Clarithromycin Healthy Young Sou-yie
Chu,
PhD,
The
David
pharmacokinetics
S. Wilson,
Pharmacokinetics in and Elderly Volunteers BA,
David
of clarithromycin
R. P. Guay,
and
its active
PharmD,
14(R)-hydroxy
FCP,
metabolite
and
Carl
Craft,
MD
were
assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited signiftcantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 ± 97 versus 476 ± 112 mL/min, respectively) and renal clearance (CLR) (84 ± 31 versus 168 ± 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CL in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.
C larithromycin
is a new macrolide antimicrobial exhibits a broad in vitro antibacterial spectrum, including staphylococci, streptococci, Haemophilus species, Neisseria gonorrhoeae, Legionella pneumophilia, Campylobacter species, Mycoplasma species, and Chlamydia species. Preliminary data indicate potential utility of this agent in the treatment of legionellosis, pneumonia, infectious exacerbations of chronic bronchitis, sinusitis, and pharyngitis in both animal models and humans.59 The pharmacokinetics of clarithromycin have been evaluated in healthy young volunteers with single doses ranging up to 1200 mg and multiple doses ranging up to 800 mg twice daily. Preliminary data indicate that the oral bioavailability of clarithromycin is approximately 55%. The pharmacokinetics of the parent compound are nonlinear, attribthat
From the Drug Metabolism Department (Drs. Chu and Craft, and Mr. Wilson), Abbott Laboratories, Abbott Park, Illinois; and The Geriatric Pharmacy Program (Dr. Guay), St. Paul-Ramsey, Medical Center, St. Paul and College of Pharmacy. University of Minnesota, Minneapolis. Supported by a grant-in-aid from Abbott Laboratories, Abbott Park, Illinois. Address for reprints: Sou-yie Chu, PhD, Drug Metabolism Department, Abbott Laboratories, One Abbott Park Road, Abbott Park, IL
60064-3500.
J COn Pharmacol
1992;32:1045-1049
utable in part to a capacity-limited formation of the active 14(R)-hydroxy metabolite. Dose-dependent terminal disposition half-lives (t#{189})of the parent compound range from 2.3 to 6.0 hours. Plasma clearance and volume of distribution of clarithromycin are in the range of 700 to 800 mL/min and 200 to 300 L, respectively. Dose-dependent t1/2s of the metabolite range from 4.2 to 8.7 hours. Renal elimination of parent compound is relatively important, constituting 15 to 30% of the orally administered dose (data on file, Abbott Laboratories, Abbott Park, IL). Body composition and organ function may change during the aging process, and elderly subjects may exhibit decreased metabolic activity or decreased renal excretion for many drugs. In addition, increased adipose tissue relative to muscle tissue and body water and decreased serum albumin concentration may contribute to changes in drug distribution.10’11 Indeed, previous studies with the macrolides josamycin and roxithromycin have suggested that the aging process is associated with increases in t#{189} and area under the plasma concentration-time curve (AUC).1214 The aim of this study was to assess the pharmacokinetics of clarithromycin after multiple oral doses administered to healthy young and elderly volunteers.
1045
CHU
METHODS Twelve healthy elderly (65-84 years of age) and 12 healthy young (18-30 years of age) volunteers were enrolled in the study after granting written, informed consent. The study protocol was approved by the Human Ethics Committee, University of East Orange, South Africa. The study was conducted at the Department of Pharmacology, University of Orange Free State, Blomfontein, Republic of South Africa. The healthy elderly group comprised 1 man and 11 women, whereas the healthy young group comprised 12 men (P < .05). Selection of a comparable gender-balanced elderly group was compromised by the healthy elderly volunteer population base available to the investigator. Each participant was judged healthy on the basis of normal findings on comprehensive medical history and physical examination, laboratory tests, electrocardiography, ophthalmology, and audiometry. Creatinine clearance was estimated using the method of Cockcroft and Gault.15 All subjects received 500 mg (four 125-mg capsules, lot 07-707-AL, Abbott Laboratories, Abbott Park, IL) every 12 hours for 5 doses. All doses were administered in a fasting state (at least 1 hour before or 2 hours after meals). Subjects were served breakfast 2 hours after dose 5, lunch after the 6-hour blood sampling, and dinner after the 10-hour blood sampling. Sequential I 5-mL blood samples for determination of clarithromycin and 14(R)-hydroxyclarithromycin concentrations were obtained immediately before administration of doses 2, 3, 4, and 5 and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration of dose 5. Plasma was subsequently separated and stored frozen at -20#{176}Cuntil assayed. Urine was collected over the intervals 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after the administration of dose 5. After the volume was measured, an aliquot of each urine collection was stored frozen at -20#{176}Cuntil assayed. Plasma and urine samples were assayed using a high-performance liquid chromatographic technique developed and performed at Abbott Laboratories, Abbott Park, Illinois. This method used a reverse-phase C8 column (5 m, 4.6 mm X 15 cm; Sepralyte, Analytichem, Harbor City, CA) and electrochemical detection (Model 5100A, Environmental Sciences Associates, Bedford, MA). The mobile phase typically consisted of acetonitrile (44% vol/vol), methanol (10%), 0.04 M sodium dihydrogen phosphate, and NaOH to produce a pH of 7.5. Detection limits for both compounds in plasma and urine were 0.03 and 0.5 mg/L, respectively. Intra-assay and interassay relative standard deviations for plasma and urine concentrations of both compounds
1046
#{149} J COn Pharmacol
1992:32:1045-1049
ET AL
over the standard curve concentration ranges (0.12.0 mg/L and 1-100 mg/L, respectively) were less than 7%16 Clarithromycin and 14(R)-hydroxyclarithromycin pharmacokinetic parameters were assessed using model-dependent methods.17 Initial estimates for the nonlinear regression analysis of the plasma concentration-time profiles were provided by the FORTRAN program CSTRIP.18 The curves then were fitted to polyexponential equations using NONLIN,19 and the quality of the fitting was compared using the Akaike Information Criterion.20’21 Absorption, formation, and terminal disposition rate constants (ka, kf, ke, respectively), terminal disposition th/2, apparent beta-phase volume of distribution (V/f), AUG from 0 to 12 hours (AUCO.12), peak and trough plasma concentrations (Cmax and Cmin, respectively), and apparent total body clearance (CL/f) were calculated by standard techniques.17 Renal clearance (CLPJ was calculated as the amount excreted in urine (Ae) from time t1 to t2 divided by the AUG over the same time interval. Fractional urinary excretion from time 0 to 12 hours after administration of dose 5 (fj also was calculated. All statistical analyses were performed using the SAS procedures FREQ, MEANS, and GLM.22 A value of P < .05 was considered statistically significant. Resuits are expressed as mean ± standard deviation unless otherwise noted. RESULTS Subject demographic characteristics are summarized in Table I. As expected, renal function as measured by estimated creatinine clearance was decreased in the healthy elderly compared with the young volunteers (68.4 ± 15.5 versus 116.5 ± 17.2 mL/min, respectively). Elderly subjects also weighed significantly less and were significantly shorter than the young subjects, probably because of the gender distribution difference between the two groups. Twenty-eight adverse events were reported by 20 (83%) of the subjects. Eleven of the 12 young subjects (92%) and 9 of the 12 elderly subjects (75%) reported adverse events. In the young subjects, these events consisted of taste perversion (five cases), headache (two cases), flatulence (eight cases), and diarrhea (two cases). In the elderly subjects, these events consisted of taste perversion (nine cases) and flatulence (two cases). All events were considered mild in nature and probably or possibly related to study drug treatment. Young subjects reported more adverse digestive system events than did elderly subjects (P < .05).
CLARITHROMYCIN
PHARMACOKINETICS
TABLE Mean Group
± SD (Range)
Age (yr)
Young
Sex
23.2 ± 2.2 (21-29) 73.6 ± 4.8 (65-81)
Elderly P value defined
Subject
Demographics#{176}
Weight
76.7
OF/12M
(kg)
±
Height
180.1
7.9
(64-88)
67.0
11F/1M
± 11.4
162.1
9.0
±
± 17.9
116.3
(97.2-152.9) 67.2 ± 15.3 (48.5-102.2)
Chu,
PhD,
The
David
pharmacokinetics
S. Wilson,
Pharmacokinetics in and Elderly Volunteers BA,
David
of clarithromycin
R. P. Guay,
and
its active
PharmD,
14(R)-hydroxy
FCP,
metabolite
and
Carl
Craft,
MD
were
assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited signiftcantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 ± 97 versus 476 ± 112 mL/min, respectively) and renal clearance (CLR) (84 ± 31 versus 168 ± 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CL in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.
C larithromycin
is a new macrolide antimicrobial exhibits a broad in vitro antibacterial spectrum, including staphylococci, streptococci, Haemophilus species, Neisseria gonorrhoeae, Legionella pneumophilia, Campylobacter species, Mycoplasma species, and Chlamydia species. Preliminary data indicate potential utility of this agent in the treatment of legionellosis, pneumonia, infectious exacerbations of chronic bronchitis, sinusitis, and pharyngitis in both animal models and humans.59 The pharmacokinetics of clarithromycin have been evaluated in healthy young volunteers with single doses ranging up to 1200 mg and multiple doses ranging up to 800 mg twice daily. Preliminary data indicate that the oral bioavailability of clarithromycin is approximately 55%. The pharmacokinetics of the parent compound are nonlinear, attribthat
From the Drug Metabolism Department (Drs. Chu and Craft, and Mr. Wilson), Abbott Laboratories, Abbott Park, Illinois; and The Geriatric Pharmacy Program (Dr. Guay), St. Paul-Ramsey, Medical Center, St. Paul and College of Pharmacy. University of Minnesota, Minneapolis. Supported by a grant-in-aid from Abbott Laboratories, Abbott Park, Illinois. Address for reprints: Sou-yie Chu, PhD, Drug Metabolism Department, Abbott Laboratories, One Abbott Park Road, Abbott Park, IL
60064-3500.
J COn Pharmacol
1992;32:1045-1049
utable in part to a capacity-limited formation of the active 14(R)-hydroxy metabolite. Dose-dependent terminal disposition half-lives (t#{189})of the parent compound range from 2.3 to 6.0 hours. Plasma clearance and volume of distribution of clarithromycin are in the range of 700 to 800 mL/min and 200 to 300 L, respectively. Dose-dependent t1/2s of the metabolite range from 4.2 to 8.7 hours. Renal elimination of parent compound is relatively important, constituting 15 to 30% of the orally administered dose (data on file, Abbott Laboratories, Abbott Park, IL). Body composition and organ function may change during the aging process, and elderly subjects may exhibit decreased metabolic activity or decreased renal excretion for many drugs. In addition, increased adipose tissue relative to muscle tissue and body water and decreased serum albumin concentration may contribute to changes in drug distribution.10’11 Indeed, previous studies with the macrolides josamycin and roxithromycin have suggested that the aging process is associated with increases in t#{189} and area under the plasma concentration-time curve (AUC).1214 The aim of this study was to assess the pharmacokinetics of clarithromycin after multiple oral doses administered to healthy young and elderly volunteers.
1045
CHU
METHODS Twelve healthy elderly (65-84 years of age) and 12 healthy young (18-30 years of age) volunteers were enrolled in the study after granting written, informed consent. The study protocol was approved by the Human Ethics Committee, University of East Orange, South Africa. The study was conducted at the Department of Pharmacology, University of Orange Free State, Blomfontein, Republic of South Africa. The healthy elderly group comprised 1 man and 11 women, whereas the healthy young group comprised 12 men (P < .05). Selection of a comparable gender-balanced elderly group was compromised by the healthy elderly volunteer population base available to the investigator. Each participant was judged healthy on the basis of normal findings on comprehensive medical history and physical examination, laboratory tests, electrocardiography, ophthalmology, and audiometry. Creatinine clearance was estimated using the method of Cockcroft and Gault.15 All subjects received 500 mg (four 125-mg capsules, lot 07-707-AL, Abbott Laboratories, Abbott Park, IL) every 12 hours for 5 doses. All doses were administered in a fasting state (at least 1 hour before or 2 hours after meals). Subjects were served breakfast 2 hours after dose 5, lunch after the 6-hour blood sampling, and dinner after the 10-hour blood sampling. Sequential I 5-mL blood samples for determination of clarithromycin and 14(R)-hydroxyclarithromycin concentrations were obtained immediately before administration of doses 2, 3, 4, and 5 and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration of dose 5. Plasma was subsequently separated and stored frozen at -20#{176}Cuntil assayed. Urine was collected over the intervals 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours after the administration of dose 5. After the volume was measured, an aliquot of each urine collection was stored frozen at -20#{176}Cuntil assayed. Plasma and urine samples were assayed using a high-performance liquid chromatographic technique developed and performed at Abbott Laboratories, Abbott Park, Illinois. This method used a reverse-phase C8 column (5 m, 4.6 mm X 15 cm; Sepralyte, Analytichem, Harbor City, CA) and electrochemical detection (Model 5100A, Environmental Sciences Associates, Bedford, MA). The mobile phase typically consisted of acetonitrile (44% vol/vol), methanol (10%), 0.04 M sodium dihydrogen phosphate, and NaOH to produce a pH of 7.5. Detection limits for both compounds in plasma and urine were 0.03 and 0.5 mg/L, respectively. Intra-assay and interassay relative standard deviations for plasma and urine concentrations of both compounds
1046
#{149} J COn Pharmacol
1992:32:1045-1049
ET AL
over the standard curve concentration ranges (0.12.0 mg/L and 1-100 mg/L, respectively) were less than 7%16 Clarithromycin and 14(R)-hydroxyclarithromycin pharmacokinetic parameters were assessed using model-dependent methods.17 Initial estimates for the nonlinear regression analysis of the plasma concentration-time profiles were provided by the FORTRAN program CSTRIP.18 The curves then were fitted to polyexponential equations using NONLIN,19 and the quality of the fitting was compared using the Akaike Information Criterion.20’21 Absorption, formation, and terminal disposition rate constants (ka, kf, ke, respectively), terminal disposition th/2, apparent beta-phase volume of distribution (V/f), AUG from 0 to 12 hours (AUCO.12), peak and trough plasma concentrations (Cmax and Cmin, respectively), and apparent total body clearance (CL/f) were calculated by standard techniques.17 Renal clearance (CLPJ was calculated as the amount excreted in urine (Ae) from time t1 to t2 divided by the AUG over the same time interval. Fractional urinary excretion from time 0 to 12 hours after administration of dose 5 (fj also was calculated. All statistical analyses were performed using the SAS procedures FREQ, MEANS, and GLM.22 A value of P < .05 was considered statistically significant. Resuits are expressed as mean ± standard deviation unless otherwise noted. RESULTS Subject demographic characteristics are summarized in Table I. As expected, renal function as measured by estimated creatinine clearance was decreased in the healthy elderly compared with the young volunteers (68.4 ± 15.5 versus 116.5 ± 17.2 mL/min, respectively). Elderly subjects also weighed significantly less and were significantly shorter than the young subjects, probably because of the gender distribution difference between the two groups. Twenty-eight adverse events were reported by 20 (83%) of the subjects. Eleven of the 12 young subjects (92%) and 9 of the 12 elderly subjects (75%) reported adverse events. In the young subjects, these events consisted of taste perversion (five cases), headache (two cases), flatulence (eight cases), and diarrhea (two cases). In the elderly subjects, these events consisted of taste perversion (nine cases) and flatulence (two cases). All events were considered mild in nature and probably or possibly related to study drug treatment. Young subjects reported more adverse digestive system events than did elderly subjects (P < .05).
CLARITHROMYCIN
PHARMACOKINETICS
TABLE Mean Group
± SD (Range)
Age (yr)
Young
Sex
23.2 ± 2.2 (21-29) 73.6 ± 4.8 (65-81)
Elderly P value defined
Subject
Demographics#{176}
Weight
76.7
OF/12M
(kg)
±
Height
180.1
7.9
(64-88)
67.0
11F/1M
± 11.4
162.1
9.0
±
± 17.9
116.3
(97.2-152.9) 67.2 ± 15.3 (48.5-102.2)
