Beauty Products : B  C  D  E  F  G  I  N  P  R  S

Pharmacokinetics
The kinetics of orally administered clarithromycin has been studied extensively in a number of animal species and adult humans. These studies have shown clarithromycin is readily and rapidly absorbed with an absolute bioavailability of approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in any species following multiple dosing. Food intake immediately before dosing increases clarithromycin bioavailability by a mean of 25%. Overall, this increase is minor and should be of little clinical significance with the recommended dosing regimens. Clarithromycin may thus be administered in either the presence or absence of food.

In vitro
In vitro studies showed the protein binding of clarithromycin in human plasma averaged about 70% at concentrations of 0.45 to 4.5 mcg/mL. A decrease in binding to 41% at 45.0 mcg/mL suggested the binding sites might become saturated, but this only occurred at concentrations far in excess of the therapeutic drug levels.

In vivo
Results of animal studies showed clarithromycin levels in all tissues, except the central nervous system, were several times higher than the circulating drug levels. The highest concentrations were usually found in the liver and lung where the tissue to plasma (T/P) ratios reached 10 to 20.

Normal Subjects
With b.i.d. dosing at 250 mg, the peak steady state plasma concentration was attained in two to three days and averaged about 1 mcg/mL for clarithromycin and 0.6 mcg/mL for 14-hydroxyclarithromycin, while the elimination half-lives of the parent drug and metabolite were three to four hours and five to six hours, respectively. With b.i.d. dosing at 500 mg, the steady state C_max for clarithromycin and its hydroxylated metabolite was achieved by the fifth dose. After the fifth and seventh doses, the steady state C_max for clarithromycin averaged 2.7 and 2.9 mcg/mL; its hydroxylated metabolite averaged 0.88 and 0.83 mcg/mL respectively. The half-life of the parent drug at the 500 mg dose level was 4.5 to 4.8 hours, while that of the 14-hydroxyclarithromycin was 6.9 to 8.7 hours. At steady state the 14-hydroxyelarithromycin levels did not increase proportionately with the clarithromycin dose, and the apparent half-lives of both clarithromycin and its hydroxylated metabolite tended to be longer at the higher doses. This non-linear pharmacokinetic behavior of clarithromycin, coupled with the overall decrease in the formation of 14-hydroxylation and N-demethylation products at the higher doses, indicates the non-linear metabolism of clarithromycin becomes more pronounced at high doses.

In human adults given single oral doses of 250 mg or 1200 mg clarithromycin, urinary excretion accounted for 37.9% of the lower dose and 46.0% of the higher dose. Fecal elimination accounted for 40.2% and 29.1 % (this included a subject with only one stool sample containing 14.1 %) of these respective doses.

Patients
Clarithromycin and its 14-OH metabolite distribute readily into body tissues and fluids. Limited data from a small number of patients suggests clarithromycin does not achieve significant levels in cerebrospinal fluid after oral doses (i.e., only 1 to 2% of serum levels in CSF in patients with normal blood-CSF barriers). Concentrations in tissues are usually several fold higher than serum concentrations. Examples from tissue and serum concentrations are presented below.

Hepatic Impairment
In a study comparing one group of healthy human subjects with a group of subjects with liver impairment who were given 250 mg of clarithromycin b.i.d. for two days and a single 250 mg dose the third day, steady state plasma levels and systemic clearing of clarithromycin were not significantly different between the two groups. In contrast, steady state concentrations of the 14- OH metabolite were markedly lower in the group of hepatic-impaired subjects. This decreased metabolic clearance of the parent compound by 14-hydroxylation was partially offset by an increase in the renal clearance of parent drug, resulting in comparable steady state levels of parent drug in the hepatic impaired and healthy subjects. These results indicate no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function.

Renal Impairment
A study was conducted to evaluate and compare the pharmacokinetic profile of multiple 500 mg oral doses of clarithromycin in subjects with normal and decreased renal function. The plasma levels, half-life, C_max and C_min for both clarithromycin and its 14-OH metabolite were higher and AUC was larger in subjects with renal impairment. Kelim and urinary excretion were lower. The extent to which these parameters differed was correlated with the degree of renal impairment; the more severe the renal impairment, the more significant the difference (see DOSAGE AND ADMINISTRATION).

Elderly Subjects
A study was also conducted to evaluate and compare the safety and pharmacokinetic profiles of multiple 500 mg oral doses of clarithromycin in healthy elderly male and female subjects to those in healthy young adult male subjects. In the elderly group, circulating plasma levels were higher and elimination slower than in the younger group for both parent drug and 14-OH metabolite. However, there was no difference between the two groups when renal clearance was correlated with creations clearance. It is concluded from those results that any effect on the handling of clarithromycin is related to renal function and not to age per se.

Mycobacterium Avium Infections
Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV infection were similar to those observed in normal subjects. However, at the higher doses which may be required to treat Mycobacterium avium infections, clarithromycin concentrations were much higher than those observed at the usual doses. In adult HIV-infected patients taking 1000 and 2000 mg/day in two divided doses, steady-state clarithromycin C_max  values ranged from 2 to 4 mcg/mL and 5 to 10 mcg/mL, respectively. Elimination half-lives appeared to be lengthened at these higher doses as compared to that seen with usual doses in normal subjects. The higher plasma concentrations and longer elimination half-lives observed at these doses are consistent with the known nonlinearity in clarithromycin pharmacokinetics.

Concomitant Omeprazole Administration
A pharmacokinetic study was conducted with clarithromycin 500 mg t.i.d. and omeprazole 40 mg once daily. When clarithromycin was given alone at 500 mg every eight hours, the mean steady-state C_max value was approximately 3.8 mcg/mL and the mean C_min value was approximately 1.8 mcg/mL. The mean AUC_0-8 , for clarithromycin was 22.9 mcg/hr/mL. The T_max, and half-life were 2.1 hr and 5.3 hr, respectively, when clarithromycin was dosed at 500 mg t.i.d.

In the same study when clarithromycin 500 mg t.i.d. was administered with omeprazole 40 mg once daily, increases in omeprazole half-life and AUC_0-24 were observed. For all subjects combined, the mean omeprazole AUC_0-24, was 89% greater and the harmonic mean for omeprazole T_1/2 was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state C_max, C_min and AUC_0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively, over values achieved when clarithromycin was administered with placebo.

At steady state, clarithromycin gastric mucous concentrations six hours post-dosing were approximately 25-fold higher in the clarithromycin/omeprazole group compared with the clarithromycin alone group. Six hours post-dosing, mean clarithromycin gastric tissue concentrations were approximately 2-fold higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo.
 

1    2    3    4    5