A Phase 1 Study to Assess the Pharmacokinetics of Sulopenem Etzadroxil (PF-03709270)

Background: Sulopenem etzadroxil is a pro-drug of sulopenem (CP-70,429) designed to enhance its bioavailability. A Phase 1 study was performed to evaluate the effect of food and probenecid on the pharmacokinetics, safety and tolerability of sulopenem etzadroxil

Methods:

This study is a randomized, double blinded (investigator and subject blinded, sponsor-open), placebo-controlled, multiple dose study in healthy volunteers of PF-03709270, with or without co-administration of probenecid, in fed or fasted state. Subjects were dosed twice a day for 6 days and once on Day 7. For the treatment groups dosed in the fed state, subjects were dosed approximately 30 minutes after the start of their meal. Pharmacokinetic sampling was done in 8 subjects per treatment group.

Results:

Treatment	Fed / Fasted	Descriptive Statistic	Parameter (Day 1)
			Cmax (ng/mL)	AUCTAU (hr*ng/mL)	T>MIC (0.5µg/ml) [hr]	T> MIC (0.5 µg/ml) [%]
500 mg PF-03709270	Fasted	Mean	1770.000	3683.093	2.660	22.2
		SD	529.474	728.892
		Median	1720.00	3478.43
		CV%	29.9	19.8	15.0
500 mg PF-03709270	Fed	Mean	1869.875	4545.342	3.127	26.1
		SD	741.019	1131.901
		Median	1725.00	4509.96
		CV%	39.6	24.9	27.9
500 mg PF-03709270 + 500 mg probenecid	Fasted	Mean	1773.750	3952.865	3.063	25.5
		SD	465.463	893.698
		Median	1830.00	4238.98
		CV%	26.2	22.6	23.2
500 mg PF-03709270 + 500 mg probenecid	Fed	Mean	1690.000	6396.538	5.364	44.7
		SD	576.517	1415.977
		Median	1500.00	6301.46
		CV%	34.1	22.1	41.9

Conclusion: Both food and probenecid increase the absorption of PF-03709270 and consequently serum levels of sulopenem. The combination of food and probenecid further increases serum exposures of sulopenem. Probenecid, food, or the combination of both, all significantly prolong the T>MIC for sulopenem. These data will help inform PKPD modelling in selection of a dose for Phase 3 studies.