Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration

Figures & data

Table 1 Minimum inhibitory concentrations (MIC₉₀) for besifloxacin, moxifloxacin, and gatifloxacin against selected Staphylococcus isolates

	Number of isolates	Besifloxacin (μg/mL) MIC90	Moxifloxacin (μg/mL) MIC90	Gatifloxacin (μg/mL) MIC90
S. aureus
MSSA-CSa	144	0.06	0.12	0.25
MRSA-CRb	81	4	32	64
S. epidermidis
MSSE-CSc	50	0.06	0.12	0.25
MRSE-CRd	29	4	64	128

a MIC₉₀ values were obtained from susceptibility testing of 144 methicillin-sensitive, ciprofloxacin-sensitive S. aureus isolates.⁷

b MIC₉₀ values were obtained from susceptibility testing of 81 methicillin-resistant, ciprofloxacin-resistant S. aureus isolates.²⁴

c MIC₉₀ values were obtained from susceptibility testing of 50 methicillin-sensitive, ciprofloxacin-sensitive S. epidermidis isolates.⁷

d MIC₉₀ values were obtained from susceptibility testing of 29 methicillin-resistant, ciprofloxacin-resistant S. epidermidis isolates.²⁴

Abbreviations: MIC₉₀, minimum inhibitory concentration to inhibit 90% of isolates; MSSA-CS, methicillin- and ciprofloxacin-sensitive S. aureus; MRSA-CR, methicillin- and ciprofloxacin-resistant S. aureus; MSSE-CS, methicillin- and ciprofloxacin-sensitive S. epidermidis; MRSE-CR, methicillin- and ciprofloxacin-resistant S. epidermidis.

Table 2 Demographics of intent-to-treat (ITT) population

	Besifloxacin 0.6% N= 38	Moxifloxacin 0.5% N = 38	Gatifloxacin 0.3% N= 43	Total N = 119
Age (years)
Mean (SD)	42.5 (14.3)	40.5 (15.0)	44.6 (17.0)	42.6 (15.5)
Range	20–66	18–68	18–74	18–74
Gender
Male	17 (44.7%)	12 (34.2%)	16 (37.2%)	46 (38.7%)
Female	21 (55.3%)	25 (65.8%)	27 (62.8%)	73 (61.3%)
Ethnicity
Hispanic or Latino	3 (7.9%)	5 (13.2%)	2 (4.7%)	10 (8.4%)
Not Hispanic or Latino	35 (92.1%)	33 (86.8%)	41 (95.3%)	109 (91.6%)
Race
American Indian/Alaskan Native	1 (2.6%)	0 (0.0%)	0 (0.0%)	1 (0.8%)
Asian	0 (0.0%)	1 (2.6%)	1 (2.3%)	2 (1.7%)
Black/African-American	1 (2.6%)	0 (0.0%)	0 (0.0%)	1 (0.8%)
White	35 (92.1%)	34 (89.5%)	39 (90.7%)	108 (90.8%)
Other	1 (2.6%)	3 (7.9%)	3 (7.0%)	7 (5.9%)
Iris color
Blue	10 (26.3%)	7 (18.4%)	10 (23.3%)	27 (22.7%)
Brown	15 (39.5%)	19 (50.0%)	21 (28.8%)	55 (46.2%)
Green	2 (5.3%)	4 (10.5%)	5 (11.6%)	11 (9.2%)
Hazel	11 (28.9%)	8 (21.1%)	7 (16.3%)	26 (21.8%)

Notes: Subject-reported races designated as ‘Other’ include: Native Indian/Latino (1), Spanish (1), Polish (1), Mulatto (1), Hispanic (1), and Puerto Rican (2).

Abbreviation: SD, standard deviation.

Figure 1 Disposition of enrolled subjects.

^aIncludes 1 subject discontinued due to investigator’s decision and 1 subject discontinued due to pregnancy. In the latter case, the subject had a negative pregnancy test at Visit 1, but reported that she had a positive pregnancy test prior to Visit 2a. The subject was discontinued immediately before the scheduled Visit 2a and did not receive any test medications.

Abbreviations: ITT, intent-to-treat population; mITT, modified intent-to-treat population.

Table 3 Disposition of enrolled subjects

	Besifloxacin 0.6%	Moxifloxacin 0.5%	Gatifloxacin 0.3%	Total
Randomized (ITT)	38 (100%)	38 (100%)	43 (100%)	119 (100%)
Completed (mITT)	36 (94.7%)	36 (94.7%)	36 (83.7%)	108 (90.8%)
Safety population	38 (100%)	36 (94.7%)	37 (86.0%)	111 (93.3%)
Per-protocol population	35 (92.1%)	36 (94.7%)	35 (81.4%)	106 (89.1%)
Discontinued	2 (5.3%)	2 (5.3%)	7 (16.3%)	11 (9.2%)
Adverse event	1 (2.6%)	0 (0.0%)	2 (4.7%)	3 (3.5%)
Consent withdrawn	0 (0.0%)	0 (0.0%)	2 (4.7%)	2 (1.7%)
Investigator’s decision	0 (0.0%)	1 (2.6%)	0 (0.0%)	1 (0.8%)
Protocol violation	1 (2.6%)	1 (2.6%)	0 (0.0%)	2 (1.7%)
Administrative reasons	0 (0.0%)	0 (0.0%)	2 (4.7%)	2 (1.7%)
Pregnancya	0 (0.0%)	0 (0.0%)	1 (2.3%)	1 (0.8%)

a Subject had a negative pregnancy test at Visit 1, but reported a positive pregnancy test prior to Visit 2a. The subject was discontinued immediately and did not receive any test medications.

Abbreviations: ITT, intent-to-treat population; mITT, modified intent-to-treat population.

Table 4 Mean and median fluoroquinolone concentrations in conjunctival tissue (mITT population)

		Besifloxacin 0.6% (μg/g) N = 36	Moxifloxacin 0.5% (μg/g) N = 36	Gatifloxacin 0.3% (μg/g) N = 36
15 minutes	Mean (SD)	2.30 (1.42)	10.7 (5.89)	4.03 (3.84)
	Median	1.65	9.23	3.04
30 minutes	Mean (SD)	2.29 (1.30)	4.04 (4.16)	2.76 (0.737)
	Median	1.75	2.80	2.61
2 hours	Mean (SD)	0.418 (0.281)	0.845 (0.440)	0.448 (0.284)
	Median	0.442	0.917	0.444
6 hours	Mean (SD)	0.324 (0.355)	0.228 (0.162)	0.162 (0.205)
	Median	0.161	0.184	0.0936
12 hours	Mean (SD)	0.122 (0.196)	0.146 (0.123)	0.0586 (0.0675)
	Median	0.0447	0.134	0.0311
24 hours	Mean (SD)	0.0338 (0.0262)	0.0248 (0.0309)	0.0186 (0.0133)
	Median	0.0309	0.00895	0.0127

Notes: Biopsies were performed at 15 ± 1 minute, 30 ± 1 minute, 2 hours ± 5 minutes, 6 hours ± 15 minutes, 12 hours ± 15 minutes, and 24 hours ± 15 minutes. Biopsy samples containing a concentration of drug below the lower limit of quantitation (LLOQ = 17.9 ng/g) were assigned a value equal to one-half the LLOQ (8.95 ng/g).

Abbreviations: mITT, modified intent-to-treat population (N = 108); SD, standard deviation.

Figure 2 Conjunctival fluoroquinolone concentrations (μg/g) in individual subjects at 24 hours (mITT population).

Abbreviations: mITT, modified intent-to-treat population (N = 108); BLQ, concentration below the limit of quantitation (17.9 ng/g).

Figure 3 Mean fluoroquinolone concentration-time curves in conjunctiva (mITT population).

Notes: Concentration data for biopsies performed at 24 hours are presented as a separate figure (Figure 3).
Abbreviation: mITT, modified intent-to-treat population (N = 108).

Table 5 Area-under-the-curve over 24 hours (AUC_{0–24 h}) and mean residence time (MRT) for fluoroquinolones in conjunctiva

Fluoroquinolone	AUC0–24 h (μg·h/g)	MRT (h)a
Besifloxacin	6.65	4.7
Moxifloxacin	11.1	3.0
Gatifloxacin	6.10	2.9

a Mean residence time (MRT) corresponds to 1.44 multiplied by the half-life (in hours) of the drug. MRT was calculated using the equation: MRT = AUMC/AUC (AUMC = area-under-the-first-moment-curve; AUC = area-under-the-curve).

Table 6 Treatment-related adverse events (AEs) occurring in the safety population

	Besifloxacin 0.6% N = 37	Moxifloxacin 0.5% N = 36	Gatifloxacin 0.3% N = 36	Total N = 109
Ocular pain	3 (8.1%)	1 (2.8%)	1 (2.8%)	5 (4.6%)
Foreign body sensation	0 (0.0%)	0 (0.0%)	1 (2.8%)	1 (0.9%)
Blurred vision	1 (2.7%)	0 (0.0%)	0 (0.0%)	1 (0.9%)
Dysgeusia	0 (0.0%)	1 (2.8%)	0 (0.0%)	1 (0.9%)
Headache	1 (2.7%)	1 (2.8%)	0 (0.0%)	2 (1.8%)
Procedural site reaction	0 (0.0%)	1 (2.8%)	0 (0.0%)	1 (0.9%)

Notes: Includes AEs determined by the investigator to have a possible, probable, or definite relationship to the study medication.

Figure 4 Ratio of fluoroquinolone AUC_{0–24 h} in conjunctiva to the MIC₉₀ for methicillin-sensitive S. aureus (MSSA) (mITT population).^a

^aMIC₉₀ values were obtained from susceptibility testing of 144 methicillin-sensitive, ciprofloxacin-sensitive S. aureus isolates. The values were 0.06 μg/mL for besifloxacin, 0.12 μg/mL for moxifloxacin, and 0.25 μg/mL for gatifloxacin.⁷

Abbreviations: AUC_{0–24 h}, area-under-the-curve, or the total amount of drug delivered to conjunctival tissue in 1 day following 1 dose; mITT, modified intent-to-treat population (N = 108).

Figure 5 Ratio of fluoroquinolone AUC_{0–24 h} in conjunctiva to the MIC₉₀ for methicillin-resistant S. aureus (MRSA) (mITT population).^a

^aMIC₉₀ values were obtained from susceptibility testing of 81 methicillin-resistant, ciprofloxacin-resistant S. aureus isolates. The values were 4 μg/mL for besifloxacin, 32 μg/mL for moxifloxacin, and 64 μg/mL for gatifloxacin.²⁴

Abbreviations: AUC_{0–24 h}, area-under-the-curve, or the total amount of drug delivered to conjunctival tissue in 1 day following 1 dose; mITT, modified intent-to-treat population (N = 108).

Figure 6 Ratio of fluoroquinolone AUC_{0–24 h} in conjunctiva to the MIC₉₀ for methicillin-sensitive S. epidermidis (MSSE) (mITT population).^a

^aMIC₉₀ values were obtained from susceptibility testing of 50 methicillin-sensitive, ciprofloxacin- sensitive S. epidermidis isolates. The values were 0.06 μg/mL for besifloxacin, 0.12 μg/mL for moxifloxacin, and 0.25 μg/mL for gatifloxacin.⁷

Abbreviations: AUC_{0–24 h}, area-under-the-curve, or the total amount of drug delivered to conjunctival tissue in 1 day following 1 dose; mITT, modified intent-to-treat population (N = 108).

Figure 7 Ratio of fluoroquinolone AUC_{0–24 h} in conjunctiva to the MIC₉₀ for methicillin-resistant S. epidermidis (MRSE) (mITT population).^a

^aMIC₉₀ values were obtained from susceptibility testing of 29 methicillin-resistant, ciprofloxacin-resistant S. epidermidis isolates. The values were 4 μg/mL for besifloxacin, 64 μg/mL for moxifloxacin, and 128 μg/mL for gatifloxacin.²⁴

Abbreviations: AUC_{0–24 h}, area-under-the-curve, or the total amount of drug delivered to conjunctival tissue in 1 day following 1 dose; mITT, modified intent-to-treat population (N = 108).

United States Food and Drug Administration. Dermatologic and Ophthalmic Drugs Advisory CommitteeBriefing Package for Besifloxacin hydrochloride ophthalmic suspension for the treatment of bacterial conjunctivitisBausch and Lomb, Inc http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4397b1-00-Index.htmAccessed July 10, 2009

 Google Scholar

ProkschJWChappaAKHaasWMorrisTWBesifloxacin, moxifloxacin, and gatifloxacin ocular tissue AUC/MIC ratios for fluoroquinolone-resistant organismsAssociation for Research in Vision and Ophthalmology (ARVO)2009 Abstract D905

 Google Scholar