Paola Coppola(1), Giorgio Di Loreto(2), Valeria Tellone(3), Alessandra Del Vecchio(3)
(1)R&D, Pharmacokinetics, ACRAF Angelini Research Center, P.le della Stazione snc, 00040 S. Palomba- Pomezia, Rome, Italy
Objectives: Prulifloxacin (Unidrox® 600 mg tablets) is the pro-drug of ulifloxacin, a fluoroquinolone antibacterial agent.
A two-centre, open label, parallel group study has been performed to investigate the influence of renal impairment on the PK of ulifloxacin following single and repeated administration of prulifloxacin.
A POP-PK model was developed to assess the dosing regimen of prulifloxacin for renal impaired subjects.
Methods: The POP-PK model was developed using data available from 11 prulifloxacin studies. The stochastic component and covariates were introduced into the model to optimize the final PK model[1]. The POP-PK analysis was performed using NONMEM. Steady-state simulations were performed according to the validated model by reducing the dose/prolonging the frequency.
Results: The best POP-PK model was two-compartment linear model with first order absorption and elimination. Creatinine clearance (CRCL), body weight and health status significantly influenced the clearance of ulifloxacin. The final model was validated by non-parametric bootstrap and VPC[1]. Based on the model, PK profiles of ulifloxacin were simulated at steady-state in renal (mild, moderate, severe) and healthy subjects.
The results indicated that dose adjustment may be not required in mild and moderate renal subjects. In severe renal impairment a two-fold dose reduction was suggested. Preliminary PK results of the multiple dosing phase of the clinical study seem to confirm the previously simulated PK profiles.
Conclusions: Following oral administration of prulifloxacin, ulifloxacin PK is described by a two-compartment linear model with first-order absorption and elimination. The covariate CRCL described the differences in the observed ulifloxacin PK profiles. Simulations to design the dosing regimen for the renal patients suggested that no dose (600 mg QD) adjustment may be required for mild and moderate renal subjects as compared to healthy subjects. A dose reduction to 300 mg QD was instead recommended for the severe renal subjects. These dosing regimens were applied during the multiple dose phase of the renal study. The preliminary mean PK results seem to confirm the simulation predictions.
References:
[1] Attkins N, Copalu W, Coppola P, Picollo R, Di Loreto G, Rosignoli MT, Pooled population pharmacokinetic analysis of prulifloxacin following administration to healthy volunteers, subjects with mild, moderate and severe renal impairment and non-renal patients [ACRAF confidential data]
Reference: PAGE 23 () Abstr 3197 [www.page-meeting.org/?abstract=3197]
Poster: Drug/Disease modeling - Infection