Transscleral Diffusion of Carboplatin

Abstract

To compare the in vitro scleral permeability of carboplatin using either a fibrin sealant or a balanced salt solution (BSS) vehicle and to measure in vivo ocular tissue levels following subconjunctival injection of carboplatin in fibrin sealant or BSS. Methods: The permeability of carboplatin in fibrin sealant or BSS through human eye bank sclera was tested using an in vitro perfusion apparatus. Levels of carboplatin permeating the sclera were measured every hour for 24 hours using atomic absorption spectrometry. In vivo studies were performed in Dutch Belted rabbits injected subconjunctivally with carboplatin in either fibrin sealant or BSS; eyes were enucleated at 1 1 ⁄2 hours, 48 hours, and 2 weeks after injection, and levels of carboplatin were measured in various tissues. Results: In vitro carboplatin in fibrin sealant had a peak permeability constant of 13.7 ± 2.3 ϫ 10 −6 cm/s; carboplatin in BSS, 27.0 ± 1.7 ϫ 10 −6 cm/s. After 24 hours, 33.2%±1.8% of the carboplatin was retained in the fibrin sealant, while 5.5%±1.0% was retained in the BSS. In vivo subconjunctival injection of carboplatin in fibrin sealant vehicle achieved 11.83±5.16 µg/mL in the vitreous at 1 1 ⁄2 hours and 0.03±0.06 µg/mL in the vitreous at 2 weeks. The fibrin sealant also attained 396.59±177.84 µg/mg in the choroid and retina at 1 1 ⁄2 hours and 3.38±1.97 µg/mg in the choroid and retina at 2 weeks. (Data are given as mean±SEM.) Conclusion: Fibrin sealant provided a more controlled and localized release of carboplatin and delivered carboplatin to the ocular tissues for up to 2 weeks. Clinical Relevance: This study reports the use of fibrin sealant as a subconjunctival delivery vehicle for carboplatin, and quantifies ocular drug levels achieved in an animal model.

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

“…Preclinical studies in rabbits showed a 6-fold increase in vitreous-toplasma AUC after periocular carboplatin compared to the same ratio after intravenous infusion (Hayden et al, 2004;Simpson et al, 2002) and, in the non-human primate, the vitreous and aqueous humor C max was over 2-fold the levels attained in plasma (Mendelsohn et al, 1998).…”

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

“…Preclinical studies in rabbits showed a 6-fold increase in vitreous-toplasma AUC after periocular carboplatin compared to the same ratio after intravenous infusion (Hayden et al, 2004;Simpson et al, 2002) and, in the non-human primate, the vitreous and aqueous humor C max was over 2-fold the levels attained in plasma (Mendelsohn et al, 1998).…”

Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma

“…As Table 2 shows, the majority of efficacy studies are conducted in mouse models of retinoblastoma (either transgenic or xenograft) and, despite the unique challenges of reaching the retina and vitreous, these studies generally fail to include exposure data. For some of the compounds evaluated, separate PK studies have been conducted, [75, 79, 97–98, 107, 187–188] but most of the published PK results have employed rabbits, as they are considered the “gold-standard” species for ocular PK testing. Though species-specific differences in exposure may exist, there has been no attempt to conduct comparison studies or correlate exposure in mice with exposure in rabbits.…”

Fibrin sealant as a carrier for sustained delivery of antibiotics

“…showed that a carboplatin-impregnated fibrin sealant maintained a two-week drug release, whereas Tredwell at al. reported a mere 2-day release of cefazolin [13,19]. Therefore, a drug's ability to depot in a fibrin sealant matrix and its elution from the sealant is possibly related to the drug's interaction with the fibrin material.…”

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

“…Preclinical studies in rabbits showed a 6-fold increase in vitreous-toplasma AUC after periocular carboplatin compared to the same ratio after intravenous infusion (Hayden et al, 2004;Simpson et al, 2002) and, in the non-human primate, the vitreous and aqueous humor C max was over 2-fold the levels attained in plasma (Mendelsohn et al, 1998).…”

Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma

“…As Table 2 shows, the majority of efficacy studies are conducted in mouse models of retinoblastoma (either transgenic or xenograft) and, despite the unique challenges of reaching the retina and vitreous, these studies generally fail to include exposure data. For some of the compounds evaluated, separate PK studies have been conducted, [75, 79, 97–98, 107, 187–188] but most of the published PK results have employed rabbits, as they are considered the “gold-standard” species for ocular PK testing. Though species-specific differences in exposure may exist, there has been no attempt to conduct comparison studies or correlate exposure in mice with exposure in rabbits.…”

Fibrin sealant as a carrier for sustained delivery of antibiotics

“…showed that a carboplatin-impregnated fibrin sealant maintained a two-week drug release, whereas Tredwell at al. reported a mere 2-day release of cefazolin [13,19]. Therefore, a drug's ability to depot in a fibrin sealant matrix and its elution from the sealant is possibly related to the drug's interaction with the fibrin material.…”

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

“…Preclinical studies in rabbits showed a 6-fold increase in vitreous-toplasma AUC after periocular carboplatin compared to the same ratio after intravenous infusion (Hayden et al, 2004;Simpson et al, 2002) and, in the non-human primate, the vitreous and aqueous humor C max was over 2-fold the levels attained in plasma (Mendelsohn et al, 1998).…”

Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma

“…As Table 2 shows, the majority of efficacy studies are conducted in mouse models of retinoblastoma (either transgenic or xenograft) and, despite the unique challenges of reaching the retina and vitreous, these studies generally fail to include exposure data. For some of the compounds evaluated, separate PK studies have been conducted, [75, 79, 97–98, 107, 187–188] but most of the published PK results have employed rabbits, as they are considered the “gold-standard” species for ocular PK testing. Though species-specific differences in exposure may exist, there has been no attempt to conduct comparison studies or correlate exposure in mice with exposure in rabbits.…”

Fibrin sealant as a carrier for sustained delivery of antibiotics

“…showed that a carboplatin-impregnated fibrin sealant maintained a two-week drug release, whereas Tredwell at al. reported a mere 2-day release of cefazolin [13,19]. Therefore, a drug's ability to depot in a fibrin sealant matrix and its elution from the sealant is possibly related to the drug's interaction with the fibrin material.…”