Pharmacokinetics and tolerability of extended-release clarithromycin

CLINICAL THERAPEUTICSVVOL.

Pharmacokinetics Clarithromycin

23, NO. 4,200l

and Tolerability of Extended-Release

David RR Guay, PharmD,’ Linda E. Gustavson, PhD,2 Karen J. Devcich, MS,2 Jie Zhang, PhD,2 Guoliang Cao, PhD,3* and Carol A. Olson, MD, PhD2 ‘Institute.for the Study of Geriatric Pharmacotherapy,

College of Pharmacy, University of Minnesota, and PartneringCare Senior Services, HealthPartners Inc, Minneapolis, Minnesota, 2Abbott Laboratories, Chicago, and 3Biometrics, Takeda Pharmaceuticals America, Lincolnshire, Illinois

ABSTRACT Background: Clarithromycin is a semisynthetic macrolide that exhibits broad-spectrum activity against gram-positive, gram-negative, and atypical respiratory tract and skin/skin structure pathogens, Mycobacterium species, and Helicobacter pylori. It is indicated for the treatment of a wide variety of respiratory and dermatologic infections in children and adults as well as prophylaxis and treatment of Mycobacterium avium complex infection and peptic ulcers due to H pylori. Objective: In this article, we review the results of 3 studies of the steady-state pharmacokinetic profiles of clarithromycin and 14(R)-hydroxy-clarithromycin after multiple oral once-daily doses of 500-mg extended-release (ER) clarithromycin tablets. We also review the drug tolerability in 2 phase III comparative clinical trials of immediate-release (IR) and ER clarithromycin conducted in adults with acute maxillary sinusitis (AMS) and acute exacerbation of chronic bronchitis (AECB). Methods: In the 3 pharmacokinetic studies, multiple-dose regimens of clarithromycin IR (one 250-mg or 500-mg tablet twice daily) and clarithromycin ER (one or two 500-mg tablets once daily), administered to healthy male and female volunteers, were evaluated. The effect of administration in nonfasting versus fasting conditions was assessed as well. Tolerability information was collected from each adult patient enrolled in phase III efficacy studies conducted to support the application for US Food and Drug Administration approval for the treatment of AMS and AECB. Regimens evaluated were 500 mg IR clarithromycin *At the time this manuscript was written, Guoliang Cao was a statistician at Abbott Laboratories, Accepted

for publication

Chicago, Illinois.

January 31, 2001.

Printed in the USA. Reproduction in whole or part is not permitted.

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0149.2918/01/$19.00

D.R.P. GUAY ET AL.

tablets twice daily or 1000 mg (2 x 500 mg) ER clarithromycin tablets once daily for 7 days (AECB) or 14 days (AMS). Results: Bioavailability of the ER clarithromyin tablet administered with food was equivalent to that of the reference IR tablet, based on area under the plasma concentration-time curve (AUC) for both parent compound and active metabolite. The bioavailability of the ER tablet was 30% lower (based on clarithromycin AUC) when administered under fasting versus nonfasting conditions. Compared with the IR tablet, administration of the ER tablet resulted in significantly lower (P < 0.05) clarithromycin peak plasma concentration (C,,,), delayed time to C max, and lower degree of concentration fluctuation, confirming its in vivo extendedrelease characteristics. The most frequently reported adverse events (AEs) in the phase III clinical trials were diarrhea, abnormal taste, and nausea and were generally mild or moderate. The incidence of AEs was comparable for the 2 formulations. The severity of gastrointestinal AEs was significantly less for the ER formulation than for the IR formulation (P = 0.018), as was the frequency of premature study discontinuation due to gastrointestinal AEs or abnormal taste (P = 0.004). Conchsions: The results from the 3 pharmacokinetic studies reviewed demonstrate the bioequivalence of the ER and IR formulations and support the use of this clarithromycin ER formulation in a once-daily dosing regimen in phase III clinical trials. The ER tablet should be taken with food to maximize bioavailability. The results of 2 phase III comparative clinical efficacy and safety trials of clarithromycin ER tablets versus IR tablets in AMS and AECB confirm the good tolerability of the ER formulation.

Key words: clarithromycin, macrolides, extended-release, pharmacokinetics. (C/in Thel: 2001;23:566-577)

INTRODUCTION Clarithromycin is a semisynthetic macrolide that exhibits broad-spectrum activity against gram-positive and gram-negative aerobes, atypical bacterial pathogens of the respiratory tract, Mycobacterium species, and Helicobacter pylori. It is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis (AECB), acute maxillary sinusitis (AMS), bacterial pneumonia, acute otitis media, streptococcal pharyngotonsillitis, uncomplicated skin/skin structure infections, prophylaxis/treatment of disseminated Mycobacterium avium complex infection, and duodenal ulcer disease due to H pylori infection in adults and children.lm5 The activity of clarithromycin is due not only to the parent molecule but also to its active 14(R)-hydroxy metabolite, especially against pathogens such as Haemophilus injluenzae.

The immediate-release (IR) clarithromycin tablet and granules for suspension formulations are dosed twice daily for respiratory tract infections. An extendedrelease (ER) clarithromycin formulation has been developed to facilitate adherence by reducing dosing frequency and perhaps improve gastrointestinal (GI) tolerability. The purpose of this paper is to (1) review the results of 3 studies that assessed the pharmacokinetics of clarithromycin ER after oral multiple doses (every 24 hours) of 500-mg tablets in healthy volunteers, and (2) review the tolerability of clarithromycin ER and clarithromycin IR in 2 comparative phase III studies in adults.

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MATERIALS Pharmucokinetic

AND METHODS Studies

Subjects Men and women aged 18 to 50 years were eligible for study participation. Subjects were judged to be in good health on the basis of normal findings on medical history, physical examinations, clinical laboratory profiles, and electrocardiographic assessments. Exclusion criteria included regular use of any medication (other than vitamins and oral contraceptives/hormone replacement therapy); receipt of any substrate, inducer, or inhibitor of cytochrome P450 within 4 weeks before study initiation; positive screening test results for hepatitis B surface antigen, hepatitis C antibody, or drugs of abuse; or history of any surgical procedure that could interfere with GI motility, pH, or absorption. All participants provided written informed consent, as required by the local institutional review board, before participation. Study Design Studies 1,2, and 3 were conducted in the United States according to multiple-dose, open-label, randomized, crossover designs. Washout periods of 21 week separated the last dose of a period from the first dose of the next period in all 3 studies. In Study 1, regimen A was two 500-mg clarithromycin ER tablets administered once daily for 5 days with food, and regimen B was one 500-mg clarithromycin IR tablet administered twice daily for 5 days with food. In Study 2, regimen A was two 500-mg clarithromycin ER tablets administered once daily for 5 days under fasting conditions (an g-hour fast before dosing and a 4-hour fast after dosing). Regimen B was two 500-mg clarithromycin ER tablets ad-

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ministered once daily for 5 days 30 minutes after starting a high-fat breakfast (-1000 kcal, with 50% of calories from fat). In Study 3, regimen A was one 500-mg clarithromycin ER tablet administered once daily for 5 days with food. Regimen B was one 250-mg clarithromycin IR tablet administered twice daily for 5 days with food. Blood Sampling In studies 1 and 3, blood samples (5 mL) were collected immediately before the morning doses on study days 1, 3, 4, and 5 and 0.5, 1,2,3,4,6, 8, 10, 12, 12.5, 13, 14, 15, 16, 18, 20, and 24 hours after the morning dose on study day 5. In Study 2, blood samples (7 mL) were collected immediately before the morning doses on study days 1 through 5 and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours after the morning dose on study day 5. Plasma Sample Analysis Plasma samples were analyzed for clarithromycin and 14(R)-hydroxy-clarithromycin content using high-performance liquid chromatography with electrochemical detection6 Standard curves were linear over a concentration range of 0.0156 to 11 mg/L. Intraday and interday coefficients of variation were typically within +6%. Lower quantifiable limits for both analytes were 0.02 mg/L using a 0.5-mL plasma sample. Data Analysis Noncompartmental methods were used to generate pharmacokinetic parameters for clarithromycin and 14(R)-hydroxyclarithromycin.7 Peak and trough plasma concentrations (Cmax and Cmin, respectively) and time to Cmax (Tma,) were read from the observed plasma concentration-

D.R.P. WAY

ET AL.

time profile. Area under the plasma concentration-time profile over 24 hours at steady state (AUC,,,) was calculated via the linear trapezoidal rule. The degree of plasma concentration fluctuation was calculated as C_ - Cmin divided by CaVs,where Cays was the AUC, divided by 24 hours. Since terminal disposition half-life data from the ER formulation cannot be compared with previous data from the IR formulation due to the prolonged concurrence of absorption, distribution, and elimination with the ER formulation, these data were not included in the pharmacokinetic analysis. In addition, biologic samples were not collected long enough to characterize the terminal disposition phase. Since apparent oral clearance (CL/F) = dose/AUC, the AUC data presented provide a surrogate measure of apparent oral clearance as well. Analyses of variance were performed for day-5 pharmacokinetic variables of both analytes, with effects for regimen, and subject nested period, sequence, within sequence at a significance level of 0.05.8 Logarithmic transformation was used for all variables except Tmax (all 3 studies) and Cmin (Study 2 only). Bioequivalence of regimens was assessed using the 2 one-sided tests procedure via 90% CIs.9

Tolerability/Clinical

Studies

Tolerability information was collected from each patient enrolled in phase III efficacy trials conducted in the United States as part of the application to the US Food and Drug Administration for approval of clarithromycin ER tablets. These studies assessed the efficacy and safety of clarithromycin ER versus clarithromycin IR tablets in the treatment of AMS’O and AECB” in patients aged >I 2 years.

Within the phase III trial program, patients who received clarithromycin ER took 1000 mg (2 x 500 mg) once daily for 7 days (AECB) or 14 days (AMS). The regimens for the comparator were as follows: clarithromycin IR 500 mg twice daily for 7 days (AECB) or 14 days (AMS). Investigators were instructed to evaluate all patients for any adverse and/or unusual experiences by using general, openended questions, followed by specific questions as appropriate, and through physical examinations and laboratory assessments, and to record these findings on the case-report form. In addition, patient records were reviewed by monitors to ensure complete reporting of all adverse events (AEs), whether or not they were believed to be related to study treatment. Investigators assessed the relationship of each AE to treatment with study drug (probable, possible, probably not, not related) and the severity of each AE (mild, AE was transient and easily tolerated by the patient; moderate, AE caused the patient discomfort and interrupted the patient’s usual activities; severe, AE caused considerable interference with the patient’s usual activities and could have been incapacitating or life threatening). A complete physical examination was performed and a battery of clinical laboratory tests (hematology and chemistry) was collected at the time of study entry to provide baseline values and these were compared with assessments obtained at the end of therapy.

Data Analysis Patients who took 21 dose were included in the safety treatment-emergent AEs (ie, gan or worsened in severity

of study drug analyses. All those that beafter the first

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CLINICAL THERAPEUTICS”

dose of study drug) were mapped to COSTART III: Coding Symbols for Thesaurus of Adverse Reaction Terms.12 Treatment-emergent adverse-event incidence rates, for all AEs and for drug-related AEs, were summarized by treatment group and compared using the Fisher exact test. In addition, GI severity scores were analyzed using l-way analysis of variance. Potentially clinically significant laboratory values were summarized within each treatment group. Mean changes from baseline in vital signs data were summarized within each treatment group.

RESULTS Pharmacokinetic

Studies

In Study 1, 30 of 36 subjects (83.3%) completed the study protocol. One patient each withdrew due to migraine headache, bacterial vaginosis, neutropenia, rash/ candidal vaginosis, inappropriate behavior, and positive drug screen. In Study 2, all 36 subjects completed the protocol. In Study 3, 32 of 36 subjects (88.9%) completed the protocol. One patient withdrew due to a positive pregnancy test, 1 due to a revocation of consent, and 2 due to a positive drug screen. Study I Mean plasma concentration-time profiles for the ER and IR clarithromycin regimens are illustrated in Figure 1. The pharmacokinetic parameters for clarithromycin and its 14(R)-hydroxy metabolite are presented in Table I. The point estimate of relative bioavailability comparing the ER regimen to the IR regimen with for clarithromycin was respect to AUC,, 0.903. For 14(R)-hydroxy-clarithromycin, the point estimate was 1.041. The 90%

570

CIs for both compounds were within the 0.80 to I .25 range required to demonstrate equivalence to the IR formulation. The significantly lower clarithromycin C,,,, delayed Tmax, and lower degree of concentration fluctuation (P < 0.05 vs IR formulation) all indicated that extended release of clarithromycin was achieved in vivo. Study 2 Mean plasma concentration-time protiles for clarithromycin ER under fasting and nonfasting conditions are illustrated in Figure 2. The pharmacokinetic parameters for clarithromycin and 14(R)-hydroxyclarithromycin are presented in Table II. The point estimate of relative bioavailability comparing the fasting regimen with the nonfasting regimen with respect to for clarithromycin was 0.70 1, inAuc,24 dicating that clarithromycin absorption from the ER tablets was 30% lower under fasting conditions. For 14(R)-hydroxyclarithromycin, the point estimate was 0.974, and the 90% CI was within the 0.80 to 1.25 range. Study 3 Mean plasma concentration-time profiles for the clarithromycin ER and IR regimens are illustrated in Figure 3. The pharmacokinetic parameters for clarithromycin and its 14(R)-hydroxy metabolite are presented in Table III. The point estimate of relative bioavailability comparing the ER regimen to the IR regimen with respect to AUC,,, for clarithromytin was 0.946. For 14(R)-hydroxy-clarithromycin, the point estimate was 0.969. The 90% CIs for both compounds were within the 0.80 to 1.25 range required to demonstrate equivalence to the IR formulation.

D.R.P. GUAY ET AL.

-O4

0

Extended-release clarithromycin Immediate-release clarithromycin

’,

I

I

I

I

I

I

0

4

8

12

16

20

24

Time After Dosing (h)

Figure

Table

I

Study 1: Mean (2 SEM) steady-state (day 5) plasma concentration-time profiles for clarithromycin extended-release (ER) (two NO-mg tablets once daily for 5 days with food) and clarithromycin immediate-release (IR) (one 500-mg tablet twice daily for 5 days with food).

I. Day-5 pharmacokinetic hydroxy-clarithromycin

Regimen*

parameters in Study

(mean f SD) for clarithromycin

and 14(R)-

1 (N = 30).

Tnax (h)

‘,i,

(ma)

AU%*‘% (m.W

2.59 f 0.7 l+ 3.51 f 0.98

7.8 + 4.0+ 2.1 + 0.6

0.76 + 0.37+ 0.91 + 0.39

42.1 2 13.2+ 46.1 + 13.8

1.08 f 0.28+ 1.38 + 0.25

0.79 f 0.17 0.82 k 0.16

8.7 f 5.2+ 2.4 + 1.7

0.42 f 0.13 0.42 f 0.10

15.1 f. 3.2 14.4 f 2.9

0.60 + 0.23+ 0.67 + 0.14

C,,,

(mgk)

DFL

Clarithromycin A (ER) B (IR) 14(R)-hydroxyclarithromycin A (ER) B (IR)

C,,, = peak plasma concentration; T,ax = time to Cmax;C,,, = trough plasma concentration; AUC,, = area under the plasma concentration-time curve over 24 hours after dosing; DF% = degree of plasma concentration fluctuation; ER = extended-release; IR = immediate-release. *Regimen A: Two 500-mg clarithromycin ER tablets administered once daily for 5 days with food. Regimen B: One 500-mg clarithromycin tablet twice daily for 5 days with food. +P c 0.05 versus IR regimen.

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0 4

Fasting Nonfasting

OL

0

4

8

12

16

20

24

Time After Dosing (h)

Figure 2. Study 2: Mean (+ SEM) steady-state (day 5) plasma concentration-time profiles for clarithromycin extended-release (two 500-mg tablets once daily for 5 days) under fasting and nonfasting conditions. Table II. Day-5 pharmacokinetic hydroxy-clarithromycin

parameters (mean + SD) for clarithromycin in Study 2 (N = 32).

and 14(R)-

AUCc44 Regimen* Claritbromycin A (fasting) B (nonfasting)

C,,, (mgW

Tmax0)

‘min (m&J

(mg.wL)

DFL

2.33 + 0.70+

5.5 f 3.1

0.76 + 0.44

35.9 f 12.4+

1.13 f 0.45+

3.91 * 1.04

5.6 + 2.0

0.80 2 0.38

49.2 + 10.5

1.53 * 0.44

0.85 + 0.27

4.9 f 4.2

0.40 + 0.17

14.2 2 3.7

0.78 f 0.34

0.85 f 0.20

6.0 f 4.0

0.39 + 0.12

14.6 2 3.1

0.76 f 0.27

14(R)-hydroxyclarithromycin A (fasting) B (nonfasting)

= area C max = peak plasma concentration; Tmax = time to C,,; C,,, = trough plasma concentration; AK,,, under the plasma concentration-time curve over 24 hours after dosing; DFL = degree of plasma concentration fluctuation. *Regimen A: Two 500.mg clarithromycin extended-release (ER) tablets administered once daily for 5 days under fasting conditions (an S-hour fast before dosing and a 4-hour fast after dosing). Regimen B: Two 500-mg clarithromycin ER tablets administered once daily for 5 days 30 minutes after starting a high-fat breakfast (-1000 kcal, with 50% of calories from fat). +P < 0.05 versus nonfasting regimen.

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D.R.P. GUAY ET AL.

-C+

0

4

6

12

Extended-release clarithromycin Immediate-release clarithromycin

16

20

24

Time After Dosing (h)

proFigure 3. Study 3: Mean (& SEM) steady-state (day 5) plasma concentration-time files for clarithromycin extended-release (one 500-mg tablet once daily for 5 days with food) and clarithromycin immediate-release (one 250-mg tablet twice daily for 5 days with food). Table III. Day-5 pharmacokinetic hydroxy-clarithromycin

parameters (mean + SD) for clarithromycin in Study 3 (N = 32).

AuL Regimen*

C,,, (m&L)

Tmax(h)

‘,i” (m&)

(mg.W

Clarithromycin A (ER) B (IR)

1.45 f 0.43+ 1.94 rt 0.68

5.6 f 2.1+ 2.4 f 1.4

0.31 + 0.23+ 0.34 f 0.15

20.4 f 8.7 21.0 f 6.9

14(R)-hydroxyclarithromycin A (ER) B (IR)

0.58 f 0.17 0.60 ? 0.15

6.0 + 2.3+ 3.0 + 2.3

0.23 f 0.13 0.24 f 0.10

9.5 f 3.5 9.6 f 2.8

and 14(R)-

DFX

1.48 f 0.54+ 1.84 * 0.40

0.98 + 0.39 0.95 f 0.23

= area concentration; Tmax = time to C,,; C,,” = trough plasma concentration; AU&, under the plasma concentration-time curve over 24 hours after dosing; DFL = degree of plasma concentration fluctuation; ER = extended-release; IR = immediate-release. *Regimen A: One NO-mg clarithromycin ER tablet administered once daily for 5 days with food. Regimen B: One 250-mg claritbromycin IR tablet administered twice daily for 5 days with food. +P < 0.05 versus IR regimen. C max = peak plasma

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These results suggest that the clarithromycin ER formulation (2 x 500 mg once daily or 1 x 500 mg once daily) is bioequivalent to the IR formulation (1 x 500 mg twice daily or 1 x 250 mg twice daily) when administered under nonfasting conditions. In addition, the significantly reduced C maXIdelayed Tmax, and lower degree of concentration fluctuation are consistent with the extended-release properties of the ER formulation in vivo.

Tolerability Studies The clarithromycin ER and clarithromycin IR treatment groups were comparable in terms of age, body weight, sex, and racial distributions, with no significant differences between groups (Table IV). The groups were also comparable in the distributions of treatment duration and

adherence (compliance) rates, with adherence rates to each of the study drug regimens 280% in 93% and’91% of ER and IR recipients, respectively. Table V summarizes the results of the 2 tolerability studies. Of the 459 patients who received clarithromycin ER, 115 (25.1%) reported 21 AE considered related to treatment (probably or possibly related to study drug). Of this group, 7 patients reported 8 severe AEs (abnormal taste in 3 patients, and diarrhea, asthenia, atrial flutter, flatulence, and rash in 1 patient each). Of the 444 patients who received clarithromycin IR, 92 (20.7%) reported 21 AE considered related to treatment (clarithromycin ER vs IR, P = NS).Of this group, 12 patients reported 14 severe AEs (diarrhea in 4 patients, gastroenteritis and nausea in 2 patients each, and headache, gastritis, dry mouth, flatulence,

Table IV. Demographic characteristics of patients enrolled in phase III clinical trials of clarithromycin extended-release (ER) versus clarithromycin immediate-release (IR). Clarithromycin ER (N = 459) Sex, no. (%) Female Male Race, no. (%) White Black Asian Other Age, Y Mean SD Range Body weight, kg Mean SD Range

574

Clarithromycin (N=444)

274 (59.7) 185 (40.3)

257 (57.9) 187 (42.1)

396 35 8 20

389 (87.6) 26 (5.9) 12 (2.7) 17 (3.8)

(86.3) (7.6) (1.7) (4.4)

50.5 16.2 13-86

50.3 17.2 15-89

81.4 22.4 42-195

81.1 20.1 44-158

IR

Clarithromycin IR 500 mg BID x 7 days

Clarithromycin ER 2xSOOmgQDx 14 days Clarithromycin IR 500 mg BID x 14 days Clarithromycin ER 2x5OOmgQDx 7 days

Drug Regimen

5

11 6

7

Adverse Events

32

28 22

17

142

141 317

303

due to Treatment-Related Adverse Events

No. of Premature Withdrawals

(ER) versus clarithromycin

No. of Patients

AMS = acute maxillary sinusitis; AECB = acute bacterial exacerbation of chronic bronchitis. *Bothstudies were randomized, double-blind, and multicenter in design.

M97-756 (AECB)”

M97-667 (AMS)‘O

Study

extended-release

Percent of Patients with Treatment-Related

Table V. Summary of tolerability results of phase III clinical trials of clarithromycin immediate-release (IR).*

F

CLINICAL THERAPEUTICS”

tongue discoloration, and abnormal taste in 1 patient each). Overall, the most commonly reported (23%) AEs in the clarithromycin ER and IR groups were diarrhea (6% and 5%, respectively), abnormal taste (6% and 6%), and nausea (3% and 5%). Abdominal pain was reported in 2% and 0% of clarithromycin ER and IR recipients, respectively (P = 0.015). When the severity of GI events was assessed on a scale of 1 to 3 (1 = mild, 2 = moderate, 3 = severe), there was a significant difference between the treatments in mean severity scores favoring the ER formulation (ER, 1.32 f 0.51; IR, 1.58 + 0.71; P = 0.018). In addition, the incidence of premature discontinuation from treatment due to GI events was significantly less with the ER formulation (ER, 0.7% [3/459]; IR, 2.9% [13/444]; P = 0.01 1), as was treatment discontinuation due to GI or abnormal taste events (ER, 0.7% [3/459]; IR, 3.4% [15/444]; P = 0.004). No patient prematurely discontinued treatment with clarithromycin ER tablets because of abnormal taste. Analyses were also performed to assess the effect of sex, race, and age on the incidence of AEs. In an analysis of events considered to be treatment related, the only significant sex-related difference between groups occurred with abdominal pain: 6 of 274 female patients (2.2%) in the clarithromycin ER group and none of the 257 female patients in the IR group reported abdominal pain (P = 0.03 1). The only significant race-related differences occurred with abdominal pain, which was reported in 6 of 396 (1.5%) and none of the 389 white patients in the ER and IR group, respectively (P = 0.031); and with dyspepsia, which was reported in 1 of 396 (0.3%) and 8 of 389 (2.1%) white patients in the ER and IR group, respectively (P = 0.020). No

576

significant age-related differences between the 2 formulations were noted in any of the 3 age strata (~40 years [n = 2661; 40-64 years [n = 4341; %4 years [n = 2031). Serum chemistry alterations that were possibly clinically significant, according to criteria developed by the sponsor, occurred in 4 patients in each study group (clarithromycin ER and IR) of the AECB study. Investigators did not consider any of the changes to be of clinical concern. No vital sign values were considered to be potentially clinically significant.

DISCUSSION Clarithromycin is an advanced-generation macrolide with a terminal disposition halflife of 4 to 5 hours that is metabolized to an active 14(R)-hydroxy metabolite with a 5- to 7-hour half-life.1,3 Thus, the IR tablet formulation is dosed twice daily for respiratory tract infections. The results from the simple noncompartmental pharmacokinetic analyses of the 3 studies reviewed demonstrate the bioequivalence of the ER and IR formulations under nonfasting conditions and support the use of this clarithromycin ER formulation in a once-daily dosing regimen in phase III clinical trials.lo~l * The results of 2 phase III comparative clinical efficacy and safety trials of clarithromycin ER tablets versus IR tablets in AMS and AECB confirm the good tolerability of the ER formulation, and indicate that it may be better tolerated than the IR formulation when evaluated in terms of severity of GI-related AEs and premature discontinuation due to GI or taste AEs.

CONCLUSIONS The ER formulation of clarithromycin bioequivalent to the IR formulation,

is is

D.R.I? GUAY ET AL.

well tolerated, and has the advantage once-daily administration.

of

ACKNOWLEDGMENTS

8. SAS

This paper was supported by an unrestricted grant from Abbott Laboratories to Dr. David Guay. REFERENCES 1. Alvarez-Elcoro S, Enzler MJ. The macrolides: Erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc. 1999;74: 613634. 2. Ong EL. Prophylaxis Mycobacterium

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avium complex

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4th ed. Gary, NC: SAS Institute Inc; 1990: 891-996.

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1987;15:657680.

10. Murray JJ, Solomon E, McCluskey D, et al. Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of adult patients with acute maxillary sinusitis. Clin Ther 2000;22:14211432.

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5. Guay DRP, Patterson DR, Seipman N, Craft JC. Overview of the tolerability profile of clarithromycin in preclinical and clinical trials. Drug Saf 1993;8:35&364.

11 Adler JL, Jannetti W, Schneider D, et al. Phase III, randomized, double-blind study of clarithromycin extended-release and immediate-release formulations in the treatment of patients with acute exacerbation of chronic bronchitis. Clin Ther 2000; 22:1410-1420.

12. COSTART 6. Chu SY, Sennello LT, Sonders RC. Simultaneous determination of clarithromytin and 14(R)-hydroxyclarithromycin in plasma and urine using high-performance liquid chromatography with electrochemical detection. J Chromatogr 1991;571: 199-208.

III: Coding

Symbols for The-

saurus of Adverse Reaction

Terms. 3rd ed. Rockville, Md: US Department of Health and Human Services, Public Health Service, Food and Drug Administration Center for Drug Evaluation and Research Office of Epidemiology and Biostatistics; 1993.

Address corr$spondence

to: David R.P. Guay, PharmD, College of Pharmacy, University of Minnesota, Weaver-Densford Hall 7-l 1X, 308 Harvard Street SE, Minneapolis, MN 55455. E-mail: guayxOO1 @tc.umn.edu

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