Division of Internal Medicine, National Ohmuta Hospital M. YOSHIDA Y. NAKANISHI. Respiratory Division, University hospital, Fukuoka University

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1 124(124) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 1 Feb. CONCENTRATION OF CLARITHROMYCIN AND 14-R-HYDROXY- CLARITHROMYCIN IN PLASMA OF PATIENTS WITH Mycobacterium avium COMPLEX INFECTION, BEFORE AND AFTER THE ADDITION OF RIFAMPICIN F. YAMAMOTO, S. HARADA, T. MITSUYAMA, Y. HARADA and Y. KITAHARA Division of Internal Medicine, National Ohmuta Hospital M. YOSHIDA Research Institute for Disease of the Chest, Graduate School of Medical, Kyusyu University Y. NAKANISHI Respiratory Division, University hospital, Fukuoka University (Received for publication October 15, 2003) Clarithromycin (CAM) and rifampicin (RFP) have both been recognized to be effective antibiotic agents against Mycobacterium avium complex (MAC) infection. Rifamycin derivatives including RFP and rifabutin modulate the CAM metabolism by inducing the hepatic cytochrome p-450 3A4. To clarify the effect of RFP on the CAM metabolism, we measured the plasma concentration of CAM and 14-R-hydroxyclarithromycin (M-5), the major metabolite of CAM, in 9 patients suffering from MAC infection before and after the addition of RFP. After the addition of RFP, the mean plasma concentration of CAM significantly decreased, while that of M-5 did not. In addition, the amount of CAM+M-5 concentration also significantly decreased. As M-5 is less effective against MAC infection than CAM, more attention should thus be paid to the plasma CAM concentration in patients administered CAM and RFP concomitantly. Lung disease due to Mycobacterium avium complex (MAC) infection is more common in Japan than in the United States or European countries. However, a curative regimen for pulmonary MAC disease has not yet been established. As both clarithromycin (CAM) and rifamycin derivatives have been shown to have a satisfactory efficacy against pulmonary MAC disease 1 3), they are both prescribed for pulmonary MAC infection. It is known that rifamycin derivative including rifampicin (RFP) and rifabutin modulates the CAM metabolism by inducing the hepatic cytochrome p-450 3A4 (CYP-450 3A4) 4,5). Through the induction of the enzyme, the plasma level of CAM decreases when CAM is administered with rifamycin derivatives. The major metabolite of CAM is 14-R-hydroxy-clarithromycin (M-5), which has been reported to be less effective against MAC than CAM 6) whereas it is as effective as CAM against some organisms such as H.

2 Feb. THE JAPANESE JOURNAL OF ANTIBIOTICS (125) influenzae, B. catarrhalis, S. aureus, S. pneumoniae 7). WALLACE et al. reported the plasma level of CAM to decrease while that of M-5 did not change after the addition of RFP when CAM is administered at high doses of 1000 mg a day 4). However, to our knowledge, the effect of RFP on CAM metabolism when CAM is administered at low doses has not yet been reported. Though M-5 is less effective against MAC than CAM, it may be possible that after adding RFP the plasma consentration of M-5 increases to compensate for the decrease in the CAM concentration when CAM is administered at low doses. In addition, RFP is the only rifamycin derivative presently available in Japan. As a result, we measured the plasma concentration of CAM and M-5 in 9 patients suffering from a pulmonary MAC infection who received low doses of CAM, ranging from mg a day, before and after the administration of RFP. Method Subjects Nine patients (patients A I, Table 1) with lung disease due to MAC, who were admitted to the National Ohmuta Hospital between June 2000 and April 2001, were enrolled in this study. Three of the patients were consistent with the diagnositic criteria of the American Thoracic Society for lung MAC disease. Six of the patients were diagnosed based on radiographic manifestations, bacteriological results and their clinical courses. The mean age and body weights were years old and kg respectively. Eight of the patients did not have any hepatic dysfunction. One patient had slight liver damage due to chronic hepatitis (patient E, Table 1). No renal dysfunction was seen in any of the patients. All subjects received CAM orally for the first week and both CAM and RFP for the following week. As a matter of principle, the dose of CAM was determined based on their body weight. Patients weighing over 50 kg received 600 mg CAM a day, while those weighing less than 50 kg received 400 mg a day. However one patient (patient D) received 600 mg CAM a day even though he weighted only 40 kg. When receiving 400 mg of CAM a day, the patients received 200 mg just after breakfast and supper. When receiving 600 mg of CAM the patients received 200 mg just after every meal. The dose of RFP was left up to the physicians in charge, and it was 300 or 450 mg a day. Remedies other than CAM and RFP were not changed throughout this study period. All patients gave their signed informed consents before entering the study. It is known that the peak concentration time of CAM is around 2 hours after administration at a dose of 200 mg CAM. We also studied the time course of CAM and the M-5 plasma concentration in 3 MAC patients (patient J L; Table 1) receiving both CAM and RFP to confirm whether the peak concentration time of CAM is around 2 hours after CAM is administered with RFP. These 3 patients had taken both CAM and RFP for periods of longer than one month; one had taken both CAM and RFP for 9 months, another for 2 months, and the other for one month. The mean age and body weight of the 3 patients were years old, and kg respectively. None had a hepato-renal dysfunction. The dose of CAM and RFP were 400 mg a day and 300 mg a day, respectively, for all 3 patients. They all signed an informed consent agreement before entering the study. Measurement Before the addition of RFP, the patients received mg CAM per day for one week. On the

3 126(126) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 1 Feb. Table 1. Characteristics of the subjects.

4 Feb. THE JAPANESE JOURNAL OF ANTIBIOTICS (127) 8th morning, just 2 hours after receiving 200 mg of CAM, 5 ml of venous blood was obtained and stored in a heparinized tube. It was thereafter immediately centrifuged at 3000 rpm for 5 minutes, and then the plasma was preserved at 20 C. The plasma concentration of CAM and M-5 was measured by high performance liquid chromatography. Next, every patient received mg CAM and mg RFP per day for a week. On the 8th morning, just 2 hours after receiving 200 mg of CAM and mg of RFP, 5 ml of venous blood was obtained and stored in a heparinized tube and treated as mentioned above. In the measurement of the time course change of CAM and M-5 plasma concentration, 5 ml of venous blood from the three patients was obtained and stored in a heparinized tube before and at 30, 60, 90, 120 and 180 minutes after receiving 200 mg CAM and 300 mg. Statistical Analysis The data are presented as the mean S.D. The plasma levels of CAM and M-5 before and after adding RFP were analyzed using Student s T test. A p value of 0.05 was considered to be statistically significant. Results Through the addition of RFP, the plasma concentration of CAM and CAM M5 significantly decreased in all 9 patients from m g/ml to m g/ml (P 0.05) and from m g/ml to m g/ml (P<0.05), respectively (Table 2). The changes in M-5 were not uniform. In 4 patients the concentration of M5 increased while in 5 patients it decreased. The mean concentration of M-5 changed from m g/ml to m g/ml (Table 2). Excluding patient D who received 600 mg CAM a day despite his body weight being below 50 kg, similar results were obtained. In the patients, except for patient D, the mean plasma concentration of CAM and CAM M-5 decreased significantly from m g/ml to m g/ml (P<0.05) and from m g/ml to m g/ml (P<0.05), respectively. The serum level of transaminase slightly increased in the patient F; GOT from 31 to 60 IU/L, GPT from 35 to 56 IU/L. The possibility that RFP or CAM caused liver damage in this patient could not be ruled out. The serum level of transaminase in patient E with chronic hepatitis decreased; GOT from 86 to 52 IU/L, GPT from 50 to 31 IU/L. In the other 7 patients, the serum level of both GOT and GPT stayed within the normal limits. No deterioration of the renal function was seen in any of the patients and none of the 9 patients reported any complaints except for those due to their underlying diseases (Table 3). The peak concentration time of CAM and M-5 in the three patients, who had taken both CAM and RFP for a period of longer than one month, was between minutes and minutes, respectively, after the administration of CAM and RFP (Table 4). Discussion Rifamycin derivative including RFP and rifabutin modulates the CAM metabolism by inducing CYP-450 3A4 4,5). RFP is known to be a more potent inducer of CYP-450 3A4 than rifabutin 8). The activity of CYP-450 3A4 comes to a steady state around 7 14 days after starting RFP. As a result, we compared the concentration of CAM and M5 on the 7th day after starting CAM and 7th day after adding

5 128(128) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 1 Feb. Table 2. The changes in the plasma levels of CAM, M-5, and CAM M-5.

6 Feb. THE JAPANESE JOURNAL OF ANTIBIOTICS (129) Table 3. Hepato-renal function before and after the study. RFP. In 3 pulmonary MAC patients who had taken both CAM and RFP for more than one month, the peak concentration time of CAM and M-5 was between minutes, or around 2 hours, after the administration of CAM and RFP (Table 4). SUWA et al. reported that the peak concentration time of CAM did not differ between the single administration of 200 mg CAM and the sequential administration of 200 mg CAM twice a day for 7 days in healthy adults, and it was hours after dosing 9). SAITOH et al. reported a peak concentration time of CAM was around 2 hours after administration when healthy adults took 200 mg of CAM alone 10). As the peak concentration time of CAM appeared to be similar even when CAM was administered concurrently with RFP, we chose the point of 2 hours after administration as the time to measure the plasma level of CAM and M-5. The metabolic pathway of CAM is proposed in Fig. 1 11). In this pathway, CYP-450 3A4 induces 14- S-hydroxylation, 14-R-hydroxylation and oxidative N-demethylation. CAM is converted into M5 through 14-R-hydroxylation, into 14-S-hydroxy-clarithromycin (14-OH(S)) through 14-S-hydroxylation, into N- demethyl clarithromycin (DM) through oxidative N-demethylation by CYP-450 3A4. These daughter compounds are metabolized by 3A4 into N-demethyl-14-S-hydroxy clarithromycin (14-OH(S)-DM), N,Ndidemethyl clarithromycin (DDM) and N-demethyl-14-R-hydroxy clarithromycin (14-OH(R)-DM) as shown in Fig. 1. SUWA et al. measured the plasma concentration of CAM and its metabolites in healthy adults 10). They reported CAM and M-5 to be the major compounds in plasma when blood was obtained at 1.5 hours after the administration of 100 mg of CAM. The proportion of plasma CAM concentration to the total plasma concentration of CAM and its metabolites was 44.8%, while that of M-5 was 40.3%. They also reported CAM and M-5 to be % when the dose of CAM was increased to mg even though the proportion of CAM in the plasma tended to increase. This implies the major metabolite of CAM to be M- 5 (Fig. 1). In our study, the plasma concentration of CAM decreased in all 9 patients after the addition of RFP. The reason for this change was supposed to be due to the effect that CYP-450 3A4 induction accelerated

7 130(130) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 1 Feb. Table 4. Time course of the CAM and the M-5 concentration in 3 MAC patients who had taken both CAM and RFP for more than one month.

8 Feb. THE JAPANESE JOURNAL OF ANTIBIOTICS (131) Fig. 1. The pathway of clarithromycin proposed by J. L. FERRERO et al. Dotted arrow solid arrow, and broken arrow indicate oxidative N-demethlation by 3A4, hydroxylation at the 14 position by CYP-3A4 and hydrolysis of the cladinose sugar not by 3A4, respectively. Main pathway is shown with a broad arrow. The abbreviation are as follows: CAM: clarithromycin; M5: 14-R-hydroxy-clarythromycin; 14-OH(S): 14-Shydroxy-clarithromycin; DM: N-demethyl clarithromycin; 14-OH(S)-DM: N-demethyl-14-S-hydroxy clarithromycin; DDM: N,N-didemethyl clarithromycin; 14-OH(R)-DM: N-demethyl-14-R-hydroxy clarithromycin; Declad: decladinosyl clarithromycin; 14-OH(R)-Declad: decladinosyl-(14r)-14-hydroxy clarithromycin. 14-R-hydroxylation and CAM was rapidly and mainly converted into M-5. We predicted that the plasma concentration of M-5 increased. However, the change of the concentration of M-5 was not individually uniform and the mean of it did not change significantly. This might be caused by the fact that CYP-450 3A4 induction concurrently accelerated oxidative N-demethylation and M-5 was rapidly converted into 14-OH(R)-DM (Fig. 1). As MAC is an intracellular parasite, we have to mention the intracellular concentration of CAM. KEES F. et al. reported that CAM exhibited a good and rapid penetration into the intracellular portion 12). But it is uncertain as to whether or not this fact can be applied to lung tissue. To our knowledge, there has been no report on the penetration of M-5 into the intracellular portion. FISH et al. studied the penetration of CAM and M-5 into lung tissue in patients who underwent thoracic surgery by simultaneously obtaining lung tissue and blood samples at hours after the last administration of CAM 13). They reported that the penetration of CAM into lung tissue is better than that of M-5. Their information may be valuable regarding the treatment of pulmonary MAC patients. COHEN et al. reported M-5 to be approximately fourfold less active against MAC than CAM in vitro; MIC of CAM against MO1 strain and LV-2 strain are 2 mg/ml and 0.5 m g/ml, respectively, and MIC of M5 was 8 m g/ml and 2 mg/ml, respectively 6). The dose of CAM might as well be increased for the treatment of pulmonary MAC patients when CAM is administered with RFP, considering that CAM penetrates lung tissue better than M-5, M-5 is less effective against MAC than CAM and the plasma concentration of M-5 does not increase in amount to compensate for the decreased efficacy of CAM against MAC due to the decreased plasma concentration of CAM. YAMAMOTO et al. reported that the efficacy of CAM against pulmonary MAC disease increased when CAM was administered at a dose of 600 mg or higher per day concomitantly antituberculous agents 14). Our findings support the idea that the dose of CAM may thus be increased in treating MAC patients when CAM is administered with RFP. When CAM is prescribed for such infections as H. influenzae, B. catarrhalis, S. aureus and S. pneumoniae to patients receiving RFP, then the dose of CAM

9 132(132) THE JAPANESE JOURNAL OF ANTIBIOTICS 57 1 Feb. might as well be increased. Because M-1 is as effective as CAM against these organisms 7) and the CAM M-5 concentration decreased after adding RFP in our study. On the other hand, HAFNER et al. reported that the AUC of rifabutin and its metabolite 25-Odesacetyl rifabutin increased 99% and 375%, respectively, when rifabutin was administered with CAM 15). JORDAN warned of the possibility of adverse effects such as uveitis, rash, bone marrow toxicity, liver damage and polyarthrits when CAM, rifabutin and fluconazole were concomitantly administered. He observed an increase in the AUC of rifabutin, which might be a causative agent of the adverse effects noted above 16). As RFP is structurally similar to rifabutin 8), adverse side effects similar to those mentioned above might occur. Fortunately, no adverse side effects were observed except for some slight liver damage in one patient (patient F; Table 3) in our study. When rifamycin derivative is prescribed with CAM, it must be remembered that the AUC of rifamycin derivative and its metabolites increase. In conclusion, the dose of CAM may thus be increased as much as possible when we treat patients with lung disease due to MAC. However, careful attention should be paid to the potential side effects due to CAM and RFP when the patients are administered CAM and RFP concomitantly. References 1) TOMONo, K.: Therapeutic efficacy of macrolide in pulmonary nontuberculous mycobacteriosis. Kekkaku 69: , ) TANAKA, E.; T. KIMOTO, I. WATANABE, et al.: Effect of clarithromycin regimen for mycobacterium avium complex pulmonary disease. Am. J. Respir. Crit. Care Med. 160: , ) YAMAMOTO, M.; F. KUZE, M. SAKATANI, et al.: The clinical study of clarithromycin for pulmonary mycobacterium avium-intracellulare complex infection. Kekkaku 72: 1 7, ) WALLACE, R. J.; B. A. BROWN, D. E. GRIFfiTH, et al.: Reduced serum levels of clarithromycin in patients treated with multidrug regimen including rifampin or rifabutin for Mycobacterium avium-m. intracellulare infection. The Journal of Infectious Disease 171: , ) BENEDETTI, M. S.: Inducing properties of rifabutin, and effects on the pharmacokinetics and metabolism of concomitant drugs. Pharmacol. Res. 32: , ) COHEN, Y.; C. PERRONNE, C. TRUFFOT-PERNOT, et al.: Activities of WIN-57273, minocycline, clarithromycin, and 14-hydroxy-clarithromycin against Mycobacterium avium complex in human macrophages. Antimicrobial Agents and Chemotherapy 36: , ) NAGATE, T.; K. ONO, K. SUGITA, et al.: Antibacterial activityof M-5, the most active metabolite of TE-031 (A-56268) in man. Chemotherapy 36(S-3): , ) BLASCHKE, T. F. & M. H. SKINNER: The clinical pharmacokinetics of rifabutin. Clin. Infect. Dis. 22 (Suppl. 1): 15 21, ) SUWA, T.; T. OHTAKE, H. URANO, et al.: Metabolite fate of TE-031 (A-56268) (IX). Chemotherapy 36: , ) SAITOH, A.; K. ISHIKAWA, M. SHINOHARA, et al.: Preclinical and clinical studies on TE-031(A-56268). Chemotherapy 36 (Suppl. 3): , ) FERRERO, J. L.; B. A. BOPP, K. C. MARSH, et al.: Metabolism and disposition of clarithromycin in man. Antimicrobial Agents and Chemotherapy 18: , ) KEES, F.; M. WELLENHOFER & H. GROBECKER: Serum and pharmacokinetics of clarithromycin 500 mg q.d and 250 mg b.i.d in volunteers. Infection 23: , ) FISH, D. N.; M. H. GOTFRIED, L. H. DANZIGER, et al.: Penetration of clarithromycin into lung tissue from patients undergoing lung resection. Antimicrobial Agents and Chemotherapy 38: , ) YAMAMOTO, M.; F. KUZE, M. SAIKATANI, et al.: The clinical study of clarithromycin for pulmonary Mycobacterium avium-intracellurae complex infection. Kekkaku 72: 1 7, ) HAFNER, R.; J. BETHEL, M. POWER, et al.: Tolerance and pharmacokinetic interaction of rifabutin and clarithromycin in himan imunodeficiency virus-infected volunteers. Antimicrobial Agents and

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