.504) and simvastatin (0.084) [17–19], simvastatin was selected as the most appropriate model substrate. Drug interactions with simvastatin leading to higher simvastatin exposure are associated with an enhanced risk of myopathy and potentially rhabdomyolysis, a severe form of myopathy with muscle breakdown leading to myoglobinuria, which may result in renal failure and death [20–23]. Simvastatin has a t½ of approximately 5 h in this study, and it is estimated that less than 5 % of a single oral dose reaches the systemic circulation as active HMG-CoA reductase inhibitor. Simvastatin is metabolized exclusively by CYP3A4. The drug is administered as lactone pro-drug and undergoes hydrolysis by esterases and paraoxonases in the liver, intestinal mucosa, and plasma to form the active open acid form [21, 24–26]. Simvastatin acid is metabolized by CYP3A4 and CYP2C8 and is also subject to glucuronidation [27]. In the present study, 1,000 mg setipiprant b.i.d. steady-state concentrations were in accordance with those reported previously and were reached within 1 day following the initiation of the twice daily dosing regimen [7]. Simvastatin, administered as a single oral dose, did not alter the mean trough concentrations of setipiprant. Setipiprant at steady-state slightly decreased the exposure to simvastatin. This slight decrease in exposure could theoretically be considered as a “net effect” of combined induction and inhibition of CYP3A4. However, considering that the capacity of setipiprant to inhibit CYP3A4 in vitro was even lower than its potential capacity to induce CYP3A4 (50 μΜ of setipiprant elicited 46 % inhibition of midazolam 1′-hydroxylation and 28 % of testosterone 6bhydroxylation), it is unlikely that a potential induction of CYP3A4 would be masked by an inhibitory effect. The approximately 16 % decrease in total exposure to simvastatin with setipiprant was consistent with the approximately 9 % decrease in t½ and Cmax, whereas median tmax remained relatively constant. The slight decrease in simvastatin exposure could theoretically be caused by a weak local induction of CYP3A4 in the gut or, although unlikely, by transient high concentrations of setipiprant in the portal vein during the hepatic first-pass. The PKs of simvastatin were overall affected only to a small extent by concomitant administration of setipiprant when compared to the effect on simvastatin and simvastatin acid AUC of potent inducers of CYP3A4 such as
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Fig. 3 Plasma simvastatin and simvastatin acid concentration versus time profiles (linear and semi-logarithmic scale). Data are presented as mean±SD (n=22)
rifampicin and carbamazepine (reduction of simvastatin AUC by 87 % and of simvastatin acid by 93 % [28], and by 75 and 82 % [29], respectively). In any case, these results suggest that setipiprant at steady-state does not modulate CYP3A4 in a clinically relevant manner.
The exposure to simvastatin acid remained constant in the presence of setipiprant. However, setipiprant markedly altered the shape of the plasma concentration–time profile of simvastatin acid. The PK analysis revealed an effect of setipiprant on the rate of simvastatin acid appearance in the systemic
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Table 1 Pharmacokinetic parameters of simvastatin and simvastatin acid with and without setipiprant (n=22) Simvastatin Parameter (unit) Cmax (ng/mL) tmax (h) AUC0–∞ (ng·h/mL) t½ (h) Cmax (ng/mL) tmax (h) AUC0–∞ (ng·h/mL) t½ (h)
Statistics
Period A
Period C
Geometric mean
7.84
7.13
95 % CI Median Min-max Geometric mean 95 % CI Geometric mean 95 % CI Geometric mean 95 % CI Median Min-Max Geometric mean 95 % CI Geometric mean 95 % CI
5.69, 10.80 1.00 0.5, 8.0 31.22 22.77, 42.81 5.01 4.152, 6.038 1.57 1.18, 2.11 3.00 0.5, 8.0 15.83 11.52, 21.76 5.92 5.06, 6.940
5.78, 8.79 1.50 0.5, 4.0 26.34 20.64, 33.62 4.58 3.50, 6.00 4.30 3.04, 6.08 1.75 1.0, 4.0 15.91 11.50, 22.00 4.44 3.07, 6.41
CI confidence interval
circulation indicated by the (higher Cmax (geometric mean increase of 2.7-fold, 90 % CI (2.1, 3.5)), the shorter tmax (median difference of −1.75 h, range (−3.00 to −0.75)), and a plateau phase of shorter duration). These results suggest that setipiprant might interact with a simvastatin acid transporter. It is well described that simvastatin and simvastatin acid are actively transported by the organic anion transporting polypeptide 1B1 (OATP1B1) transporter from plasma into hepatocytes and that simvastatin acid has a higher affinity for OATP1B1 than simvastatin [30, 31]. However, the fact that simvastatin and simvastatin acid do not present an increased overall exposure suggests that OATP1B1 is not involved in the interaction.
Table 2 Summary of main statistical analysis of the effect of setipiprant on PK parameters of simvastatin and simvastatin acid Substance
Cmax
t½
AUC0–∞
tmax (h)
Simvastatin
0.91 (0.73, 1.13) 2.73 (2.11, 3.54)
0.92 (0.71, 1.18) 0.75 (0.54, 1.03)
0.84 (0.72, 0.99) 0.96 (0.80, 1.16)
0.25 (−0.25 1.00) −1.75 (−3.00, −0.75)
Simvastatin acid
Data are geometric mean ratios (90 % CI), and for tmax the median of difference (min, max) (n=22). Comparison of setipiprant (1,000 mg b.i.d.) and simvastatin (40 mg) versus simvastatin (40 mg) alone; simvastatin alone was used as reference
The small intestine can limit the bioavailability of a drug not only by its local metabolism but also via active drug transport back into the lumen using efflux transporters located in the apical brush border membrane of the enterocyte such as P-glycoprotein (P-gp) or multidrug resistance 1 (MDR1), multidrug resistance-related protein 2 (MRP2), breast cancer resistance protein (BCRP) [32], or a transporter located in the basolateral membrane of the enterocyte: the organic cationic transporter (OCT) [33]. In contrast, uptake transporters such as peptide transporter 1 (PEPT1), OATP1A2, or OATP2B2 [34, 35] will facilitate the absorption. The modulation of the activity of such transporters might impact the bioavailability of orally administered drugs. The increased rate of simvastatin acid appearance in the systemic circulation would rather suggest the involvement of an active transporter at the gut level. Simvastatin acid has not been reported as a substrate of any intestinal transporter. However, the hypothesis of alterations in simvastatin acid PK in the presence of setipiprant might be explained by inhibition of an efflux transporter in intestinal epithelial cells. To fully explain the PK profile of simvastatin and simvastatin acid in the presence of setipiprant, the transporter would need to present a marked selectivity for simvastatin acid. Additional in vitro experiments might be needed to identify which of the cited transporters could be responsible for the modifications of simvastatin acid PK. The clinical relevance of the interaction observed with simvastatin acid is difficult to assess for several reasons. It is well established that the risk of myopathy/ rhabdomyolysis is simvastatin dose related. In a clinical trial, in patients treated with simvastatin, the incidence of myopathy was approximately 0.03, 0.08, and 0.61 % at 20, 40, and 80 mg/day, respectively [36], whereas it is also reported that simvastatin has dose-proportional PK up to 160 mg [37]. The results of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) [38] led to the update of the simvastatin product information [36] to include warnings about increased risk of myopathy in patients receiving the highest licensed dose (80 mg). However, it is not clear whether the risk of myopathy is associated with simvastatin, simvastatin acid, or their combined exposure. Moreover, myopathy risk is generally correlated with increased exposure to simvastatin/simvastatin acid, but it remains unclear whether this is linked to AUC and/or Cmax since in all described cases both parameters are modified in parallel. The interaction observed in the presence of setipiprant does modify neither the AUC of simvastatin lactone and acid forms, nor the Cmax of the lactone form to a clinically relevant extent. However, it leads to a 2.7-fold increase in Cmax of the acid form. Additional clinical studies would be needed to further characterize the observed drug-drug interaction. Since local
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Fig. 4 Individual change in exposure to simvastatin and simvastatin acid expressed as Cmax and AUC0–∞ due to setipiprant. Period A, 40 mg simvastatin; period C, 40 mg simvastatin +1,000 mg setipiprant
concentrations of setipiprant in the gastrointestinal tract are likely to be related to the observed effects, it would also be interesting to investigate whether the time interval between setipiprant and simvastatin administration can impact the extent of interaction observed with simvastatin acid [39]. In this study, simvastatin was administered 1 h after setipiprant aimed at maximizing the interaction. An inverted sequence of administration or even concomitant administration might reduce the extent of the interaction with the efflux transporter in the intestinal epithelial cells. Inhibition of the transporter could be missed if the window of simvastatin acid absorption is
small or it could be delayed. An inverted sequence of administration might also influence simvastatin exposure if the net effect observed was the result of both induction and inhibition of CYP3A4. In this hypothetical scenario, the potential maximum inhibition of CYP3A4 would occur later than in the actual design. It would result in a decrease of simvastatin bioavailability due to an increased first-pass effect, as well as in a delayed appearance of the faster elimination of simvastatin and simvastatin acid in the presence of setipiprant. To conclude, setipiprant does not appear to modulate CYP3A4 in a clinically relevant manner.
22 Conflict of interest M.G., P.N.S., A.H., C.G., A.T., and J.D. had support from Actelion Pharmaceuticals Ltd for the submitted work; M.G., P.N.S., C.G., A.T., and J.D. were full-time employees of Actelion Pharmaceuticals Ltd in the previous 4 years; A.H. was a full-time employee of CRS in the previous 4 years; no other relationships or activities that could appear to have influenced the submitted work.
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13.
14. Author contributions P.N.S., A.H., and J.D. gave substantial contributions to the design of the work; M.G., P.N.S., A.H., C.G., A.T., and J.D. gave substantial contributions to the acquisition, analysis, or interpretation of study data; M.G. drafted the manuscript; P.N.S., A.H., C.G., A.T., and J.D. reviewed it critically, and all authors gave final approval of the version to be published.
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16. 17.
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CLINICAL TRIAL
Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist Martine Gehin & Patricia N. Sidharta & Carmela Gnerre & Alexander Treiber & Atef Halabi & Jasper Dingemanse
Received: 12 May 2014 / Accepted: 6 October 2014 / Published online: 18 October 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Setipiprant, a selective oral CRTH2 antagonist, has been investigated for the treatment of allergic rhinitis and asthma. In vitro data showed that setipiprant has a weak induction potential on CYP3A4. An interaction at the hepatic level between setipiprant and CYP3A4 substrates was not expected even at the dosing regimen of 1,000 mg setipiprant b.i.d. due to the high plasma protein binding. However, at this dosing regimen, interactions at the gut level could not be excluded. Methods In this single-center, open-label study, 40 mg of simvastatin was administered orally on Day 1, and then concomitantly with setipiprant on Day 10 following 9 days of setipiprant 1,000 mg b.i.d. to 22 healthy male subjects. Results In the presence of setipiprant, the simvastatin concentration–time profile was similar to that of simvastatin alone. The concentrations of simvastatin were, however, slightly lower, resulting in a 9 % decrease in Cmax (geometric mean ratio (GMR) 0.91, 90 % confidence interval (CI) (0.73, 1.13)) and in a 16 % lower AUC0–∞ (GMR 0.84, 90 % CI (0.72, 0.99)). Exposure to simvastatin acid was similar when comparing simvastatin with or without setipiprant. The GMR and 90 % CI for AUC0–∞ were within the 0.8 to 1.25 limits, Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1767-x) contains supplementary material, which is available to authorized users. M. Gehin (*) : P. N. Sidharta : J. Dingemanse Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland e-mail: [email protected] C. Gnerre : A. Treiber Department of DMPK, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland A. Halabi CRS, Kiel, Germany
whereas those for Cmax were outside (GMR 2.73, 90 % CI (2.11, 3.53)). Moreover, the median tmax of simvastatin acid occurred earlier (1.8 h) when combined compared to 3.0 h when administered alone. Conclusions As setipiprant has little impact on simvastatin pharmacokinetics, it does not modulate CYP3A4 in a clinically relevant manner. Keywords Setipiprant . CRTH2 . CYP3A4 . Drug-drug interaction study . Simvastatin . Simvastatin acid
Introduction CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) is a G-protein-coupled receptor expressed by Th2 lymphocytes, eosinophils, and basophils. The receptor mediates the activation and chemotaxis of these cell types in response to prostaglandin D2 (PGD2), the major prostanoid produced by mast cells [1–4]. Setipiprant (ACT-129968), an orally active, selective antagonist of CRTH2, was developed for the treatment of allergic diseases, such as allergic asthma [5, 6]. Its pharmacokinetic properties have been explored in early phase I studies [7–9]. After single- and multiple-dose administration, setipiprant was rapidly absorbed with a tmax of approximately 3 h, and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2–3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food [7]. Setipiprant is mainly excreted in feces (81.7 %) in the form of the parent drug (50 %) and in smaller amounts as its two main metabolites M7 and M9. The recovered amount of unchanged setipiprant in urine accounted for 3.7 % [9]. Cytochrome P450 (CYP) 3A4, the most abundant isoenzyme in the human liver and intestinal membranes, is
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Period B consisted of 1,000 mg setipiprant twice daily for 8 days (days 2–9). Period C consisted of concomitant administration of a single morning oral dose of 40 mg simvastatin combined with 1,000 mg setipiprant b.i.d. (Day 10). All drug administrations were done under direct medical supervision at the clinical research unit. After discharge on Day 2, the subjects visited the clinical research unit for the morning and evening intake of setipiprant. In the evening of Day 9, the subjects were admitted again to the clinical research unit until day 11. No study drug was administered after Day 10. Medications were taken in the morning after an overnight fast with 240 mL of water, and in the evening 2 h after finishing a light dinner. The interval between intakes of setipiprant was 12±0.5 h. On the morning of Day 10, simvastatin was administered 1 h after setipiprant. The intake of water was ad libitum except for 1 h before and up to 1 h after study drug administration. Setipiprant was administered as four capsules of 250 mg. Simvastatin was administered as one tablet of 40 mg simvastatin (Zocor® forte, Dieckmann Arzneimittel GmbH, Haar, Germany). The administration of simvastatin was followed by an observation period of 24 h.
responsible for the metabolism of approximately 50 % of all marketed drugs [10]. Pre-clinical experiments in human hepatocytes have shown that setipiprant has a weak induction potential on CYP3A4. A concentration of 10 μM setipiprant elicited an effect on CYP3A4 activity and mRNA of about 30 to 50 % of the effect caused by rifampicin at 10 μM. In the entry-into-man study [7], Cmax following setipiprant 1,000 mg b.i.d. at steady state was around 20 μM. This dosing regimen of 1,000 mg b.i.d. was shown to reduce both the allergeninduced late asthmatic response and the associated allergeninduced airway hyperresponsiveness in allergic asthmatics in a proof-of-mechanism study [11]. With the very high plasma protein binding of setipiprant (99.7 %), the resulting maximum free concentration should be around 60 nM. Therefore, a dosing regimen of 1,000 mg b.i.d. is unlikely to reach systemic free drug concentrations of 10 μM. Consequently, an interaction between setipiprant and CYP3A4 substrates is not expected in the liver. However, at 1,000 mg b.i.d., higher concentrations of free drug are present at the site of absorption, and an interaction of setipiprant on CYP3A4 cannot be excluded. Drugs with low bioavailability and high first-pass effect such as simvastatin could be affected [12]. The aim of this study was to evaluate the pharmacokinetic (PK) interaction between setipiprant and a CYP3A4dependent drug, simvastatin, in order to establish the potential clinical relevance of pre-clinical findings. Single oral doses of simvastatin, a CYP3A4 substrate considered as sensitive by the Food and Drug Administration (FDA) for this kind of study [12], was administered both alone and together with setipiprant at steady state to healthy male subjects.
Subjects The aim was to enroll 22 healthy male subjects in the study in order to have at least 18 evaluable subjects completing the study. Healthy males were eligible and enrolled if they were between 18 and 60 years of age with a body mass index (BMI) of 18–30 kg/m2 and in good health, based on a physical examination, 12-lead electrocardiogram (ECG) recordings, vital signs, and standard laboratory tests. Subjects with excessive caffeine consumption, a history of alcoholism or drug abuse, and any contraindication and/or hypersensitivity to simvastatin or to any excipients of the drug formulations, as well as smokers, were excluded. Drinking of alcoholic beverages or xanthine-containing beverages was not permitted from 48 h prior to the first clinic admission until the end-of-study (EOS) visit. No concomitant medication was allowed during the course of this study, except for the treatment of adverse events (AEs). All subjects gave written informed consent. The study was conducted in Germany in accordance with good
Methods Study design This was an open-label, multiple-dose setipiprant and singledose simvastatin phase I study conducted at a single center in Germany (Actelion trial ID: AC-060-103; EudraCT Number: 2010-023527-18). The study consisted of three periods (A, B, and C) (Fig. 1). In total, 22 healthy male subjects were recruited. Period A consisted of a single oral dose of 40 mg simvastatin on Day 1. Fig. 1 Study design. EOS: End of study
Screening
Period A
Period C
Period B
40 mg simvastatin
-21
-3 1
2
3
4
EOS
Follow-up
14 15 16
40
40 mg simvastatin 5
6
7
8
1000 mg setipiprant
9
10 11
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clinical practice and the Declaration of Helsinki and was approved by the local ethics committee (Ethikkommission Schleswig-Holstein) and the Medicines and the Federal Institute for Drugs and Medical Devices of Germany (BfArM). Pharmacokinetics Blood samples, 2.7 and 4 mL, were collected in EDTA tubes for the measurement of simvastatin/simvastatin acid (the active form of simvastatin) and setipiprant (trough samples only), respectively. PK samples were collected immediately prior to and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 h after study drug administration on Day 1, and immediately prior to and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, and 24 h after study drug administration on Day 10 to measure simvastatin and simvastatin acid. Morning setipiprant trough samples were collected on Days 3, 5, 7, 8, 9, and 11. For the quantification of setipiprant in plasma, two calibration ranges were validated. The low and high calibration ranges were 1 to 1,000 ng/mL and 20 to 20,000 ng/mL, respectively [7, 8]. Quantification of setipiprant was performed using a liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assay operating in the positive ionization detection mode. The inter-day coefficients of variation (CVs) were below 8.0 and 7.0 % and intra-assay CVs were below 13.7 and 9.8 %, for the low and high calibration range, respectively. The inter-assay accuracy for setipiprant was between 1.0 and 8.8 %. Plasma concentrations of simvastatin and simvastatin acid were determined using a validated LC-MS/MS method. The lower limit of quantification (LOQ) was 0.1 ng/mL for both simvastatin and simvastatin acid [13]. The inter-day CVs were 7.4 and 9.4 % and intra-assay CVs were 12.3 and 5.8 % for simvastatin and simvastatin acid, respectively. The inter-assay accuracy ranged from −5.1 to 0.7 % and from −6.5 to −4.7 % for simvastatin and simvastatin acid, respectively. The PK parameters of simvastatin and simvastatin acid were determined by noncompartmental analysis from the plasma concentration–time data using Phoenix WinNonlin software ver. 6.1 (Pharsight Corp, Mountain View, CA).
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The following PK parameters were summarized for periods A and C: Cmax, AUC0–∞, elimination half-life (t½), and time to reach Cmax (tmax). Trough concentrations were summarized for periods B and C. The differences between the two periods (with [C] and without [A] setipiprant at steady-state) for AUC0–∞, Cmax, and t½ were explored by calculating the ratios of the geometric means and their 90 % CIs with simvastatin alone as reference. Differences between periods for tmax were explored using the median difference and its 90 % CI. All calculations were performed in Statistical Analysis System (SAS®) software, version 9.2 (SAS Institute, Cary, NC, USA).
Results Demographics and baseline characteristics A total of 22 healthy male subjects were enrolled. All of them completed the study without any major deviation to the protocol and were therefore used for the PK analysis set. Subjects were on average 34.7±10.7 (± standard deviation (SD)) years of age (range 21–60 years) and had a mean BMI of 26.2±2.9 (range 20.8–29.8) kg/m2. Twenty-one subjects were White, one was Asian. Pharmacokinetics Trough setipiprant concentrations Visual inspection of the mean morning trough plasma concentrations of setipiprant measured during periods B and C indicated that apparent steady-state conditions were reached on Day 3 (Fig. 2). Mean trough setipiprant concentrations were approximately 1.6 μg/mL and high variability (CV 56–84 %)
Statistical analysis No formal statistical hypothesis was set for this study. Assuming a within-subject CVof 38 % for the area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) of simvastatin based on previously reported data [14, 15], it was estimated that, with a sample size of 18 evaluable subjects, the lower and upper bounds of the 90 % confidence interval (CI) for the true ratio of test (simvastatin plus setipiprant)/reference (simvastatin) would be within ±24 % for AUC0–∞. Therefore, the 90 % CI is approximately (0.81, 1.24) for AUC0–∞ if the ratio was 1.
Fig. 2 Mean trough concentrations of setipiprant (±SE). Setipiprant dosing regimen: 1,000 mg b.i.d. from Day 3 to Day 10 (n=22)
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was observed on all days of measurement. Single-dose administration of simvastatin on Day 10 did not appear to affect the morning trough concentration of setipiprant on Day 11. Effect of setipiprant on the PK of simvastatin and simvastatin acid The mean plasma concentration versus time profiles of simvastatin and simvastatin acid with and without setipiprant at steady state are shown in Fig. 3. A summary of the PK parameters of simvastatin and simvastatin acid and the statistical analysis results is presented in Table 1. In the absence of setipiprant (period A), the plasma concentration–time profile of simvastatin on Day 1 was characterized by a median tmax occurring 1.0 h after drug administration. Between 1 and 8 h after dosing, simvastatin concentrations decreased by approximately 80 %. With respect to simvastatin, concomitant administration of simvastatin with setipiprant resulted in a similar shape of the plasma concentration–time profile although plasma concentrations were slightly lower in the presence of setipiprant. The geometric mean ratios and their 90 % CI for Cmax, AUC0–∞, and t½ are presented in Table 2. The CIs of these parameters were outside the (0.8 to 1.25) interval. tmax remained relatively constant. Analysis of the individual changes in simvastatin exposure due to setipiprant (Fig. 4) showed that the overall decrease in simvastatin AUC0–∞ and Cmax of 16 % and 9 %, respectively, was elicited by approximately 50 % of the subjects. In the absence of setipiprant (period A), the plasma concentration–time profile of simvastatin acid on Day 1 was characterized by a median tmax occurring 3.0 h after drug administration (Fig. 3). Between 1 and 8 h after dosing, simvastatin acid concentrations varied little, i.e., appeared plateau-like. In the presence of setipiprant (treatment C), the shape of the plasma concentration– time profile of simvastatin acid was markedly different when compared to period A with, most notably, a plateau phase at a higher level and of shorter duration. Simvastatin acid appeared more quickly in the systemic circulation (i.e., higher Cmax, shorter tmax). After attainment of Cmax, simvastatin acid plasma concentrations decreased more rapidly during treatment C when compared to treatment A, as evidenced by a shorter t½ (approximately 4.4 vs 5.9 h). Overall, the exposure to simvastatin acid (as based on AUC) was similar when comparing treatments A and C (Table 1). The geometric mean ratio and 90 % CI for AUC0–∞ were within the limits of 0.80 to 1.25 (Table 2), whereas those for Cmax and t½ were not within these limits. This was confirmed by the individual changes in simvastatin acid exposure due to setipiprant as presented in Fig. 4.
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Discussion In order to investigate the CYP3A4 induction potential of setipiprant, a CRTH2 antagonist, we conducted a drug-drug interaction study with single oral doses of simvastatin, which is a sensitive CYP3A4 model substrate. The choice of simvastatin as substrate of CYP3A4 for this study was based on one of Kato’s conclusions in his 2008 review [16]: The effect of a CYP3A4 inducer is inversely proportional to the value of FaFG (fraction absorbed × fraction escaping the gut clearance). Based on the FaFG values obtained for midazolam (0.504) and simvastatin (0.084) [17–19], simvastatin was selected as the most appropriate model substrate. Drug interactions with simvastatin leading to higher simvastatin exposure are associated with an enhanced risk of myopathy and potentially rhabdomyolysis, a severe form of myopathy with muscle breakdown leading to myoglobinuria, which may result in renal failure and death [20–23]. Simvastatin has a t½ of approximately 5 h in this study, and it is estimated that less than 5 % of a single oral dose reaches the systemic circulation as active HMG-CoA reductase inhibitor. Simvastatin is metabolized exclusively by CYP3A4. The drug is administered as lactone pro-drug and undergoes hydrolysis by esterases and paraoxonases in the liver, intestinal mucosa, and plasma to form the active open acid form [21, 24–26]. Simvastatin acid is metabolized by CYP3A4 and CYP2C8 and is also subject to glucuronidation [27]. In the present study, 1,000 mg setipiprant b.i.d. steady-state concentrations were in accordance with those reported previously and were reached within 1 day following the initiation of the twice daily dosing regimen [7]. Simvastatin, administered as a single oral dose, did not alter the mean trough concentrations of setipiprant. Setipiprant at steady-state slightly decreased the exposure to simvastatin. This slight decrease in exposure could theoretically be considered as a “net effect” of combined induction and inhibition of CYP3A4. However, considering that the capacity of setipiprant to inhibit CYP3A4 in vitro was even lower than its potential capacity to induce CYP3A4 (50 μΜ of setipiprant elicited 46 % inhibition of midazolam 1′-hydroxylation and 28 % of testosterone 6bhydroxylation), it is unlikely that a potential induction of CYP3A4 would be masked by an inhibitory effect. The approximately 16 % decrease in total exposure to simvastatin with setipiprant was consistent with the approximately 9 % decrease in t½ and Cmax, whereas median tmax remained relatively constant. The slight decrease in simvastatin exposure could theoretically be caused by a weak local induction of CYP3A4 in the gut or, although unlikely, by transient high concentrations of setipiprant in the portal vein during the hepatic first-pass. The PKs of simvastatin were overall affected only to a small extent by concomitant administration of setipiprant when compared to the effect on simvastatin and simvastatin acid AUC of potent inducers of CYP3A4 such as
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Fig. 3 Plasma simvastatin and simvastatin acid concentration versus time profiles (linear and semi-logarithmic scale). Data are presented as mean±SD (n=22)
rifampicin and carbamazepine (reduction of simvastatin AUC by 87 % and of simvastatin acid by 93 % [28], and by 75 and 82 % [29], respectively). In any case, these results suggest that setipiprant at steady-state does not modulate CYP3A4 in a clinically relevant manner.
The exposure to simvastatin acid remained constant in the presence of setipiprant. However, setipiprant markedly altered the shape of the plasma concentration–time profile of simvastatin acid. The PK analysis revealed an effect of setipiprant on the rate of simvastatin acid appearance in the systemic
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Table 1 Pharmacokinetic parameters of simvastatin and simvastatin acid with and without setipiprant (n=22) Simvastatin Parameter (unit) Cmax (ng/mL) tmax (h) AUC0–∞ (ng·h/mL) t½ (h) Cmax (ng/mL) tmax (h) AUC0–∞ (ng·h/mL) t½ (h)
Statistics
Period A
Period C
Geometric mean
7.84
7.13
95 % CI Median Min-max Geometric mean 95 % CI Geometric mean 95 % CI Geometric mean 95 % CI Median Min-Max Geometric mean 95 % CI Geometric mean 95 % CI
5.69, 10.80 1.00 0.5, 8.0 31.22 22.77, 42.81 5.01 4.152, 6.038 1.57 1.18, 2.11 3.00 0.5, 8.0 15.83 11.52, 21.76 5.92 5.06, 6.940
5.78, 8.79 1.50 0.5, 4.0 26.34 20.64, 33.62 4.58 3.50, 6.00 4.30 3.04, 6.08 1.75 1.0, 4.0 15.91 11.50, 22.00 4.44 3.07, 6.41
CI confidence interval
circulation indicated by the (higher Cmax (geometric mean increase of 2.7-fold, 90 % CI (2.1, 3.5)), the shorter tmax (median difference of −1.75 h, range (−3.00 to −0.75)), and a plateau phase of shorter duration). These results suggest that setipiprant might interact with a simvastatin acid transporter. It is well described that simvastatin and simvastatin acid are actively transported by the organic anion transporting polypeptide 1B1 (OATP1B1) transporter from plasma into hepatocytes and that simvastatin acid has a higher affinity for OATP1B1 than simvastatin [30, 31]. However, the fact that simvastatin and simvastatin acid do not present an increased overall exposure suggests that OATP1B1 is not involved in the interaction.
Table 2 Summary of main statistical analysis of the effect of setipiprant on PK parameters of simvastatin and simvastatin acid Substance
Cmax
t½
AUC0–∞
tmax (h)
Simvastatin
0.91 (0.73, 1.13) 2.73 (2.11, 3.54)
0.92 (0.71, 1.18) 0.75 (0.54, 1.03)
0.84 (0.72, 0.99) 0.96 (0.80, 1.16)
0.25 (−0.25 1.00) −1.75 (−3.00, −0.75)
Simvastatin acid
Data are geometric mean ratios (90 % CI), and for tmax the median of difference (min, max) (n=22). Comparison of setipiprant (1,000 mg b.i.d.) and simvastatin (40 mg) versus simvastatin (40 mg) alone; simvastatin alone was used as reference
The small intestine can limit the bioavailability of a drug not only by its local metabolism but also via active drug transport back into the lumen using efflux transporters located in the apical brush border membrane of the enterocyte such as P-glycoprotein (P-gp) or multidrug resistance 1 (MDR1), multidrug resistance-related protein 2 (MRP2), breast cancer resistance protein (BCRP) [32], or a transporter located in the basolateral membrane of the enterocyte: the organic cationic transporter (OCT) [33]. In contrast, uptake transporters such as peptide transporter 1 (PEPT1), OATP1A2, or OATP2B2 [34, 35] will facilitate the absorption. The modulation of the activity of such transporters might impact the bioavailability of orally administered drugs. The increased rate of simvastatin acid appearance in the systemic circulation would rather suggest the involvement of an active transporter at the gut level. Simvastatin acid has not been reported as a substrate of any intestinal transporter. However, the hypothesis of alterations in simvastatin acid PK in the presence of setipiprant might be explained by inhibition of an efflux transporter in intestinal epithelial cells. To fully explain the PK profile of simvastatin and simvastatin acid in the presence of setipiprant, the transporter would need to present a marked selectivity for simvastatin acid. Additional in vitro experiments might be needed to identify which of the cited transporters could be responsible for the modifications of simvastatin acid PK. The clinical relevance of the interaction observed with simvastatin acid is difficult to assess for several reasons. It is well established that the risk of myopathy/ rhabdomyolysis is simvastatin dose related. In a clinical trial, in patients treated with simvastatin, the incidence of myopathy was approximately 0.03, 0.08, and 0.61 % at 20, 40, and 80 mg/day, respectively [36], whereas it is also reported that simvastatin has dose-proportional PK up to 160 mg [37]. The results of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) [38] led to the update of the simvastatin product information [36] to include warnings about increased risk of myopathy in patients receiving the highest licensed dose (80 mg). However, it is not clear whether the risk of myopathy is associated with simvastatin, simvastatin acid, or their combined exposure. Moreover, myopathy risk is generally correlated with increased exposure to simvastatin/simvastatin acid, but it remains unclear whether this is linked to AUC and/or Cmax since in all described cases both parameters are modified in parallel. The interaction observed in the presence of setipiprant does modify neither the AUC of simvastatin lactone and acid forms, nor the Cmax of the lactone form to a clinically relevant extent. However, it leads to a 2.7-fold increase in Cmax of the acid form. Additional clinical studies would be needed to further characterize the observed drug-drug interaction. Since local
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Fig. 4 Individual change in exposure to simvastatin and simvastatin acid expressed as Cmax and AUC0–∞ due to setipiprant. Period A, 40 mg simvastatin; period C, 40 mg simvastatin +1,000 mg setipiprant
concentrations of setipiprant in the gastrointestinal tract are likely to be related to the observed effects, it would also be interesting to investigate whether the time interval between setipiprant and simvastatin administration can impact the extent of interaction observed with simvastatin acid [39]. In this study, simvastatin was administered 1 h after setipiprant aimed at maximizing the interaction. An inverted sequence of administration or even concomitant administration might reduce the extent of the interaction with the efflux transporter in the intestinal epithelial cells. Inhibition of the transporter could be missed if the window of simvastatin acid absorption is
small or it could be delayed. An inverted sequence of administration might also influence simvastatin exposure if the net effect observed was the result of both induction and inhibition of CYP3A4. In this hypothetical scenario, the potential maximum inhibition of CYP3A4 would occur later than in the actual design. It would result in a decrease of simvastatin bioavailability due to an increased first-pass effect, as well as in a delayed appearance of the faster elimination of simvastatin and simvastatin acid in the presence of setipiprant. To conclude, setipiprant does not appear to modulate CYP3A4 in a clinically relevant manner.
22 Conflict of interest M.G., P.N.S., A.H., C.G., A.T., and J.D. had support from Actelion Pharmaceuticals Ltd for the submitted work; M.G., P.N.S., C.G., A.T., and J.D. were full-time employees of Actelion Pharmaceuticals Ltd in the previous 4 years; A.H. was a full-time employee of CRS in the previous 4 years; no other relationships or activities that could appear to have influenced the submitted work.
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13.
14. Author contributions P.N.S., A.H., and J.D. gave substantial contributions to the design of the work; M.G., P.N.S., A.H., C.G., A.T., and J.D. gave substantial contributions to the acquisition, analysis, or interpretation of study data; M.G. drafted the manuscript; P.N.S., A.H., C.G., A.T., and J.D. reviewed it critically, and all authors gave final approval of the version to be published.
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16. 17.
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