Distribution of topical ocular nepafenac and its active metabolite amfenac to the posterior segment of the eye.

Nepafenac ophthalmic suspensions, 0.1% (NEVANAC(®)) and 0.3% (ILEVRO™), are topical nonsteroidal anti-inflammatory drug (NSAID) products approved in the United States, Europe and various other countries to treat pain and inflammation associated with cataract surgery. NEVANAC is also approved in Europe for the reduction in the risk of postoperative macular edema (ME) associated with cataract surgery in diabetic patients. The efficacy against ME suggests that topical administration leads to distribution of nepafenac or its active metabolite amfenac to the posterior segment of the eye. This article evaluates the ocular distribution of nepafenac and amfenac and the extent of local delivery to the posterior segment of the eye, following topical ocular instillation in animal models. Nepafenac ophthalmic suspension was instilled unilaterally in New Zealand White rabbits as either a single dose (0.1%; one drop) or as multiple doses (0.3%, one drop, once-daily for 4 days, or 0.1% one drop, three-times daily for 3 days and one morning dose on day 4). Nepafenac (0.3%) was also instilled unilaterally in cynomolgus monkeys as multiple doses (one drop, three-times daily for 7 days). Nepafenac and amfenac concentrations in harvested ocular tissues were measured using high-performance liquid chromatography/mass spectrometry. Locally-distributed compound concentrations were determined as the difference in levels between dosed and undosed eyes. In single-dosed rabbit eyes, peak concentrations of locally-distributed nepafenac and amfenac showed a trend of sclera > choroid > retina. Nepafenac peak levels in sub-samples posterior to the eye equator and inclusive of the posterior pole (E-PP) were 55.1, 4.03 and 2.72 nM, respectively, at 0.25 or 0.50 h, with corresponding amfenac peak levels of 41.9, 3.10 and 0.705 nM at 1 or 4 h. By comparison, peak levels in sclera, choroid and retina sub-samples in a band between the ora serrata and the equator (OS-E) were 13- to 40-fold (nepafenac) or 11- to 23-fold (amfenac) higher, indicating an anterior-to-posterior directional concentration gradient. In multiple-dosed rabbit eyes, with 0.3% nepafenac instilled once-daily or 0.1% nepafenac instilled three-times daily, cumulative 24-h locally-distributed levels of nepafenac in E-PP retina were similar between these groups, whereas exposure to amfenac once-daily dosing nepafenac 0.3% was 51% of that achieved with three-times daily dosing of 0.1%. In single-dosed monkey eyes, concentration gradients showed similar directionality as observed in rabbit eyes. Peak concentrations of locally-distributed nepafenac were 1580, 386, 292 and 13.8 nM in E-PP sclera, choroid and retina, vitreous humor, respectively, at 1 or 2 h after drug instillation. Corresponding amfenac concentrations were 21.3, 11.8, 2.58 and 2.82 nM, observed 1 or 2 h post-instillation. The data indicate that topically administered nepafenac and its metabolite amfenac reach pharmacologically relevant concentrations in the posterior eye segment (choroid and retina) via local distribution, following an anterior-to-posterior concentration gradient. The proposed pathway involves a choroidal/suprachoroidal or periocular route, along with an inward movement of drug through the sclera, choroid and retina, with negligible vitreal compartment involvement. Sustained high nepafenac concentrations in posterior segment tissues may be a reservoir for hydrolysis to amfenac.

Pharmacokinetics of CIPRODEX otic in pediatric and adolescent patients.

OBJECTIVE: Describe the pharmacokinetics of ciprofloxacin and dexamethasone after administration of CIPRODEX Otic Suspension (CIP/DEX) into the middle ears of children. DESIGN: Open-label, single-dose, pharmacokinetic studies, administering four drops of CIP/DEX instilled into each middle ear through the tympanostomy tubes immediately following tube placement. Blood was collected for 6h and analyzed for ciprofloxacin and dexamethasone concentrations using a validated liquid chromatography and tandem mass spectrometry (LC/MS/MS) method. SETTING: The study was conducted through a referral pediatric otolaryngology practice with actual surgical procedures performed in an ambulatory care center. PATIENTS: Twenty-five randomly selected patients, 1-14 years of age (mean age, 5 years), receiving tympanostomy tubes. RESULTS: Peak ciprofloxacin plasma levels were observed at about 1h, with a mean C(max) of 1.33+/-0.96 ng/mL (range <0.5-3.45 ng/mL) and an estimated half-life of 3.0+/-1.2h. Peak dexamethasone plasma levels were observed within 2h with a mean C(max) of 0.90+/-1.04 ng/mL (range <0.05-5.10 ng/mL) and an estimated half-life of 3.9+/-2.9h. CONCLUSION: These results demonstrated low systemic exposure of ciprofloxacin and dexamethasone following topical otic administration in pediatric patients.

Ex situ aqueous mineral carbonation.

The U.S. Department of Energy's National Energy Technology Laboratory (NETL) located in Albany, OR (formerly the Albany Research Center) has studied ex situ mineral carbonation as a potential option for carbon dioxide sequestration. Studies focused on the reaction of Ca-, Fe-, and Mg-silicate minerals with gaseous CO2 to form geologically stable, naturally occurring solid carbonate minerals. The research included resource evaluation, kinetic studies, process development, and economic evaluation. An initial cost estimate of approximately $69/ton of CO2 sequestered was improved with process improvements to $54/ton. The scale of ex situ mineral carbonation operations, requiring 55 000 tons of mineral to carbonate, the daily CO2 emissions from a 1-GW, coal-fired power plant, may make such operations impractical.

Pharmacokinetics and metabolism of anecortave acetate in animals and humans.

The ocular delivery of anecortave acetate was tested in preclinical and clinical pharmacokinetic and metabolism studies. Results of initial studies led to the design of a new cannula that could effectively deliver anecortave acetate as a posterior juxtascleral depot, providing adequate retinal and choroidal drug concentrations for up to 6 months after a single administration. A counter-pressure device was designed to prevent drug reflux during and immediately after posterior juxtascleral depot administration. Pharmacokinetic studies support the effectiveness of these devices. Anecortave acetate is rapidly hydrolyzed by esterases to pharmacologically active anecortave desacetate, and is further reductively metabolized to one major and several minor products that circulate as glucuronide conjugates. Low levels of these anecortave acetate metabolites were detectable for only approximately 2 weeks in the plasma after a 15-mg posterior juxtascleral depot administration to age-related macular degeneration patients. Studies show that posterior juxtascleral depot administration of anecortave acetate is an effective, minimally invasive method of delivering this drug to the choroid and retina.

Concentrations of betaxolol in ocular tissues of patients with glaucoma and normal monkeys after 1 month of topical ocular administration.

PURPOSE: To measure the concentration of betaxolol in tissues of humans with glaucoma and normal monkeys after topical administration. METHODS: Enucleated eyes (n = 7) of patients with glaucoma (age range, 27-79 years), without apparent anatomic disruption that would be likely to influence betaxolol absorption and intraocular distribution (exceptions: one pseudophakic, one aphakic) or other disease, were analyzed for betaxolol concentrations after self-administration of 0.25% betaxolol twice daily for 28 days or longer. The last instillation was made within 6 hours of surgery. Cynomolgus monkeys (n = 3) received 0.25% betaxolol twice daily unilaterally for 30 days. Betaxolol was measured by HPLC and tandem mass spectrometry (MS/MS) in plasma and ocular tissues. RESULTS: In humans, mean betaxolol concentrations (excluding the aphakic patient) were 71.4 +/- 41.8 ng/g in the retina, 31.2 +/- 14.8 ng/g in the optic nerve head, and 1290 +/- 1170 ng/g in the choroid. Mean concentrations in the iris and ciliary body were 73,200 +/- 89,600 and 4,250 +/- 3,020 ng/g, respectively. Betaxolol concentration was higher in all ocular tissues than in the plasma (0.59 +/- 0.32 ng/mL). In the monkeys the concentrations in the posterior tissues of the treated eyes were higher than in the untreated eyes, with mean differences in the retina and optic nerve head of 121 and 130 ng/g, respectively. CONCLUSIONS: Topically applied betaxolol was bioavailable to posterior ocular tissues, including the retina and optic nerve head, of patients with glaucoma and of normal cynomolgus monkeys. The higher betaxolol levels in the treated versus untreated monkey eyes are consistent with betaxolol's reaching posterior tissues by local absorption and distribution.

Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans.

The ocular penetration and pharmacokinetics of moxifloxacin in comparison to other fluoroquinolones (ofloxacin, ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, and lomefloxacin) have been determined by in vitro and ex vivo techniques, as well as in animal and human studies. This article reviews the original pharmacokinetics work performed by Alcon and other studies reported in the ocular fluoroquinolone literature. The results consistently demonstrate higher maximum concentrations for moxifloxacin relative to the other fluoroquinolones in ocular tissues with levels well above its minimum inhibitory concentrations for relevant ocular pathogens. This superior performance is due to the unique structure of moxifloxacin that combines high lipophilicity for enhanced corneal penetration with high aqueous solubility at physiological pH. The latter property creates a high concentration gradient at the tear film/corneal epithelial interface providing a driving force for better ocular penetration for moxifloxacin. In addition, the higher concentration of moxifloxacin in VIGAMOX (i.e., 0.5% vs. 0.3%) allows more antibiotic to be available to ocular tissues. It is clear from the array of studies summarized in this report that moxifloxacin penetrates ocular tissues better (two- to three-fold) than gatifloxacin, ciprofloxacin, ofloxacin, or levofloxacin. This consistent, enhanced penetration of topical moxifloxacin offers powerful advantages for ophthalmic therapy.

Absorption of topical moxifloxacin ophthalmic solution into human aqueous humor.

PURPOSE: To investigate the absorption of moxifloxacin into human aqueous humor after administration of moxifloxacin hydrochloride ophthalmic solution, 0.5% as base. METHODS: Cataract patients were randomly allocated to receive 1 drop every 15 minutes for 4 doses before surgery (group 1) or 1 drop 4 times per day on the day before surgery plus the same preoperative regimen as group 1 (group 2). The last dose was administered 0.25, 0.50, 1, 2, or 3 hours before aqueous humor sampling. Samples from 30 patients per group were analyzed by a validated HPLC/MS/MS method. RESULTS: For group 1, the mean +/- SD C(max) was 1.50 +/- 0.75 microg/mL and occurred at 0.5 hour after dosing. The mean C(max) for group 2 was 1.74 +/- 0.66 microg/mL and was reached at 1 to 2 hours. Mean AUC(0-3h) for groups 1 and 2 were 3.16 +/- 0.29 and 4.41 +/- 0.48 microg.h/mL, respectively. The difference in AUC(0-3h) was statistically significant (P = 0.04), but the difference in Cmax was not. CONCLUSIONS: Topical moxifloxacin was well absorbed. Maximum moxifloxacin concentrations were approximately 30 times higher than the median MICs for common pathogens in bacterial endophthalmitis, indicating that either regimen may provide sufficient concentrations to prevent postoperative endophthalmitis.