Interaction between midazolam and clarithromycin in the elderly

Abstract

Aim: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrate midazolam and clarithromycin in the elderly.

Methods: On day 1, 16 volunteers (eight male, eight female) aged 65-75 years weighing 59-112 kg received simultaneous doses of midazolam intravenously (i.v.) (0.05 mg kg(-1) over 30 min) and orally (p.o.) (3.5 mg of a stable isotope, (15)N(3)-midazolam). Starting on day 2, clarithromycin 500 mg was administered orally twice daily for 7 days. On day eight, i.v. and p.o. doses of midazolam were administered 2 h after the final clarithromycin dose. Serum and urine samples were assayed for midazolam, (15)N(3)-midazolam and metabolites by gas chromatography/mass spectometry.

Results: Men and women exhibited similar i.v. (30.4 vs. 36.0 l h(-1)) and p.o. (119 vs. 124 l h(-1)) clearances of midazolam. Midazolam hepatic availability was significantly (P = 0.006) greater in men [0.79, 95% confidence interval (CI) 0.75, 0.84] than in women (0.66, 95% CI 0.59, 0.73), but midazolam intestinal availability (0.39 vs. 0.55) was not different. Following clarithromycin dosing, a significant decrease in systemic (33.2 l h(-1) to 11.5 l h(-1)) and oral (121 l h(-1) to 17.4 l h(-1)) midazolam clearance occurred. Oral, hepatic and intestinal availability was significantly increased after clarithromycin dosing from 0.34 to 0.72, 0.73 to 0.91 and 0.47 to 0.79, respectively. Clarithromycin administration led to an increase in the AUC of midazolam by 3.2-fold following i.v. dosing and 8.0-fold following p.o. dosing. Similar effects were observed for males and females.

Conclusions: Intestinal and hepatic CYP3A inhibition by clarithromycin significantly reduces the clearance of midazolam in the elderly.

Figure 1

Relationship between the oral and intestinal availability of midazolam prior to (closed symbols, N = 16) and after 7 days of clarithromycin (500 mg bid, open symbols, N = 16) (A). The relationship between hepatic and intestinal availability of midazolam before and after 7 days of clarithromycin (500 mg bid) (B) and the relationship between hepatic and oral availability of midazolam before and after 7 days of clarithromycin (500 mg bid) (C). Circles and squares represent values from women and men, respectively. The correlation coefficient (r) is provided for each comparison

Figure 2

The mean (±SD) blood concentration vs. time curve of clarithromycin, 14-hydroxyclarithromycin and N-desmethylclarithromcyin following oral administration of 500 mg twice daily for 7 days in 16 healthy volunteers. Mean (±SD) clarithromycin serum concentrations, (○); mean (±SD) 14-hydroxyclarithromycin concentration, (□); mean (±SD) N-desmethylclarithromycin concentrations on day 7 of clarithromycin dosing, (Δ)

Figure 3

The mean (± SD) blood concentration vs. time curve of midazolam and ¹⁵N₃-midazolam after simultaneous intravenous and oral (n = 16) administration. Mean blood concentrations on day 1, (•); mean blood concentrations following the oral administration of clarithromycin (500 mg bid) for 7 days, (○)

Figure 4

Relationship between the fold change in hepatic or intestinal availability and initial intestinal or hepatic availability. The correlation coefficient (r) is given for each comparison. Solid squares and circles represent the values for men and women, respectively