W-038
Evaluation of Methods to Predict Joint Probability of PK/PD Target Attainment in the Development of blactam (BL) and b-lactamase Inhibitor (BLI) Combination Antibiotics
Jianguo Li*, Diansong Zhou, Nidal Al-Huniti
Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts, USA
Objectives: To evaluate methods to estimate joint probability of PK/PD target attainment (JPTA) in dose
determination for Phase 2b/3 studies in the development of BL and BLI combination.
Methods: JPTAs for piperacillin (PIP) and tazobactam (TAZ), 30% free PIP concentration above minimum
inhibition concentration (% fT>MIC) and the same time of free TAZ concentration above a threshold concentration
(% fT>CT), were evaluated using 5 methods (M1-M5) and compared to a “true” JPTA for PIP-TAZ dose regimen
of 3.75 mg, 0.5 h infusion every 6h. The detailed descriptions for the calculation of “true” JPTA (M0) and each
method of M1-M5 are shown in the table. The MIC used in the JPTA calculation was the PIP-TAZ non-species
specific PK-PD breakpoint (8mg/L), while the stringent CT of 2mg/L was used for TAZ [1]. Three cases of between
subject variability (BSV) for clearance and volume of distribution of PIP and TAZ, small (25%), medium (50%) and
large (75%), were examined for the impact of the magnitude of BSVs on JPTA prediction. 100 data sets each with
100 subjects were simulated, and each data set was re-fit for PIP and TAZ separately or simultaneously according to
M1-M5 methods.
Results: The calculated “true” JPTA by M0, and predicted median, 5th and 95th percentiles of JPTAs from the 100
simulated data sets for the joint PK/PD targets are shown in the table.
Conclusions: While M5 produced the least biased prediction of JPTAs among 5 methods, M3 is a resource-saving
method and produced similar JPTA predictions to M5. M2 could be used reasonably to predict JPTAs for small and
medium BSVs of PK for the BL and BLI. The larger the BSV, the lower the JPTA.
References:
[1] Nicasio et al. Poster A-298, 2013 ICAAC Denver
[2] Li et al. J Antimicrob Chemother, 2005,56:388-395
[3] Shoji et al, Br J Clin Pharmacol, 2013,77:509-521