E. Soto(1), Y.Tomono (2), C.Muto(2), S. Marshall(1), S. Shoji(2)
(1) Pharmacometrics, Pfizer, UK; (2) Clinical pharmacology, Pfizer, Japan
Introduction and Objectives: Unasyn® (injectable combination of sulbactam sodium and ampicillin sodium, dose ratio 1:2) has been marketed over 60 countries in the world, and prescribed for the treatment of various types of infections. It is currently used in doses up to 12g/day however in Japan approved doses are up to 6 g/day. The aim of this analysis was to study the pharmacokinetics (PK) of ampicillin and sulbactam after doses of 12g/day divided in 4 doses (i.e. 3 g QID) in Japanese patients with moderate or severe community-acquired pneumonia. The PK model was then used to explore the efficacy of the drug through the calculation of the expected time above the minimum inhibitory concentration (MIC) for the different pathogens identified in the patients.
Methods: The population PK analysis was performed using NONMEM 6.2 based on log-transformed plasma concentration samples. Simultaneous fit of the concentration data of both drugs was evaluated by the use of the L2 item in NONMEM. The MIC concentration for ampicillin/sulbactam was reported as ampicillin concentration. The time above MIC (TAM) during the treatment duration period for all the patients for which the MIC value was available was integrated using the following equation:
dA/dt = CPDGAM/(CPDGAM+MICGAM)
Where CPD is ampicillin concentration at each time point, MIC is the MIC value for each patient, GAM is a factor fixed to 99, in order to create a function which gives an all or nothing response. When divided by the duration of the treatment (hrs), the fraction time above MIC was obtained.
Results: In total, 222 plasma concentration observations for both sulbactam and ampicillin coming from 47 patients were available for the analysis. A two-compartment model described both the ampicillin and the sulbactam PK, where inter-patient variability was estimated for clearance and for peripheral volume. Creatinine clearance and body weight were included in the final model. Final PK parameters were similar between the two compounds and similar to previously reported values [1 – 3]. The percentage of time above the MIC value established for each identified pathogen ranged from 55 to 100%. Simulations showed how the QID schedule provided concentrations over the MIC [for all the range seen in the study (0.06-16)] for at least 50% of the time.
Conclusion: A PK model that described both ampicillin and sulbactam plasma concentration data was established. This model was used to make inferences on the efficacy of the drug through the calculation of TAM for different pathogens and different dosing schedules.
References:
[1] Ripa S, Ferrante L, Prenna M. Pharmacokinetics of sulbactam/ampicillin in humans after intravenous and intramuscular injection. Chemotherapy. 1990; 36:185-92.
[2] Blum RA, Kohli RK, Harrison NJ, et al. Pharmacokinetics of ampicillin (2.0 grams) and sulbactam (1.0 gram) coadministered to subjects with normal and abnormal renal function and with end-stage renal disease on hemodialysis. Antimicrob Agents Chemother. 1989; 33:1470-6.
[3] Shiba K, Saito A, Shimada J, et al. Clinical studies on sulbactam-ampicillin. Chemotherapy. 1988; 36; 149-59.
Reference: PAGE 21 () Abstr 2310 [www.page-meeting.org/?abstract=2310]
Poster: Infection