Pharmacokinetics of garenoxacin in elderly patients with respiratory tract infections

International Journal of Antimicrobial Agents 35 (2010) 603–605

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Pharmacokinetics of garenoxacin in elderly patients with respiratory tract infections Yoshinobu Ohsaki a,∗ , Kazutoyo Morita b , Hiroki Takeda c , Satoshi Kishino d , Shunsuke Okumura a , Satoru Fujiuchi e a

Respiratory Center, Asahikawa Medical College, 2-1-1-1 Midorigaoka Higashi, Asahikawa, Hokkaido 078-8510, Japan Shibetsu City Hospital, Shibetsu, Japan Asahikawa Yoshida Hospital, Asahikawa, Japan d Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Tokyo, Japan e Department of Clinical Research, National Hospital Organization, Dohoku Hospital, Asahikawa, Japan b c

a r t i c l e

i n f o

Article history: Received 22 December 2009 Accepted 12 January 2010 Keywords: Garenoxacin Pharmacokinetics/pharmacodynamics Elderly patients Respiratory tract infection

a b s t r a c t The pharmacokinetics of the new oral des-fluoroquinolone antimicrobial garenoxacin (GRNX) was investigated in elderly patients with respiratory tract infections. Patients were treated with GRNX (200 mg or 400 mg) once daily for 7 days. Plasma GRNX concentrations were determined and pharmacokinetic parameters were estimated by Bayesian predictions using reported population pharmacokinetic parameters. At each dose, the maximum plasma concentration (Cmax ) and the area under the concentration–time curve (AUC) were comparable with those reported in young subjects, except that the estimated Cmax and AUC values in one patient receiving the 200 mg dose whose body weight and creatinine clearance rate (CLCr ) were 38 kg and 17 mL/min, respectively, were higher than those of the other patients given 200 mg GRNX and were comparable with those of patients who received the 400 mg dose. These results suggest that the recommended dose of GRNX should be 400 mg for most elderly and young patients, but only 200 mg in patients whose body weight and CLCr are <40 kg and <30 mL/min, respectively. © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Community-acquired pneumonia (CAP) is a common respiratory illness that is frequently life threatening in elderly patients. Treatment of lower respiratory infections, particularly CAP, often includes the use of the newer respiratory fluoroquinolones [1]. It has been demonstrated that the relationship between drug exposure and the minimum inhibitory concentration (MIC) for an infective organism is predictive of microbiological eradication [2]. It has also been reported that the ratio between the area under the concentration–time curve (AUC) and the MIC for fluoroquinolones correlates with optimal clinical and microbiological outcomes in patients infected with Gram-positive and Gramnegative pathogens [2–4]. Garenoxacin (GRNX) is a novel des-fluoro(6)-quinolone that exhibits dual activity against DNA gyrase and topoisomerase and has activity against a wide range of clinically important pathogens. GRNX shows potent activity against Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, which often cause respiratory and

∗ Corresponding author. Tel.: +81 166 69 3290; fax: +81 166 69 3299. E-mail address: [email protected] (Y. Ohsaki).

otorhinolaryngological infections [5–7]. In clinical studies, the efficacy of GRNX ranged from 92% to 96% in patients with bacterial pneumonia, mycoplasma pneumonia, chlamydial pneumonia and acute bronchitis [7]. The pharmacokinetics of GRNX is proportional to its dose. GRNX is eliminated by renal excretion and hepatic metabolism, with ca. 40–50% of the dose excreted in the urine unchanged [7–9]. A GRNX dosage of 400 mg once daily was determined appropriate for clinical use [7]. Hepatic and renal function can be affected by age, especially in elderly patients. Unfortunately, the optimal dosage of GRNX for elderly patients has not been investigated in detail. In this study, the pharmacokinetics of GRNX in elderly patients with respiratory tract infections (RTIs) was examined. 2. Materials and methods GRNX (Astellas Pharma Inc., Tokyo, Japan), 200 mg or 400 mg, was administered once daily to 10 elderly (≥65 years of age) patients with RTIs. Blood was collected 2, 4 and 24 h after administration on Days 1 and 4–5. The plasma concentration of GRNX was measured by high-performance liquid chromatography (HPLC) [10]. The maximum plasma concentration (Cmax ), drug clearance (CL) and AUC at steady state were estimated by Bayesian predictions using reported population pharmacokinetic parameters

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Y. Ohsaki et al. / International Journal of Antimicrobial Agents 35 (2010) 603–605

Table 1 Demographic characteristics of the study patients. Characteristic

N

Mean ± S.D.

Age (years)

10

80.5 ± 8.0

65–94

51.9 ± 13.6

38–85

± ± ± ± ± ± ± ± ± ±

8–34 8–33 160–294 7–52 0.28–0.71 5.1–7.6 1.9–3.1 7.8–28.9 0.30–1.20 17–136

Sex Male Female

Range

5 5

Body weight (kg)

10

GRNX dose 200 mg 400 mg

8 2

Infection Pneumonia Acute bronchial pneumonia Respiratory tract infection

8 1 1

Clinical laboratory test results AST ALT ALP ␥-GPT Total bilirubin Total protein Albumin BUN Serum creatinine CLCr

10 10 6 6 6 10 6 10 10 10

18 16 230 27 0.48 6.2 2.7 15.7 0.64 74

7 7 47 18 0.18 0.8 0.4 7.1 0.29 34

S.D., standard deviation; GRNX, garenoxacin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; ␥-GTP, ␥-glutamyl transpeptidase; BUN, blood urea nitrogen; CLCr , creatinine clearance.

[11]. Hepatic and renal functions were assessed by aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, ␥-glutamyl transpeptidase, total bilirubin, total protein, serum creatinine and blood urea nitrogen before initiation of GRNX therapy. Creatinine clearance (CLCr ) was calculated using the Cockcroft–Gault equation [12]. Witten informed consent was obtained from each patient before initiation of any study-related procedures. 3. Results 3.1. Patient characteristics Five males and five females participated in and completed the study. Their demographic characteristics are summarised in Table 1. Their mean age was 80.5 years (range 65–94 years). Although marked individual differences in renal function were observed, there were no patients with severe impairment of

Fig. 1. Typical pharmacokinetic profile following oral doses of 200 mg or 400 mg of garenoxacin (GRNX): (a) 200 mg or (b) 400 mg of GRNX was administered once daily to Patients 1 and 6, respectively. Open circles show observed plasma concentrations.

hepatic function. Eight patients were administered 200 mg GRNX once daily and two patients were administered 400 mg once daily. 3.2. Pharmacokinetics A typical pharmacokinetic profile, estimated using a Bayesian prediction following an oral dose of 200 mg or 400 mg, is presented in Fig. 1. The predicted pharmacokinetic profiles fit the observed GRNX concentrations well in all patients (data not shown). Three predicted pharmacokinetic parameters (CL, Cmax and AUC) are summarised in Table 2. In each dose group, there were no marked differences in CL, Cmax and AUC between patients, except that Patient 7 had estimated Cmax and AUC values higher than the rest of the 200 mg dose group. Patient 7 had a lower body weight and CLCr than the other members of the group (38 kg and 17 mL/min, respectively). The mean CL value in the 200 mg dose group was comparable with that in the 400 mg dose group, and the mean Cmax

Table 2 Pharmacokinetic parameters estimated by Bayesian predictions. Dose (mg)

Patient No.

Sex

Age (years)

Body weight (kg)

CL (mL/min)

Cmax (␮g/mL)

AUC (␮g h/mL)

200

1 2 3 4 5 6 7 8

Male Female Male Male Male Female Female Female

77 87 78 65 75 79 94 84

41.0 48.6 48.1 52.0 64.6 45.4 38.0 48.2

42 89 68 77 61 54 17 89

50.7 58.9 58.4 62.8 71.7 61.3 32.6 40.3

4.50 4.58 3.96 4.14 3.25 4.65 6.27 5.38

66 57 57 53 47 54 102 83

Mean ± S.D.

–

79.9 ± 8.7

48.2 ± 8.0

62.1 ± 24.5

54.6 ± 12.8

4.59 ± 0.91

65 ± 19

9 10

Male Female

79 87

48.0 85.0

136 106

64.0 50.8

7.87 7.78

104 131

Mean

–

83

66.5

121

57.4

7.83

118

400

CLCr (mL/min)

S.D., standard deviation; CLCr , creatinine clearance; CL, clearance; Cmax , maximum plasma concentration; AUC, area under the concentration–time curve.

Y. Ohsaki et al. / International Journal of Antimicrobial Agents 35 (2010) 603–605

and AUC values in the 400 mg dose group were approximately twice those of the 200 mg dose group, suggesting dose proportionality. 4. Discussion GRNX is eliminated by renal excretion and hepatic metabolism. Although there were no patients with severe impairment of hepatic function in this study, individual differences were observed among the patient’s CLCr values. However, the estimated pharmacokinetic parameters (CL, Cmax and AUC) were not affected by age or renal function in any of the patients, except for Patient 7 who weighed 38 kg and had a CLCr of 17 mL/min. This patient had higher estimated Cmax and AUC values than the other patients in the 200 mg dosage group and her values were comparable with patients receiving 400 mg. Following multiple administration of 200 mg and 400 mg of GRNX to healthy adult subjects (mean age 21.7–22.2 years), Cmax and AUC values on the 7th day were reported to be 4.49 ␮g/mL and 11.06 ␮g/mL and 48.8 ␮g h/mL and 110.9 ␮g h/mL, respectively [8]. These reported values are comparable with the values of the elderly patients in this study, except for Patient 7. Kobayashi et al. [11] reported that Cmax and AUC values of elderly patients (age ≥65 years) were 1.1–1.2 times higher than those of younger patients (age <65 years) and that AUC values of patients with a body weight of <40 kg and ≥40 kg were 145 ␮g h/mL and 120 ␮g h/mL, respectively. Cmax and AUC values of subjects with severe renal impairment were increased by 51% and lowered by 20%, respectively, and the terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls [9]. A GRNX dose of 400 mg is recommended, except for patients with a body weight of <40 kg and CLCr < 30 mL/min. In those patients, a 200 mg dose is recommended [11]. In vitro, animal and clinical data for fluoroquinolones suggest a fAUC/MIC90 ratio (where f indicates free fraction in serum or plasma and MIC90 is the MIC for 90% of the organisms) of 25–34 is predictive of bacterial eradication in CAP caused by S. pneumoniae and that a target fAUC/MIC90 ratio of 100–120 is associated with deceased resistance of S. pneumoniae [4]. The GRNX ex vivo serum protein binding and MIC90 against S. pneumoniae were 78.9–79.8% (mean 79.4%) and 0.12 ␮g/mL, respectively [8,13]. The AUC values at 200 mg and 400 mg in this study were 47–102 ␮g h/mL (mean 65 ␮g h/mL) and 104–131 ␮g h/mL (mean 118 ␮g h/mL), and the AUC/MIC90 ratio was calculated as 81–175 (mean 111) and 179–225 (mean 203), respectively. Madaras-Kelly and Demasters [14] and Craig [2] demonstrated that fluoroquinolone resistance occurred when the Cmax /MIC ratio was <5 and <8–10, respectively. In the present study, Cmax values for the 200 mg and 400 mg doses were 3.25–6.27 ␮g/mL (mean 4.59 ␮g/mL) and 7.78–7.87 ␮g/mL (mean 7.83 ␮g/mL), respectively; therefore, the Cmax /MIC90 ratio was calculated to be 6–11 (mean 8) and 13–14 (mean 13), respectively. Thus, the estimated mean values for the 200 mg dose were comparable with the target AUC/MIC90 and Cmax /MIC ratio, and the

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estimated mean values for the 400 mg dose were higher than the target ratios. However, when the MIC of the responsible bacteria is >0.12 ␮g/mL, a higher AUC and/or Cmax might be required. In addition, maximising the pharmacodynamics of fluoroquinolones may maximise clinical efficacy [4]. It is well established that the 400 mg dose does not lead to serious adverse effects [7]. Therefore, we recommend that a GRNX dose of 400 mg/day be given to elderly and young patients unless their body weight and CLCr are <40 kg and <30 mL/min, respectively, in which case they should be given 200 mg/day. Because this study was limited by the small number of patients, verification of these observations will require further studies with an increased patient sample size. Funding: No funding sources. Competing interests: None declared. Ethical approval: The study protocol was reviewed and approved by the Institutional Review Board at Asahikawa Medical College (Hokkaido, Japan) (approval no. #434). References [1] File Jr TM, Niederman MS. Antimicrobial therapy of community-acquired pneumonia. Infect Dis Clin North Am 2004;18:993–1016. [2] Craig WA. Does the dose matter? Clin Infect Dis 2001;33(Suppl. 3):S233–7. [3] Andes D, Craig WA. Pharmacodynamics of the new des-f(6)-quinolone garenoxacin in a murine thigh infection model. Antimicrob Agents Chemother 2003;47:3935–41. [4] Noreddin AM, Reese AA, Ostroski M, Hoban DJ, Zhanel GG. Comparative pharmacodynamics of garenoxacin, gemifloxacin, and moxifloxacin in community-acquired pneumonia caused by Streptococcus pneumoniae: a Monte Carlo simulation analysis. Clin Ther 2007;29:2685–9. [5] Takahata M, Shimakura M, Hori R, Kizawa K, Todo Y, Minami S, et al. In vitro and in vivo efficacies of T-3811ME (BMS-284756) against Mycoplasma pneumoniae. Antimicrob Agents Chemother 2001;45:312–5. [6] Ameyama S, Shinmura Y, Takahata M. Inhibitory activities of quinolones against DNA gyrase of Chlamydia pneumoniae. Antimicrob Agents Chemother 2003;47:2327–9. [7] Takagi H, Tanaka K, Tsuda H, Kobayashi H. Clinical studies of garenoxacin. Int J Antimicrob Agents 2008;32:468–74. [8] Uchida E. Phase 1 clinical studies of oral garenoxacin in healthy Japanese adult subjects. Jpn J Chemother 2007;55(Suppl. 1):95–115. [9] Krishna G, Gajjar D, Swan S, Marbury T, Grasela DM, Wang Z. Garenoxacin pharmacokinetics in subjects with renal impairment. Curr Med Res Opin 2007;23:649–57. [10] Hayakawa H, Fukushima Y, Kato H, Fukumoto H, Kadota T, Yamamoto H, et al. Metabolism and disposition of novel des-fluoro quinolone garenoxacin in experimental animals and an interspecies scaling of pharmacokinetic parameters. Drug Metab Dispos 2003;31:1409–18. [11] Kobayashi H, Tanigawara Y, Watanabe A, Aoki N, Sano Y, Odagiri S, et al. Phase III study of garenoxacin in patients with secondary infection of chronic respiratory diseases. Jpn J Chemother 2007;55(Suppl. 1):144–61. [12] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [13] Otani T, Tanaka M, Ito E, Kurosaka Y, Murakami Y, Onodera K, et al. In vitro and in vivo antibacterial activities of DK-507k, a novel fluoroquinolone. Antimicrob Agents Chemother 2003;47:3750–9. [14] Madaras-Kelly KJ, Demasters TA. In vitro characterization of fluoroquinolone concentration/MIC antimicrobial activity and resistance while simulating clinical pharmacokinetics of levofloxacin, ofloxacin, or ciprofloxacin against Streptococcus pneumoniae. Diagn Microbiol Infect Dis 2000;37: 253–60.