Sunitinib in combination with clarithromycin or azithromycin – is there a risk of interaction or not?

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Sunitinib in combination with clarithromycin or azithromycin – is there a risk of interaction or not?

Edyta Sza³ek¹, Agnieszka Karbownik¹, Wojciech Po³om², Marcin

Matuszewski², Katarzyna Sobañska¹, Hanna Urjasz¹, Tomasz Grabowski³, Anna Wolc⁴, Edmund Grzeœkowiak¹

1Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences, Œw. Marii Magdaleny 14, PL 61-861 Poznañ, Poland

2Department of Urology, University Clinical Centre, Kliniczna 1a, PL 80-402 Gdañsk, Poland

3Polpharma Biologics, Trzy lipy 3, PL 80-172 Gdañsk, Poland

4Department of Genetics and Animal Breeding, Poznan University of Life Sciences, Wo³yñska 33, PL 60-637 Poznañ, Poland

Correspondence: Edyta Sza³ek, e-mail: szalekedyta@wp.pl

Abstract:

Background: Macrolides are the most widely prescribed antibiotics. Clarithromycin is a well-known inhibitor of cytochrome P450 CYP3A4 and causes numerous drug interactions that are not found for azithromycin. CYP3A4 is involved in the metabolism of the new oral multikinase inhibitor sunitinib and its active N-desethyl metabolite (SU012662). This study investigated the effects of oral single dose of clarithromycin or azithromycin on the pharmacokinetics of sunitinib.

Methods: Rabbits were subjected to one of three study drug groups: sunitinib + clarithromycin (n = 6), sunitinib + azithromycin (n = 6), or sunitinib (n = 6). The rabbits were treated with sunitinib in the oral dose of 25 mg. Plasma concentrations of sunitinib were measured with validated HPLC method with UV detection.

Results: Comparison of the sunitinib C_maxfor the sunitinib + clarithromycin group with that of the sunitinib group gave a ratio of 94.4% [90% confidence interval (CI) (76.1, 117.1)]; for the sunitinib + azithromycin group, the ratio was 106.2% (90% CI 85.5, 131.7). Comparison of the sunitinib AUC_0-tof the sunitinib + clarithromycin and sunitinib + azithromycin groups with that of the sunitinib group showed ratios of 86.86% (90% CI 69.7, 108.3) and 99.8% (90% CI 80.1, 124.5), respectively.

Conclusions: No significant effect of the coadministration of clarithromycin or azithromycin on the pharmacokinetics of sunitinib in rabbits was found in this study.

Key words:

sunitinib, azithromycin, clarithromycin, interaction, pharmacokinetics, rabbits

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Introduction

Sunitinib and its active N-desethyl metabolite (SU012- 662) are oral multikinase inhibitors that block vascular endothelial growth factor receptors (VEGFRs-1, -2, and -3), platelet-derived growth factor receptors (PDGFRs-a and -b) [4, 21], stem cell factor receptor (KIT), FMS- like tyrosine kinase 3 (FLT-3), colony-stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neuro- trophic factor receptor [20]. Sunitinib is approved for the treatment of advanced renal cell carcinoma (RCC), imatinib-refractory gastrointestinal stromal tumor (GIST), and advanced pancreatic neuroendocrine tumors [22].

Sunitinib is extensively metabolized in all species.

SU012662 is the major circulating metabolite [22] in mice, rats, monkeys, rabbits and humans [8, 20, 23]. The active metabolite is also metabolized by cytochrome P4503A4 [13]. N-desethylsunitinib and sunitinib repre- sent total active drug exposure [13, 24]. The half-life of sunitinib and its main metabolite are 40–60 h and 80–110 h, respectively. Steady state is achieved after 10–14 days, but no significant changes in pharmacokinetics are observed between repeated and single dosing.

Sunitinib and its metabolites are excreted with feces and less than 16% with urine [12, 13, 25]. Sunitinib is char- acterized by linear pharmacokinetics at doses of 50–150 mg/day [3]. The minimum concentration at steady state ranging between 50– 100 ng/ml determines the pharmacological activity [1].

Sunitinib and its metabolite SU012662 have not revealed clinically important drug-drug interactions so far [12], but the influence of concomitantly administered drugs (potential inducers or inhibitors of CYP3A4) on the metabolism of the multikinase inhibitor may determine subtherapeutic or toxic levels of both substances [5, 10]. Macrolides may be divided into three groups according to their affinity for CYP3A4, which determines the possibility of pharmacokinetic drug interactions. Erythromycin and its prodrugs (group 1) inhibit drug metabolism and may produce drug interactions and increased risk of ad- verse effects. Group 2 (e.g., clarithromycin) rarely causes interactions. Azithromycin belongs to group 3 and does not inactivate CYP3A4 [6, 26, 31, 32].

Usage of sunitinib is now increased, and therefore, it is important to know whether the two widely used macrolides influence on the concentrations and pharmacokinetic of the kinase inhibitor. The current study was conducted to investigate the effect of clarithromy-

cin and azithromycin on the pharmacokinetics of sunitinib. We performed a National Library of Medicine’s bibliographic database (MEDLINE^®) search and found no evidence in the literature regarding the effects of these macrolides on the pharmacokinetics of sunitinib.

Materials and Methods

Reagents

Sunitinib was purchased from LGC Standards (£omianki, Poland), HPLC grade acetonitrile, ammonium acetate and acetic acid were from Sigma-Aldrich and metha- nol from Merck. Water used in the mobile phase was deionized, destilled and filtered through a Milipore system before use. Sutent^® was purchased (batch number P177H) from Pfizer Trading Polska Sp. z o.o., Warszawa, Poland.

Animals

Adult New Zealand male rabbits, weighing 2.7–4.7 kg, were used for experiments. All the rabbits were kept in individual metal cages located in the animal labora- tory of the University of Medical Sciences, Depart- ment and Unit of Clinical Pharmacy and Biophar- macy. They were acclimatized for two weeks prior to the experiments and were maintained under standard conditions of temperature (23 ± 2°C) and humidity (56–60%) with an alternating 12 h light/dark cycles.

New Zealand Rabbits were provided with 100 g of commercial pelleted diet (Labofeed KB^®: 9.8 MJ/kg metabolic energy, 16.00% total protein, 0.65% vitamin P, 15,000 IU vitamin A, 1500 IU vitamin D₃, and 65 mg vitamin E) and tap water ad libitum. All ex- perimental procedures related to this study were approved by the Local Ethics Committee of Poznañ University of Medical Sciences.

Evaluation of sunitinib pharmacokinetics

The rabbits were divided into three groups (6 animals in each): the rabbits receiving sunitinib and clarithromycin, the rabbits receiving sunitinib and azithromycin and the rabbits receiving sunitinib. Clarithromycin (Klacid^®250 mg/5 ml; Abbott, Warszawa, Poland) as a suspension was administered po at the dose of 30 mg/kg

Sunitinib in combination with clarithromycin or azithromycin

Edyta Sza³ek et al.

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ing the antibiotic, sunitinib (Sutent^® 25 mg) was ad- ministered po at the single dose of 25 mg (suspended in 10 ml of normal saline).

The measurement of sunitinib concentration in the blood plasma was made by means of the HPLC (high-performance liquid chromatography) method with UV detection, which was a modification of the method developed by Etienne-Grimaldi et al. [7].

Separation was achieved by isocratic elution of the mobile phase, ammonium acetate 20 mM pH 3.4 (ad- justed with acetic acid) – acetonitrile (60:40, v/v), at a flow rate of 1.0 ml/min through a Symmetry^®C8 column (250 mm × 4.6 mm, 5.0 µm particle size) (Waters). The column temperature was maintained at 40°C, the UV detection wavelength was set at 431 nm, and the injection volume was 50 µl. The total analysis time for each run was 6 min. The lower limit of quanti- fication (LLOQ) and limit of detection (LOD) for sunitinib were 1.0 ng/ml and 0.5 ng/ml. Intra- and inter-day precision and accuracy of the low quality control (5.0 ng/ml), medium quality control (50.0 ng/

ml), and high quality control (200.0 ng/ml) were well within the acceptable limit of 10% coefficient of variation (CV%) for sunitinib. The calibration for sunitinib was linear in the range 2.5–200 ng/ml (r = 0.999).

Pharmacokinetics analysis

Pharmacokinetic parameters were estimated by non- compartmental methods using validated software (WinNonlin^® Professional Version 5.3; Pharsight^® Corp., USA). The following pharmacokinetic parameters were calculated for sunitinib: absorption rate constant (k_a), elimination rate constant (k_el), area under the plasma concentration-time curve from time zero to infinity (AUC_0inf), area under the plasma concentration-time curve from zero to the time of last measurable concentration (AUC_0t), half-life in elimination phase (t_1/2b), clearance (CL), volume of distribution (V_d), area under the first moment curve (AUMC_0t), mean residence time (MRT).

Statistical analysis

The effect of drug formulation was tested by one-way analysis of variance in PROC GLM of the SAS package (SAS In- stitute Inc. 2002–2003. The SAS System for Windows ver-

dence intervals were based on the difference of medians.

Results

All the data were expressed as the mean ± standard deviation (SD). The three analyzed groups under study did not differ significantly in body mass.

There was a wide intersubject variability in the pharmacokinetic parameters, as evidenced by the co- efficients of variation (CV%) (Tab. 1). The mean C_max was similar for both the sunitinib + clarithromycin and sunitinib groups (132.09 ± 82.87 and 135.11 ± 62.03, respectively; Tab. 1). However, the mean C_max of the sunitinib + azithromycin group tended to be higher (153.53 ± 54.70; Tab. 1). The comparison of the C_maxfor the sunitinib + clarithromycin group and that for the sunitinib group gave a ratio of 94.4%

(90% CI 76.1, 117.1). The comparison of the C_maxfor the sunitinib + azithromycin group and that for the sunitinib group gave a ratio of 106.2% (90% CI 85.6, 131.7). There were no significant differences between the analyzed groups (p = 0.8397).

The mean AUC_0-t was similar for sunitinib + clarithromycin and sunitinib + azithromycin and sunitinib groups (2821.75 ± 1698.93, 3720.46 ± 1791.43 and 3745.49 ± 1751.02, respectively; Tab. 1). The comparison of the AUC_0-t for the sunitinib + clarithromycin group and that for the sunitinib group gave a ratio of 86.9% (90% CI 69.7, 108.3). The comparison of the AUC_0-tfor the sunitinib + azithromycin group and that for the sunitinib group gave a ratio of 99.8% (90% CI 80.1, 124.5). There were no significant differences between the analyzed groups (p = 0.5914).

The mean t_maxwas similar for all the three groups.

The comparison of the difference for the sunitinib + clarithromycin group and that for the sunitinib group gave an estimated increase in t_maxof 1.0 h (90%

CI –1.2, 3.2). The comparison of difference for the sunitinib + azithromycin group and that for the sunitinib group gave an estimated increase in t_maxof 1.5 h (90% CI –0.7, 3.7).

The volume of distribution was comparable in the evaluated rabbit groups (p = 0.4447). No statistically significant differences were revealed for absorption

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Tab. 1. Plasma pharmacokinetic parameters for sunitinib following a single oral dose of sunitinib 25 mg

Pharmacokinetics parameters^a

I (n = 6)

II (n = 6)

III (n = 6)

Gmean ratio^b (90% CI)

I vs. II I vs. III II vs. III k_a(1/h) 0.129 ± 0.105

(81.5)

0.123 ± 0.018 (14.3)

0.055 ± 0.032 (58.0)

87.9 (55.9, 138.5)

135.2 (89.4, 204.6)

153.7 (94.2, 250.9) k_el(1/h) 0.039 ± 0.005

(13.3)

0.045 ± 0.010 (22.7)

0.037 ± 0.017 (45.8)

94.2 (82.9, 106.8)

106.1 (93.5, 120.4)

112.7 (99.3, 127.9) AUC_0–t

(ng ´ h/ml)

2821.75 ± 1698.93 (60.2)

3720.46 ± 1791.43 (48.2)

3745.49 ± 1751.02 (46.8)

87.0 (69.8, 108.5)

86.9 (69.7, 108.3)

99.8 (80.1, 124.5) AUC_0–¥

(ng ´ h/ml)

2810.87 ± 1264.43 (45.0)

4130.97 ± 2183 (52.9)

3324.9 ± 1905.37 (57.3)

86.3 (68.5, 108.6)

95.5 (75.8, 120.2)

110.6 (87.9, 139.3) t_1/2kel(h) 18.05 ± 2.61

(14.4)

15.83 ± 2.84 (18.0)

22.06 ± 8.68 (39.4)

106.2 (93.6, 120.5)

94.2 (83.1, 106.9)

88.7 (78.2, 100.7) Cl (ml/h) 11.36 ± 5.25

(46.2)

8.04 ± 3.57 (44.4)

8.05 ± 3.65 (45.3)

114.9 (92.2, 143.3)

115.1 (92.3, 143.5)

110.2 (80.3, 124.9) V_d(ml) 291.15 ± 138.93

(47.7)

184.50 ± 92.97 (50.4)

262.64 ± 190.21 (72.4)

122.1 (95.2, 156.4)

108.5 (84.7, 139.1)

88.9 (69.3, 113.9) C_max(mg/l) 132.09 ± 82.87

(62.7)

153.53 ± 54.70 (35.6)

135.11 ± 62.03 (45.9)

88.9 (71.6, 110.3)

94.4 (76.1, 117.1)

106.2 (85.6, 131.7) t_max(h) 8.0

(16.3)

8.5 (22.5)

7 (21.2)

–0.5 (–2.7, 1.7)

1.0 (–1.2, 3.2)

1.5 (–0.7, 3.7) MRT (h) 19.14 ± 4.86

(25.4)

22.44 ± 2.89 (12.9)

24.47 ± 6.28 (25.7)

92.4 (83.8, 1.02)

89.7 (81.3, 98.9)

97.0 (88.0, 107.0) AUMC_0–t

(ng ´ h²/ml)

52956.15

± 32784.02 (61.9)

84254.67

± 43786.28 (52.0)

98673.03

± 67000.26 (67.9)

80.41 (61.95, 104.38)

77.91 (60.02, 101.13)

96.88 (74.63, 125.76)

I – sunitinib + clarithromycin; II – sunitinib + azithromycin; III – sunitinib; CI – confidence interval; k_a– absorption rate constant; k_el– elimination rate constant; AUC_0t– area under the plasma concentration-time curve from zero to the time of last measurable concentration; AUC_0¥– area under the plasma concentration-time curve from zero to infinity; t_1/2kel– elimination half-life time; Cl – clearance; V_d– volume of distribution;

C_max– maximum observed plasma concentration; t_max– time to reach maximum concentration; MRT – mean residence time; AUMC_0t– area under the first moment curve.^aArithmetic means ± standard deviations (CV%) are presented, except for t_max, where medians (ranges) are presented.^bRatio of geometric means (Gmean) between groups (%) with the upper and lower bounds of a 90% confidence interval in the brackets, except for t_max, where median differences are presented

0 25 50 75 100 125 150 175 200

0 20 40 60 80 100

Time [h]

sunitinib + azithromycin sunitinib + clarithromycin sunitinib

Concentration[ng/ml]

Fig. 1. Sunitinib plasma concentration–time profiles following a single oral dose of sunitinib 25 mg in rabbits (arithmetic mean with standard deviation)

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(p = 0.2979) or elimination half-life (p = 0.1709).

The arithmetic mean concentrations of sunitinib in the blood plasma are shown in Figure 1.

Discussion

Macrolides are the most widely prescribed antibiotics because of their beneficial properties and immuno- modulatory activity. Macrolide antibiotics regulate damaging inflammation with increased mucus clearance, decreased bacterial virulence and they prevent biofilm formation [22]. The main disadvantage of antibacterial drugs, especially erythromycin and clarithromycin, is the fact that they cause numerous drug interactions [2, 11, 16, 19, 29, 30]. The inhibition of CYP3A4 may cause accumulation and toxicity of drugs requiring cytochrome P 450. In rabbits, CYP3A6 corresponds to CYP3A4 activity in human hepatocytes. The rabbit isoform CYP3A6 and the human isoform CYP3A4 have similar substrate specific- ity [17, 18, 27]. When macrolides are required, prefer- ential use of azithromycin should be considered, especially in geriatric patients receiving the drugs which are substrates for CYP3A4 [29]. Azithromycin has many advantages as an antibacterial. The azalide is safer during pregnancy, has a single daily dose regi- men and does not cause interactions found with clarithromycin [2, 28]. Because of the frequent use of macrolides for the treatment of common respiratory and skin infections, there is a wide possibility to asso- ciate this group of drugs in patients on sunitinib. For this reason it is important to check the pharmacokinetic consequences of coadministration of the afore- mentioned drugs, because in the summary of product characteristics we read that co-administration of sunitinib with potent CYP3A4 inhibitors should be avoided [15].

The results of this study show that coadministration of an oral suspension of clarithromycin or azithromycin has no significant effect on the pharmacokinetics of oral, single-dose sunitinib in healthy rabbits. When coadministered with clarithromycin, the mean sunitinib C_max and AUC_0-t were approxi- mately 2.2% and 24.7% lower, respectively, when compared with the administration of sunitinib only.

ministration of sunitinib only. These ratios and their associated 90% CIs did not suggest any clinically relevant effect on the sunitinib exposure. The obtained C_maxand AUC_0-tvalues correspond to the val- ues obtained by Patyna et al. (143 ng/ml and 2220 ng×h/ml, respectively), who administered sunitinib to rabbits at a dose of 5 mg/kg body weight [20]. In our research, the animals received a constant dose of 25 mg, i.e., from 5.3 to 9.3 mg/kg body weight. Also for the other pharmacokinetic parameters (k_a, k_el, t_1/2kel, V_d, Cl, MRT, AUMC_0-t) no statistically significant differences between the groups under analysis were observed. A limitation of the study is the lack of dosage per body mass, although it resulted from the fact that sunitinib is administered to patients in constant daily doses and the dose depends only on indi- vidually assessed safety and toleration [14, 15]. In the summary of product characteristics we can find the information that population pharmacokinetic analyses of demographic data indicate that no starting dose ad- justments are necessary for weight [15].

The data collected in this study indicate no significant effect of oral clarithromycin or azithromycin on the pharmacokinetic profile of sunitinib after single administration. However, other macrolides metabolized by the same pathway should be investigated.

Conclusion

No significant effect of the coadministration of clarithromycin or azithromycin on the pharmacokinetics of sunitinib in rabbits was found in this study.

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Received: February 3, 2012; in the revised form: August 30, 2012;

accepted: September 13, 2012.