Both formulations of MP-376 tested produced very high sputum concentrations with low systemic exposure. The 180- and 240-mg doses using the 100-mg/ml formulation produced 24-h serum AUCs (AUC0–24
) of 9.05 and 14.77 mg · hr/liter, respectively. These measures of serum levofloxacin exposure from MP-376 are only 12 to 19% of the 24-hour serum AUC achieved in another study of CF patients dosed with 750 mg oral levofloxacin (AUC0–24
= 76.6 mg · hr/liter) (3
). Systemic absorption from the lung was very rapid, with serum Tmax
occurring within 20 min of dose administration.
For CF patients who spend considerable time taking their prescribed daily inhaled medications, it is important to consider the treatment burden when developing new therapies. This pharmacokinetic study showed that the 100-mg/ml formulation of MP-376 produced serum and sputum levels of levofloxacin that were similar to those obtained with the 50-mg/ml formulation and required less time for nebulization.
After 7 days of 240 mg daily dosing using the 100-mg/ml formulation, the serum and sputum exposures were approximately dose proportional with those obtained with the 180-mg dose with regard to Cmax
and seemed higher than dose proportional with regard to AUC values. However, there was very high intersubject variability, with standard deviations approximating or exceeding the mean values, making it difficult to evaluate dose proportionality. This high degree of variability can be seen in most studies of aerosol drugs and stems from factors that include breathing patterns during drug inhalation (tidal volume, inspiratory flow, and respiratory rate) and disease severity (degree and location of airway obstruction) (4
). Sputum concentrations of inhaled antibiotics are frequently measured in clinical trials as a guide to ensure that they exceed the MIC of the bacteria. However, as a measure of deposited dose in the airways, sputum levels can be misleading, as the drug is not evenly distributed in the airways and the exact source of sputum may differ between specimens, leading to more variability (4
Aerosol dosing with MP-376 produced a mean sputum AUC of 4,500 mg/liter and a mean sputum Cmax
of 4,700 mg · hr/liter after a 240-mg dose. Extensive in vitro
and animal pharmacokinetic-pharmacodynamic studies, as well as both retrospective and prospective clinical studies, have established a clear link between exposure to fluoroquinolones and antibacterial effects. Studies with levofloxacin show that bacterial killing and clinical efficacy are linked to the plasma drug area under the curve (AUC)/MIC ratio or the Cmax
/MIC ratio (6
). Studies with levofloxacin also show that high levels of exposure relative to the MIC can reduce the selection of drug-resistant bacteria in vitro
and in vivo
). Based on a MIC90
to P. aeruginosa
of 16 mg/liter for levofloxacin, aerosol administration of MP-376 resulted in a sputum AUC/MIC90
ratio of 280 and a Cmax
ratio of 290. These sputum exposures are greater than those that can be achieved with either parenteral or oral administration.
While sputum levofloxacin exposures were very high, serum exposures were only 10 to 16% of those previously reported with 750 mg oral dosing (). (3
) With lower systemic exposures, aerosol MP-376 should improve the safety and tolerability profile compared to that of either parenteral or oral administration of levofloxacin.
Overall, this study demonstrated that aerosol administration of MP-376 was well tolerated and produced sputum levofloxacin exposures that should maximize bacterial killing while minimizing the development of resistance. Based on these data, the 100-mg/ml formulation of MP-376 was advanced into phase 2 studies (2