DRUG DISPOSITION

Clin Pharmacokinet 1999 Nov; 37 (5): 385-398 0312-5963/99/0011-0385/$07.00/0 © Adis International Limited. All rights reserved.

Clinical Pharmacokinetics of Clarithromycin Keith A. Rodvold Colleges of Pharmacy and Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1 Oral Tablets in Adults . . . . . . . . . . . . . . . . 1.1.2 Oral Suspension in Adults . . . . . . . . . . . . . . 1.1.3 Oral Suspension in Infants and Children . . . . . 1.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacokinetics of Clarithromycin in Special Populations 2.1 Patients with Renal Impairment . . . . . . . . . . . . . . 2.2 Patients with Hepatic Impairment . . . . . . . . . . . . 2.3 Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . 4. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Clarithromycin is a macrolide antibacterial that differs in chemical structure from erythromycin by the methylation of the hydroxyl group at position 6 on the lactone ring. The pharmacokinetic advantages that clarithromycin has over erythromycin include increased oral bioavailability (52 to 55%), increased plasma concentrations (mean maximum concentrations ranged from 1.01 to 1.52 mg/L and 2.41 to 2.85 mg/L after multiple 250 and 500mg doses, respectively), and a longer elimination half-life (3.3 to 4.9 hours) to allow twice daily administration. In addition, clarithromycin has extensive diffusion into saliva, sputum, lung tissue, epithelial lining fluid, alveolar macrophages, neutrophils, tonsils, nasal mucosa and middle ear fluid. Clarithromycin is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and has an active metabolite, 14-hydroxyclarithromycin. The reported mean values of total body clearance and renal clearance in adults have ranged from 29.2 to 58.1 L/h and 6.7 to 12.8 L/h, respectively. In patients with severe renal impairment, increased plasma concentrations and a prolonged elimination half-life for clarithromycin and its metabolite have been reported. A dosage ad-

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Rodvold

justment for clarithromycin should be considered in patients with a creatinine clearance <1.8 L/h. The recommended goal for dosage regimens of clarithromycin is to ensure that the time that unbound drug concentrations in the blood remains above the minimum inhibitory concentration is at least 40 to 60% of the dosage interval. However, the concentrations and in vitro activity of 14-hydroxyclarithromycin must be considered for pathogens such as Haemophilus influenzae. In addition, clarithromycin achieves significantly higher drug concentrations in the epithelial lining fluid and alveolar macrophages, the potential sites of extracellular and intracellular respiratory tract pathogens, respectively. Further studies are needed to determine the importance of these concentrations of clarithromycin at the site of infection. Clarithromycin can increase the steady-state concentrations of drugs that are primarily depend upon CYP3A metabolism (e.g., astemidole, cisapride, pimozide, midazolam and triazolam). This can be clinically important for drugs that have a narrow therapeutic index, such as carbamazepine, cyclosporin, digoxin, theophylline and warfarin. Potent inhibitors of CYP3A (e.g., omeprazole and ritonavir) may also alter the metabolism of clarithromycin and its metabolites. Rifampicin (rifampin) and rifabutin are potent enzyme inducers and several small studies have suggested that these agents may significantly decrease serum clarithromycin concentrations. Overall, the pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug interactions occur with clarithromycin compared with older macrolides such as erythromycin and troleandomycin.

Clarithromycin is a semisynthetic macrolide antibacterial with a 14-membered ring.[1-3] Its chemical structure differs from erythromycin by the methylation of the hydroxyl group at position 6 on the lactone ring. These chemical modifications are responsible for clarithromycin being acid stable, having an increased spectrum of activity, better pharmacokinetic properties and fewer gastrointestinal adverse effects than erythromycin.[1-9] The purpose of this article is to review the data regarding the pharmacokinetics and drug interactions of oral clarithromycin. Emphasis is placed on the most recent published studies, as several excellent reviews have extensively discussed the earlier pharmacokinetic and drug interaction data for clarithromycin.[4,8-11] 1. Pharmacokinetics The pharmacokinetics of oral clarithromycin and its active metabolite, 14-hydroxyclarithromycin, have been studied in healthy young and elderly volunteers, in patients with impaired renal or © Adis International Limited. All rights reserved.

hepatic function, and in children. In these studies, plasma, body fluid and tissue concentrations have most commonly been measured by microbiological assay or high performance liquid chromatography (HPLC).[12-17] 1.1 Absorption 1.1.1 Oral Tablets in Adults

The mean maximum drug plasma concentrations (Cmax) of clarithromycin ranged from 0.78 to 0.94 mg/L and 1.01 to 1.52 mg/L after oral administration of single and multiple 250mg doses, respectively (table I).[8,9,17-22] The Cmax ranged from 1.65 to 2.12 mg/L and 2.41 to 2.85 mg/L after single and multiple 500mg doses, respectively. Clarithromycin tablets are usually rapidly absorbed, with the mean time to maximum concentration (tmax) ranging between 1.8 and 2.8 hours. The mean steady-state trough plasma drug concentrations (Cmin) of clarithromycin after multiple 250 and 500mg doses ranged from 0.19 to 0.28 mg/L and 0.73 to 1.27 mg/L, respectively. The bioavailability of clarithromycin 250mg Clin Pharmacokinet 1999 Nov; 37 (5)

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387

Table I. Mean pharmacokinetic parameters of oral clarithromycin in healthy volunteers n

Doses

Cmax (mg/L)

tmax (h)

ka (h–1)

AUC (mg • h/L)

Vβ/F (L)

t1⁄2β (h)

CL/F (L/h)

CLR (L/h)

Reference

58.1

NR

17

41.3

12.8

Clarithromycin 250mg 17 1 0.78

1.8

3.4

4.36

236

2.7

17

5

1.01

2.1

NR

6.44

217

3.5

17

7

1.14

2.0

NR

6.86

228

3.7

39.5

6.84

12

5

1.52

NR

NR

9.29

138

3.3

29.2

6.66

18

12

1

0.94

2.1

NR

5.80

NR

3.3

NR

NR

19

12

9

1.23

2.1

NR

7.85

NR

4.0

NR

NR

Clarithromycin 500mg 17 1 2.12

2.0

1.7

14.08

306

4.3

42.1

NR

17

5

2.67

2.6

NR

19.59

222

4.5

28.8

6.84

17

7

2.85

2.6

NR

20.48

191

4.8

26.2

7.20

25

1

1.65

2.8

2.24

12.62

NR

NR

NR

NR

20

12

5

2.41

NR

1.04

18.87

201

4.9

28.6

10.1

21

12

1

2.10

2.25

NR

15.63

NR

4.2

NR

NR

19

17

AUC = area under the concentration-time curve; CL/F = total body clearance; CLR = renal clearance; Cmax = maximum plasma drug concentration; ka = absorption rate constant; n = number of participants; NR = not reported; tmax = time to Cmax; t1⁄2β = elimination half-life; Vβ/F = apparent volume of distribution.

tablets has been reported to be 52 to 55%.[22] Bioavailability appears to be slightly increased (by 24%) when clarithromycin tablets are taken with food.[20] The administration of a meal did not have any significant changes in the clarithromycin values for tmax (2.0 vs 2.8h) or the area under the concentration-time curve (AUC) [10.47 vs 9.58 mg • h/L] of its metabolite. These data suggest that clarithromycin tablets can be taken with or without a meal.

The mean Cmax of 14-hydroxyclarithromycin after oral administration of single and multiple clarithromycin doses of 250mg ranged from 0.46 to 0.65 mg/L and 0.49 to 0.83 mg/L, respectively (table II).[8,9,17-22] The Cmax of the metabolite ranged from 0.78 to 1.0 mg/L and 0.66 to 0.88 mg/L after single and multiple 500mg doses, respectively. The mean steady-state Cmin of 14-hydroxyclarithromycin after multiple 250 and 500mg doses ranged

Table II. Mean pharmacokinetic parameters of 14-hydroxyclarithromycin in healthy volunteers Cmax (mg/L)

tmax (h)

AUC (mg • h/L)

Clarithromycin 250mg 17 1

0.65

2.3

4.97

17

5

0.62

2.9

4.70

17

7

0.61

2.3

4.90

5.7

6.24

12

5

0.83

NR

6.10

5.1

6.72

18

12

1

0.46

2.2

4.59

6.2

NR

19

12

9

0.49

2.5

4.02

6.75

NR

Clarithromycin 500mg 17 1

1.00

1.9

9.95

5.5

NR

17

5

0.88

2.6

7.37

6.9

8.04

17

7

0.83

2.5

7.29

8.7

8.22

26

1

0.88

3.0

11.18

NR

NR

20

12

5

0.66

NR

6.00

7.2

8.40

21

12

1

0.78

2.3

9.45

7.1

NR

19

n

Doses

t1⁄2β (h)

CLR (L/h)

Reference

4.1

NR

17

4.6

7.80

17

AUC = area under the concentration-time curve; CLR = renal clearance; Cmax = maximum drug plasma concentration; n = number of participants; NR = not reported; tmax = time to Cmax; t1⁄2β = elimination half-life.

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Clin Pharmacokinet 1999 Nov; 37 (5)

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Table III. Mean pharmacokinetic parameters of oral clarithromycin suspension in healthy volunteers n

Doses

Group

Clarithromycin Cmax (mg/L)

14-Hydroxyclarithromycin tmax (h)

AUC (mg • h/L)

Cmax (mg/L)

tmax (h)

AUC (mg • h/L)

Adults (receiving clarithromycin 250mg) 22 1 Nonfasting 0.95

5.3

6.41a

0.38

5.8

3.74

22

1

Fasting

1.24

3.3

6.89a

0.42

3.4

3.79

17

1

Fasting

1.34

3.2

7.80b

0.46

3.4

4.87

17

5

Fasting

1.98

2.8

11.48b

0.67

2.9

5.33

17

7

Fasting

2.15

3.1

12.74b

0.72

3.0

5.85

Infants and children (receiving clarithromycin 7.5 mg/kg) 10 1 Fasting 3.59 3.1 10.0c 10 10

1.19

3.2

3.66

1

Nonfasting

4.58

2.8

14.2c

1.26

4.0

4.37

7-9

Fasting

4.60

2.8

15.7c

1.64

2.7

6.69

a

AUC was for 0 to 24 hours after administration.

b

AUC for single dose study was 0 to ∞; AUC for multiple dose study was 0 to 12 hours after administration.

c

AUC was for 0 to 6 hours after administration.

Reference

23 23

25

AUC = area under the concentration-time curve; Cmax = maximum plasma concentrations; n = number of participants; NR = not reported; tmax = time to Cmax.

from 0.20 to 0.25 mg/L and 0.32 to 0.65 mg/L, respectively. 1.1.2 Oral Suspension in Adults

For adults receiving clarithromycin suspension in a fasting state, the mean Cmax after single and multiple 250mg doses ranged from 1.24 to 1.34 mg/L and 1.98 to 2.15 mg/L, respectively (table III).[23] The mean tmax for clarithromycin suspension ranged between 2.8 and 3.3 hours. The mean steady-state Cmin of clarithromycin after multiple 250mg doses ranged from 0.32 to 0.39 mg/L. The mean Cmax of 14-hydroxyclarithromycin after the administration of single and multiple clarithromycin doses of 250mg as an oral suspension ranged from 0.42 to 0.46 mg/L and 0.67 to 0.72 mg/L, respectively.[23] The mean tmax for the metabolite was similar to the parent drug (2.9 to 3.4h). The mean steady-state Cmin of the metabolite was between 0.23 and 0.27 mg/L. A comparison of the AUC for clarithromycin suspension and tablet formulations suggests that the extent of absorption does not significantly differ between formulations.[23] However, the onset and/or rate of absorption of clarithromycin (3.3 vs 1.7h) and its metabolite (3.4 vs 1.9h) was slightly slower for the suspension formulation compared with the tablets. In addition, the administration of © Adis International Limited. All rights reserved.

a meal with the suspension formulation in adults slightly decreased the Cmax (1.24 vs 0.95 mg/L) and prolonged the tmax of clarithromycin (5.3 vs 3.3h) and its metabolite (5.8 vs 3.4h). These alterations are probably not clinically significant. The pharmacokinetics of clarithromycin and 14-hydroxyclarithromycin were evaluated in 16 critically ill patients after the administration of 2 single 500mg doses of clarithromycin suspension.[24] This study included 16 adult patients (7 males and 9 females aged 31 to 67 years) admitted to the intensive care unit (ICU) and who had a nasogastric tube in place. Patients had not been receiving concomitant drug therapy known to interact with clarithromycin and had no evidence of significant gastrointestinal, hepatic or renal dysfunction. No statistical significant differences were observed in the Cmax (2.1 ± 0.9 vs 2.3 ± 0.6 mg/L), tmax (3.5 ± 0.8 vs 3.3 ± 0.6 hours) or AUC (17.6 ± 2.8 vs 18.2 ± 2.6 mg • h/L) of clarithromycin between study days 1 and 4. Also, no significant differences were observed for the parameters of 14-hydroxyclarithromycin. The authors concluded that the pharmacokinetic parameters of clarithromycin and its metabolite were similar to those previously reported for adults. In addition, minimal intrapatient variability Clin Pharmacokinet 1999 Nov; 37 (5)

Clarithromycin

of pharmacokinetic parameters was observed in this group of relatively stable ICU patients. 1.1.3 Oral Suspension in Infants and Children

For paediatric patients receiving clarithromycin suspension in a fasting state, the mean Cmax after single and multiple doses of 7.5 mg/kg were 3.59 and 4.60 mg/L, respectively (table III).[23,25] The mean tmax for clarithromycin suspension ranged between 2.8 and 3.1 hours. The mean steady-state Cmin of clarithromycin after multiple 7.5 mg/kg doses was 1.67 mg/L. The mean Cmax of 14-hydroxyclarithromycin after the administration of the oral suspension in single and multiple doses of 7.5 mg/kg was 1.19 and 1.64 mg/L, respectively. The mean tmax for the metabolite ranged between 2.7 and 4.0 hours. The mean steady-state Cmin of the metabolite was 1.08 mg/L. The coadministration of food was associated with improved bioavailability (mean AUC increased by 42%) of the clarithromycin suspension in infants and children.[23,25] However, a comparison of the Cmax and AUC for clarithromycin suspension administered with and without a meal in paediatric patients suggested that these changes in the extent of absorption were not statistically different. The Cmax and AUC of clarithromycin suspension has also been reported in children with acquired immunodeficiency syndrome (AIDS) who were treated for systemic Mycobacterium avium complex infection.[26] The ranges of Cmax were 0.7 to 8.2 μmol/L, 2.4 to 10.0 μmol/L and 2.0 to 26.1 μmol/L, and the AUC were 2.7 to 54.8 μmol • h/L, 13.2 to 96.9 μmol • h/L and 15.6 to 175.3 μmol • h/L when clarithromycin was administered at the dosages of 3.75, 7.5 and 15 mg/kg, respectively, every 12 hours without the addition of zidovudine or didanosine. The authors concluded that the Cmax and AUC for clarithromycin increased proportionally over the 3 dose levels. 1.2 Distribution

The mean apparent volume of distribution (Vβ/F) of clarithromycin in adults ranges from 191 © Adis International Limited. All rights reserved.

389

to 306L (table I).[8,9,18-22] Protein binding ranges from 42 to 72%. α1-Acid glycoprotein (AAG) may contribute to a portion of this protein binding.[18] Clarithromycin and 14-hydroxyclarithromycin are widely distributed into various body fluids and tissues.[27-39] Clarithromycin has extensive diffusion into saliva, sputum, lung tissue, epithelial lining fluid, tonsils, nasal mucosa and middle ear fluid. In respiratory tract tissues and fluids, clarithromycin concentrations are 3- to 30-fold higher than plasma concentrations.[32,35-39] Clarithromycin and its active metabolite also rapidly penetrate into neutrophils and alveolar macrophages, and extremely high intracellular concentrations are achieved.[27,28,35-39] Alveolar macrophage concentrations are often higher than plasma concentrations by a factor of 102 to 103 (table IV). Such high drug concentrations at the site of infection may contribute to improved clinical outcomes. No data are available regarding the penetration of clarithromycin into the cerebrospinal fluid. 1.3 Metabolism

Clarithromycin undergoes extensive hepatic metabolism and at least 8 metabolites have been recovered.[40] Hydroxylation and oxidative N-demethylation are the 2 major pathways identified for the metabolism of clarithromycin; hydrolysis of the cladinose sugar is considered to have only a minor contribution. The metabolism of clarithromycin is unique since it is the only 14membered macrolide to demonstrate a 14-hydroxylation in humans. As a result, 14-hydroxy-Rclarithromycin is the most active metabolite recovered in the highest concentrations in both plasma and urine. A recent in vitro study has determined that cytochrome P450 (CYP) 3A is the major subfamily of microsomes involved with the 14-hydroxylation and N-demethylation of clarithromycin.[41] These findings are of clinical significance since they explain the majority of drug interactions associated with clarithromycin and its 14-hydroxy metabolite. Clin Pharmacokinet 1999 Nov; 37 (5)

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Rodvold

1.4 Excretion

After a single 250mg dose of radiolabelled clarithromycin, approximately 18.4 and 4.4% of clarithromycin and 13.7 and 6.0% of 14-hydroxyclarithromycin are recovered in the urine and faeces, respectively.[40] When a single 1200mg dose of radiolabelled clarithromycin is administered to healthy humans, the recovery of unchanged clarithromycin increased by 75% whereas the metabolites of 14-hydroxylation and N-demethylation decreased by 40 to 45%. In addition, a 13-fold increase in AUC, prolonged elimination half-life (t1⁄2β) [4.39 vs 11.27h] and a decrease in total body clearance (CL/F) [66.96 vs 24.18 L/h] was observed when the dose was increased from 250 to 1200mg (less than 5-fold). These observations suggest that the metabolism of clarithromycin is saturable and that elimination may be dose-dependent. The nonlinear, dose-dependent elimination of clarithromycin has been confirmed in a single ascending dose study of 100, 200, 400, 600, 800 and 1200mg of clarithromycin tablets in 39 healthy

male volunteers.[42] The mean t1⁄2β of clarithromycin was increased from 2.27 to 5.98 hours at doses of 100 and 1200mg, respectively. Over the same dose range, the mean t1⁄2β of 14-hydroxyclarithromycin also increased from 2.4 to 9.19 hours. Significant dose-dependency was also demonstrated for AUC and CL/F. The oral bioavailability and renal elimination of the parent compound or metabolite does not appear to be dose-dependent. The reported mean values of CL/F and renal clearance (CLR) after multiple doses of 250mg tablets in adults have ranged from 29.16 to 41.34 L/h and 6.66 to 12.78 L/h, respectively (table I).[8,9,17-22] Similar or slightly lower values for these 2 parameters have been reported after multiple doses of 500mg.[17,22] The t1⁄2β of clarithromycin in adults with healthy renal and hepatic function increased from 3.3 to 4.0 hours after multiple doses of 250mg up to 4.5 to 4.9 hours following 500mg every 12 hours. The t1⁄2β of 14-hydroxyclarithromycin increased from 4.6 to 6.8 hours after doses of 250mg to 6.9 to 8.7 hours with doses of 500mg (table II).[8,9,18-22] The mean 12-hour urinary excretion

Table IV. Mean clarithromycin and 14-hydroxyclarithromycin concentrations in plasma, epithelial lining fluid and alveolar macrophages in healthy volunteers. The clarithromycin dose was 500mg in all studies No. of samples

Site

Clarithromycin (mg/L) q4h

14-Hydroxyclarithromycin (mg/L)

q8h

q12h

q4h

q8h

q12h

Reference

Single dose studies 4 Serum

NR

1.0a

0.25

NR

0.60a

0.44

4

ELF

NR

39.6a

0

NR

0a

0

35

4

AV

NR

181a

80.1

NR

40.3a

32.8

35

35

Multiple dose studies 10 Serum

3.96

NR

NR

0.68

NR

NR

36

3 or 4

Plasma

2.2

2.6

0.8

1.2

1.1

0.4

37

5 or 6

Plasma

3.29

1.58

0.91

1.43

0.81

0.64

38

5

Plasma

2.00

1.55

1.22

0.49

0.52

0.61

39

6 or 8

ELF

20.46

NR

NR

1.90

NR

NR

36

3 or 4

ELF

29.3

72.1

48.6

1.3

8.2

1.2

37

5

ELF

34.02

20.63

23.01

NR

NR

NR

38 39

5

ELF

0.95

5.3

6.41

NR

NR

NR

8 or 9

AV

372.7

NR

NR

36.6

NR

NR

36

3 or 4

AV

505.8

256.7

236.5

46.6

22.8

13.6

37

2, 4 or 5

AV

1996

703

531

317

256

124

38

4 or 5

AV

480

220

181

89.3

51.9

41.9

39

a

Sampling was at 6 hours.

AV = alveolar macrophages; ELF = epithelial lining fluid; NR = not reported; qxh = every x hours.

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Clin Pharmacokinet 1999 Nov; 37 (5)

Clarithromycin

following multiple doses of 250 and 500mg have been reported as 24.5 and 36.2% for clarithromycin and 15.4 and 9.6% for 14-hydroxyclarithromycin, respectively. 2. Pharmacokinetics of Clarithromycin in Special Populations A limited number of studies have determined if the pharmacokinetics of clarithromycin and its active metabolite 14-hydroxyclarithromycin are altered in special patient populations. The focus of these studies has been patients with renal or liver disease, and healthy elderly individuals. No studies have been performed in patients with acute hepatitis or combined hepatic and renal disease. Overall, dosage adjustments for clarithromycin should be considered in patients with severe renal impairment [creatinine clearance (CLCR) <1.8 L/h]. 2.1 Patients with Renal Impairment

The pharmacokinetics of clarithromycin and its metabolite have been studied in patients with mild to moderately (CLCR 1.8 to 4.2 L/h) and severely (CLCR 0.6 to 1.74 L/h) impaired renal function.[8,9] After 5 doses of oral clarithromycin 500mg every 12 hours, the mean values of Cmax (2.47 ± 0.75 vs 3.76 ± 1.77 vs 8.27 ± 3.13 mg/L) and Cmin (1.04 ± 0.46 vs 2.27 ± 1.45 vs 6.34 ± 2.69 mg/L) of clarithromycin progressively increased in the 2 groups of patients with impaired renal function compared with individuals with healthy renal function. A similar increase in Cmax (1.02 ± 0.29 vs 2.01 ± 1.10 vs 6.43 ± 3.85 mg/L, respectively) and Cmin (0.65 ± 0.19 vs 1.72 ± 1.10 vs 6.18 ± 3.76 mg/L, respectively) was observed for 14-hydroxyclarithromycin. The increased plasma concentrations were associated with a prolonged t1⁄2β for clarithromycin (6.7 vs 11.5 vs 21.6h, respectively) and its metabolite (12.0 vs 30.5 vs 46.9h, respectively). Overall, these data suggest that dosage adjustments are needed for clarithromycin in patients with severe renal impairment. For patients with a CLCR <1.8 L/h, Hardy et al.[9] suggested that a regimen consisting of a 500mg loading dose followed © Adis International Limited. All rights reserved.

391

by a maintenance dose of 250mg every 12 hours results in similar plasma concentrations as 500mg every 12 hours in individuals with no renal impairment. These authors also suggested that a regimen of 250mg once daily in patients with severe renal impairment is comparable with 250mg every 12 hours in individuals with no renal impairment. 2.2 Patients with Hepatic Impairment

The pharmacokinetics of clarithromycin and 14-hydroxyclarithromycin have been compared in 6 adults with Pugh grade B or C hepatic impairment and 6 healthy volunteers.[18] After 5 doses of oral clarithromycin 250mg every 12 hours, the mean values of Cmin were similar between doses 2 to 5 in both groups and showed no significant drug accumulation. A trend towards a longer t1⁄2β (3.3 vs 5.0h) and larger Vβ/F (138 ± 19 vs 305 ± 211L), CL/F (29.16 ± 9.96 vs 42.78 ± 35.58 L/h) and CLR (6.66 ± 1.02 vs 10.2 ± 4.14 L/h), of clarithromycin were observed in patients with hepatic impairment. Alterations in protein binding probably explained the observed increases in Vβ/F and CLR, as no significant differences in urinary recoveries of clarithromycin (24.2 ± 6.6% vs 31.6 ± 16.0%) suggest no alterations in oral bioavailability. Significant correlations were documented between plasma AAG and CLR/CLCR, CLR or CL/F. Patients with hepatic impairment had a decreased AAG, which was associated with a higher unbound fraction of clarithromycin. Overall, the decreased CL/F would probably offset its increased CLR, resulting in minimal changes in the steady-state plasma concentrations of clarithromycin. In addition, the increased unbound fraction and larger Vβ/F would slightly lower the total drug concentration (e.g., Cmax). Overall, similar unbound drug concentrations of clarithromycin would be expected in patients with hepatic impairment as those found in healthy individuals. The disposition of 14-hydroxyclarithromycin was significantly altered in patients with hepatic impairment.[18] Significant decreases were observed in Cmax (0.83 ± 0.37 vs 0.36 ± 0.23 mg/L), AUC to 12 hours (AUC12) [6.10 ± 2.08 vs 3.17 ± Clin Pharmacokinet 1999 Nov; 37 (5)

392

2.27 mg • h/L] and ratios of metabolite to parent based on urinary recoveries (0.67 ± 0.18 vs 0.35 ± 0.19) and on AUC12 (0.67 ± 0.18 vs 0.33 ± 0.21). The pharmacokinetic parameters of clarithromycin and 14-hydroxyclarithromycin are not significant altered in patients with mild alcoholic liver disease (defined as modest elevations in transaminases and no elevation in total bilirubin). A summary of these data is provided in Hardy et al.[9] Overall, these data suggest that dosage adjustments of clarithromycin in patients with moderate to severe hepatic impairment with no renal impairment do not appear to be necessary, and are not recommended. However, if the active metabolite 14-hydroxyclarithromycin is necessary for antimicrobial activity (see section 3), caution must be used before prescribing clarithromycin for the treatment of infections in patients with moderate to severe liver disease. 2.3 Elderly

Twelve young (18 to 30 years of age) and 12 elderly (65 to 84 years of age) healthy volunteers received 5 doses of oral clarithromycin 500mg every 12 hours.[21] Significant increases were observed in Cmax (2.41 ± 0.67 vs 3.28 ± 0.80 mg/L), Cmin (0.73 ± 0.27 vs 1.69 ± 0.69 mg/L) and AUC12 (18.87 ± 5.55 vs 30.76 ± 8.50 mg • h/L) of clarithromycin in the elderly participants. These observed changes in plasma concentrations were associated with a reduced CL/F (28.56 ± 6.72 vs 18 ± 5.82 L/h) and CLR (10.08 ± 2.1 vs 5.04 ± 1.86 L/h) of clarithromycin. For 14-hydroxyclarithromycin, significant increases in Cmax (2.41 ± 0.67 vs 3.28 ± 0.80 mg/L), Cmin (0.73 ± 0.27 vs 1.69 ± 0.69 mg/L) and AUC12 (18.87 ± 5.55 vs 30.76 ± 8.50 mg • h/L) were also observed in the elderly group. Compared with the younger group, a lower CLR (8.4 ± 1.68 vs 4.62 ± 1.62 L/h) and longer t1⁄2β (7.2 vs 14.0h) was observed in the elderly group. The increase in the drug concentrations of clarithromycin and its active metabolite were well tolerated in this study and not associated with an increase incidence or severity of adverse reactions. No alterations in the dos© Adis International Limited. All rights reserved.

Rodvold

age of clarithromycin are recommended in elderly patients with normal renal function. 3. Pharmacodynamics Our understanding of the relationships between antibacterial concentrations and in vitro-in vivo bactericidal activity has rapidly expanded during the past decade.[43] The application of this knowledge is useful for the design of antibacterial dosage regimens that can maximise efficacy, minimise toxicity and limit the development of bacterial resistance. Clarithromycin has a moderate ‘postantibiotic effect’ and displays concentration-independent bactericidal activity.[44] The most important pharmacodynamic parameter associated with the in vivo activity of such concentration-independent antibacterials is the duration of time that the unbound drug concentrations are above the minimum inhibitory concentration (t>MIC). The recommended goal for dosage regimens of clarithromycin is to maintain t>MIC for at least 40 to 60% of the dosage interval. The adult dosage regimens of clarithromycin 250 and 500mg twice daily achieve unbound concentration-time profiles that satisfy this goal as long as the MIC values are between 0.25 and 0.5 mg/L, and 0.5 and 1.0 mg/L, respectively. For certain pathogens (e.g., Haemophilus influenzae), the concentrations and in vitro activity of the active metabolite, 14-hydroxyclarithromycin, must be considered.[45,46] The current dosage regimens of clarithromycin maintain a 2 : 1 ratio of the parent to metabolite serum concentrations during the 12-hour dosage interval. The additive and/or synergistic effects of the parent and metabolite against H. influenzae complicate the interpretation of necessary target concentrations for clarithromycin. Pharmacodynamic parameters such as t>MIC are based on data using blood concentrations of antibacterial. However, for macrolide antibacterials, concentrations in body fluids and cells do not seem to be proportional to unbound blood concentrations. Compared with serum concentrations, clarithromycin achieves significantly higher drug conClin Pharmacokinet 1999 Nov; 37 (5)

Clarithromycin

centrations in the epithelial lining fluid and alveolar macrophages (table IV), the potential sites of extracellular and intracellular respiratory pathogens, respectively. This may limit the application of t>MIC based only on blood concentrations in predicting bacteriological and clinical efficacy in the treatment of lower respiratory tract infections, including resistant strains of Streptococcus pneumoniae.[47] Are concentrations of clarithromycin at the site of infection the most appropriate target concentration to incorporate into t>MIC? Further studies are needed to determine if clarithromycin concentrations in the epithelial lining fluid and alveolar macrophages are better predictors of clinical efficacy of lower respiratory tract infections. 4. Drug Interactions Our knowledge and understanding of the CYP isozyme system has dramatically increased during the past decade. These recent advances allow for the identification of which isozyme activity is responsible for specific metabolic pathways of a drug. In addition, the prediction of potential drug interactions is also theoretically possible. Clarithromycin is primarily metabolised by CYP3A isozymes.[41] CYP3A has a broad substrate specificity and can be subject to inhibition and induction by a variety of therapeutic agents. In vitro studies have shown that potent inhibitors of CYP3A (e.g. ketoconazole and ritonavir) alter the metabolism of clarithromycin. In addition, studies in the hepatic microsomes of rats have demonstrated that clarithromycin and its N-demethylated and N-oxide metabolites can induce CYP3A1 and form a specific metabolite complex with CYP.[48,49] These observations suggest that clarithromycin would be expected to be associated with drug interactions that involved CYP3A, but to a lesser extent than older macrolides, such as erythromycin and troleandomycin.[1,4,6,11] Several excellent reviews have been published on the drug interactions of clarithromycin and other macrolides.[4,6,11,50-55] The following section will briefly review the clinical impact of the more © Adis International Limited. All rights reserved.

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recently published drug interaction studies of clarithromycin.[56-110] Table V provides an extensive summary of the reported drug interactions of clarithromycin. 4.1 Inhibition

Clarithromycin can increase the AUC or steadystate concentrations of drugs that are primarily depend upon CYP3A metabolism. The most clinically significant of these interactions have been with drugs such as astemizole, cisapride, pimozide and terfenadine.[62-64,89,102,103] Concurrent administration of these agents and clarithromycin is contraindicated. Several studies and post-marketing reports have also indicated that clarithromycin can dramatically decrease the clearance and increase the AUC of midazolam and triazolam.[84-86,106] Caution should be used in prescribing these agents together, and dosage reductions of these benzodiazepines are usually necessary. Clarithromycin increases the serum concentrations of drugs associated with a narrow therapeutic index, such as carbamazepine, cyclosporin, digoxin and theophylline.[57-60,65-69,71-78,104,105] The magnitude of increase in the serum drug concentrations of these agents is significantly less for clarithromycin compared with erythromycin. However, the monitoring of serum drug concentrations and/or appropriate reductions in dosage should still be considered when clarithromycin is simultaneously used with these agents. Similar precautions (e.g. monitoring of International Normalised Ratio and/or dosage reduction) may be necessary with oral anticoagulants.[107,108] Potent inhibitors of CYP3A may also alter the metabolism of clarithromycin and its metabolites. Omeprazole has been shown to increase the serum and gastric tissue concentrations of clarithromycin and 14-hydroxyclarithromycin.[87,88] At the same time, clarithromycin increases the AUC and Cmax of omeprazole. These interactions may prove be beneficial in the eradication of Helicobacter pylori infections. Similarly, concomitant administration of clarithromycin and ranitidine bismuth citrate is associated with a significant increase in the plasma Clin Pharmacokinet 1999 Nov; 37 (5)

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Rodvold

Table V. Literature reports of drug interactions with clarithromycin and their clinical significance Interacting agent

Pharmacokinetic significance

Clinical significance

Antacids

None

None

Carbamazepine

Carbamazepine: ↑AUC, ↑Css; 11-epoxide metabolite: ↓Cmax, ↓AUC, ↓t1⁄2β ↑ risk of toxicity

References 56 57-60

Cimetidine

C and 14-OH: ↑Cmax, ↑t1⁄2β, ↔AUC

None

61

Cisapride

Cisapride: 3-fold ↑AUC, ↑Css, ↑Cmax

↑ risk of toxicity

62-64

Cyclosporin

Cyclosporin: ↑AUC, ↑Css

↑ risk of toxicity

65-69

Didanosine

None

None

26,70

Digoxin

Digoxin: ↑Css

↑ risk of toxicity

71-78

Disopyramide

?

↑ risk of toxicity

79

Fluconazole

C: ↑18% AUC, ↑33% Cmin

None

80

Grapefruit juice

C and 14-OH: ↑tmax

None

81

Loratadine

Loratadine: ↑76% AUC, ↑36% Cmax; descarboxyethyl metabolite: ↑49% AUC, ↑69% Cmax

None

82

Methyprednisolone

Methyprednisolone: ↓CL/F, ↑t1⁄2β

↑ risk of toxicity

83

Midazolam

Midazolam: ↓64% CLs, ↓86% CL/F

↑ risk of toxicity

84-86

Omeprazole

C: ↑15% AUC, ↑27% Cmin; ↑tissue Cp; 14-OH: ↑45% AUC, ↑44% Cmax, ↑57% Cmin , ↑tissue Cp; omeprazole: ↑89% AUC, ↑30% Cmax, ↑34% t1⁄2β

None

87, 88

Pimozide

Pimozide: ↑113% AUC, ↑39% Cmax, ↓46% CLs

↑ risk of toxicity

89

Prednisolone

None

None

83

Prednisone

?

None

91

Ranitidine

None

None

56

Ranitidine bismuth citrate Ranitidine: ↑57% Cp; bismuth: ↑48% Cmin; 14-OH: ↑31% Cp Rifabutin

Rifabutin: ↑94% AUC, ↑400% Cp; 25-O-desacetylrifabutin: ↑375% AUC, ↑3700% Cp; C: ↓44% AUC; 14-OH: ↑57% AUC

None

92, 93

↑ risk of toxicity

94-98

Rifampicin (rifampin)

C: ↓↓ Cp; 14-OH: ↔ Cp

None

98, 99

Ritonavir

C: ↑77% AUC, ↑31% Cmax, ↑182% Cmin; 14-OH: completely inhibited

None

100

Tacrolimus

Tacrolimus: ↑Cmin

None

101

Terfenadine

Acid metabolite: ↑109% Cmax, ↑154% AUC

↑ risk of toxicity

102, 103

Theophylline

Theophylline: ↑0-17% AUC

↑ risk of toxicity

104, 105

Triazolam

Triazolam: ↑425% AUC, ↑97% Cmax, ↓77% CL/F

↑ risk of toxicity

106

Warfarin

?

↑ risk of toxicity

107, 108

Zafirlukast

None

None

90

Zidovudine

Zidovudine: ↓ AUC, ↓↑Cmax, ↓↑tmax

None

26, 109, 110

AUC = area under the concentration-time curve; C = clarithromycin; CL/F = total body clearance; CLs = systemic clearance; Cmax = maximum drug plasma concentration; Cmin = minimum drug plasma concentration; Cp = concentration; Css = steady-state drug concentration; t1⁄2β = elimination half-life; tmax = time to Cmax; 14-OH = 14-hydroxyclarithromycin; ? = unknown; ↑ = increase; ↓ = decrease; ↓↓ = marked decrease; ↔ = no change; ↑↓== variable effect .

concentrations of ranitidine, bismuth and 14hydroxyclarithromycin.[92,93] Ritonavir is a protease inhibitor used in the treatment of patients with HIV. It is a potent inhibitor of several CYP isoforms, including CYP3A, and has been shown to significantly increase the AUC, Cmax and Cmin of clarithromycin.[100] However, formation of 14-hydroxyclarithromycin is nearly completely inhibited by ritonavir. The concurrent use of ritonavir and clarithromycin should be approached with caution in cases where 14© Adis International Limited. All rights reserved.

hydroxyclarithromycin is necessary for antimicrobial activity (e.g. H. influenzae). 4.2 Induction

Rifampicin (rifampin) and rifabutin are potent enzyme inducers of several CYP isozymes, including CYP3A. Several small studies have suggested that rifampicin may significantly decrease serum clarithromycin concentrations.[98,99] Rifampicin Clin Pharmacokinet 1999 Nov; 37 (5)

Clarithromycin

seems to have minimal to no effect on the concentrations of 14-hydroxyclarithromycin. The drug interactions between rifabutin and clarithromycin include both induction and inhibition.[94-98] Rifabutin decreases the AUC of clarithromycin and increases the AUC of 14-hydroxyclarithromycin. Clarithromycin significantly increases the AUC of rifabutin and its metabolite 25-O-desacetylrifabutin. The pharmacokinetic interaction between clarithromycin and rifabutin should be avoided because of the associated increased incidence of rifabutin toxicity, including uveitis and polyarthritis. 5. Conclusions The pharmacokinetic advantages that clarithromycin has over erythromycin include increased oral bioavailability, increased plasma and tissue concentrations, and a longer elimination half-life to allow twice daily administration. Clarithromycin is primarily metabolised by CYP3A isozymes. In vitro and in vivo studies have shown that potent inhibitors of CYP3A alter the metabolism of clarithromycin and 14-hydroxyclarithromycin. In addition, clarithromycin is involved with drug interactions that are associated with inhibition of CYP3A. Overall, the pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug interactions occur with clarithromycin compared with the older macrolides, such as erythromycin and troleandomycin. References 1. Piscitelli SC, Danziger LH, Rodvold KA. Clarithromycin and azithromycin: new macrolide antibiotics. Clin Pharm 1992; 11: 137-52 2. Peters DH, Clissold SP. Clarithromycin: a review of its antimicrobial activity, pharmacokinetic properties, and clinical efficacy. Drugs 1992; 44: 117-64 3. Sturgill MG, Rapp RP. Clarithromycin: review of a new macrolide antibiotic with improved microbiologic spectrum and favorable pharmacokinetic and adverse effect profiles. Ann Pharmacother 1992; 26: 1099-108 4. Rodvold KA, Piscitelli SC. New oral macrolide and fluoroquinolone antibiotics: an overview of pharmacokinetics, interactions, and safety. Clin Infect Dis 1993; 17 Suppl. 1: S192-9 5. Barradell LB, Plosker GL, McTavish D. Clarithromycin: a review of its pharmacological properties and therapeutic use in Mycobacterium avium-intracellulare complex infection in

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6. 7.

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26. Husson RN, Ross LA, Sandelli S, et al. Orally administered clarithromycin for the treatment of systemic Mycobacterium avium complex infection in children with acquired immunodeficiency syndrome. J Pediatr 1994; 124: 807-14 27. Ishiguro M, Koga H, Kohno S, et al. Penetration of macrolides into human polymorphonuclear leucocytes. J Antimicrob Chemother 1989; 24: 719-29 28. Fietta A, Merlini C, Grassi GG. Requirements for intracellular accumulation and release of clarithromycin and azithromycin by human phagocytes. J Chemother 1997; 9: 23-31 29. Wust J, Hardegger U. Penetration of clarithromycin into human saliva. Chemotherapy 1993; 39: 293-6 30. Scaglione F, Pintucci JP, Tassi GF, et al. Penetration of clarithromycin into oral and respiratory tissues. Drug Invest 1993; 6: 104-9 31. Tsang KWT, Roberts P, Read RC, et al. The concentration of clarithromycin and its 14-hydroxy metabolite in sputum of patients with bronchiectasis following single dose oral administration. J Antimicrob Chemother 1994; 33: 289-97 32. Fish DN, Gotfried MH, Danziger LH, et al. Penetration of clarithromycin into lung tissues from patients undergoing lung resection. Antimicrob Agents Chemother 1994; 38: 876-8 33. Sundberg L, Cederberg A. Penetration of clarithromycin and its 14-hydroxy metabolite into middle ear effusion in children with secretory otitis media. J Antimicrob Chemother 1994; 33: 299-307 34. Gan VN, McCarty JM, Chu SY, et al. Penetration of clarithromycin into middle ear fluid of children with acute otitis media. Pediatr Infect Dis J 1997; 16: 39-43 35. Conte JE, Golden J, Duncan S, et al. Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects. Antimicrob Agents Chemother 1996; 40: 1617-22 36. Honeybourne D, Kees F, Andrews JM, et al. The levels of clarithromycin and its 14-hydroxy metabolite in the lung. Eur Respir J 1994; 7: 1275-80 37. Conte JE, Golden J, Duncan S, et al. Intrapulmonary pharmacokinetics of clarithromycin and erythromycin. Antimicrob Agents Chemother 1996; 40: 1617-22 38. Patel KB, Xuan D, Tessier PR, et al. Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agents Chemother 1996; 40: 2375-9 39. Rodvold KA, Gotfried MH, Danziger LH, et al. Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers. Antimicrob Agents Chemother 1997; 41: 1399-402 40. Ferrero JL, Bopp BA, March KC, et al. Metabolism and disposition of clarithromycin in man. Drug Metab Dispos 1990; 18: 441-6 41. Rodrigues AD, Roberts EM, Mulford DJ, et al. Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P4503A (CYP3A) subfamily. Drug Metab Dispos 1997; 25: 623-30 42. Chu SY, Sennello LT, Bunnell ST, et al. Pharmacokinetics of clarithromycin, a macrolide, after single ascending oral doses. Antimicrob Agents Chemother 1992; 36: 2447-53 43. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1-12 44. Craig WA. Postantibiotic effects and the dosing of macrolides, azalides and streptogramins. In: Zinner SH, Young LS, Acar JF, et al., editors. Expanding indications for the new macrolides, azalides and streptogramins. New York: Marcel Dekker Inc, 1997: 27-38

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45. Hardy DJ, Swanson RN, Rode RA, et al. Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans. Antimicrob Agents Chemother 1990; 34: 1407-13 46. Jorgensen JH, Maher LA, Howell AW. Activity of clarithromycin and its principal metabolite against Haemophilus influenzae. Antimicrob Agents Chemother 1991; 35: 1524-6 47. Amsden GW. Pneumococcal macrolide resistance: myth or reality? J Antimicrob Chemother 1999; 44: 1-6 48. Tinel M, Descatoire V, Larrey D, et al. Effects of clarithromycin on cytochrome P-450: comparison with other macrolides. J Pharmacol Exp Ther 1989; 250: 746-51 49. Ohmori S, Ishii I, Kuriya SI, et al. Effects of clarithromycin and its metabolites on the mixed function oxidase system in hepatic microsomes of rats. Drug Metab Disp 1993; 21: 358-63 50. Ludden TM. Pharmacokinetic interactions of macrolide antibiotics. Clin Pharmacokinet 1985; 10: 63-79 51. Periti P, Mazzei T, Mini E, et al. Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet 1992; 23: 106-31 52. von Rosenstiel NA, Adam D. Macrolide antibacterials: drug interactions of clinical significance. Drug Saf 1995; 13: 105-22 53. Amsden GW. Macrolide versus azalides: a drug interaction update. Ann Pharmacother 1995; 29: 906-17 54. Nahata M. Drug interactions with azithromycin and the macrolides: an overview. J Antimicrob Chemother 1996; 37 Suppl. C: 133-42 55. Watkins VS, Polk RE, Stotka JL. Drug interactions of macrolides: emphasis on dirithromycin. Ann Pharmacother 1997; 31: 349-56 56. Zundorf H, Wischmann L, Fassbender M, et al. Pharmacokinetics of clarithromycin and possible interaction with H2 blockers and antacids [abstract no. 515]. In: Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy; 1991 Sep 29-Oct 21; Chicago (IL). Washington, DC: American Society for Microbiology, 1991: 185 57. Yasui N, Otani K, Kaneko S, et al. Carbamazepine toxicity induced by clarithromycin coadministration in psychiatric patients. Int Clin Psychopharmacol 1997; 12: 225-9 58. Metz DC, Getz HD. Helicobacter pylori gastritis therapy with omeprazole and clarithromycin increases serum carbamazepine levels. Dig Dis Sci 1995; 40: 912-4 59. Albani F, Riva R, Baruzzi A. Clarithromycin-carbamazepine interaction: a case report. Epilepsia 1993; 34: 161-2 60. Richens A, Chu SY, Sennello LT, et al. Effect of multiple doses of clarithromycin on the pharmacokinetics of carbamazepine [abstract no. 760]. In: Program and Abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1990 Oct 21-24; Atlanta (GA). Washington, DC: American Society for Microbiology, 1990: 213 61. Amsden GW, Cheng KL, Peloquin CA, et al. Oral cimetidine prolongs clarithromycin absorption. Antimicrob Agents Chemother 1998; 42: 1578-80 62. van Haarst AD, van’t Klooster GAE, van Gerven JMA, et al. The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 1998; 64: 542-6 63. Sekkarie MA. Torsades de pointes in two chronic renal failure patients treated with cisapride and clarithromycin. Am J Kidney Dis 1997; 30: 437-9 64. Piquette RK. Torsade de pointes induced by cisapride/clarithromycin interaction. Ann Pharmacother 1999; 33: 22-6 65. Sadaba B, Lopez de Ocariz A, Azanaz JR, et al. Concurrent clarithromycin and cyclosporin A treatment. J Antimicrob Chemother 1998; 42: 393-5

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Correspondence and reprints: Dr Keith A. Rodvold, m/c 886, Pharmacy Practice, College of Pharmacy, Room #164, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 606012, USA. E-mail: [email protected]

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