Modulation of pharmacokinetics of theophylline by antofloxacin, a novel 8-amino-fluoroquinolone, in humans

Abstract

Aim: To evaluate the pharmacokinetic interactions between theophylline and antofloxacin in vivo and in vitro.

Methods: A randomized, 5-day treatment and 3-way crossover design was documented in 12 healthy subjects. The subjects were orally administered with antofloxacin (400 mg on d 1 and 200 mg on d 2 to 5), theophylline (100 mg twice a day and morning dose 200 mg on d 1 and 5), or theophylline plus antofloxacin. The plasma and urinary pharmacokinetics of antofloxacin and theophylline were characterized after the first and last dose. The effect of antofloxacin on theophylline metabolism was also investigated in pooled human liver microsomes.

Results: The 5-day treatment with antofloxacin significantly increased the area of the plasma concentration-time curve and peak plasma concentration of theophylline, accompanied by a decrease in the excretion of theophylline metabolites. On the contrary, theophylline did not affect the pharmacokinetics of antofloxacin. In vitro studies using pooled human hepatic microsomes demonstrated that antofloxacin was a weak reversible and mechanism-based inhibitor of CYP1A2. The clinical interaction between theophylline and antofloxacin was further validated by the in vitro results.

Conclusion: The results showed that antofloxacin increases the plasma theophylline concentration, partly by acting as a mechanism-based inhibitor of CYP1A2.

Figure 1

Comparison of TP concentration in plasma after an oral dose of TP alone (open circle) and co-administration of ATFX (filled circle). For TP, on d 1 and 5, 200 mg of TP was given to subjects as a single morning dose, and on d 2 to 4, 400 mg of TP was given to subjects twice daily (morning dose and evening dose). For ATFX, on d 1, 400 mg was given to subjects as a single morning dose, and on d 2 to 5, 200 mg of ATFX was given to subjects once daily (morning dose). The results are expressed as the mean±SD (n=12).

Figure 2

Comparison of ATFX concentrations in plasma after an oral dose of ATFX alone (open circle) and co-administration of TP (filled circle). For TP, on d 1 and 5, 200 mg of TP was given to subjects as a single morning dose, and on d 2 to 4, 400 mg of TP was given to subjects twice daily (morning dose and evening dose). For ATFX, on d 1, 400 mg was given to subjects as a single morning dose, and on d 2 to 5, 200 mg of ATFX was given to subjects once daily (morning dose). The results are expressed as the mean±SD (n=12).

Figure 3

Kinetics of inactivation of microsomal TP metabolism by ATFX (n=5). Human liver microsomes were pre-incubated for the indicated times in an NADPH-generating system, and ATFX, followed by CYP1A2 activity, was measured. Symbols: open circle, 0 μg/mL ATFX; filled circle, 100 μg/mL ATFX; open square, 200 μg/mL ATFX; filled square, 400 μg/mL ATFX, and open triangle, 800 μg/mL ATFX. The insets correspond to the double reciprocal of the inactivation rates as a function of ATFX concentration.