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AXPAXLI (axitinib intravitreal implant)

Neovascular age-related macular degeneration

Also known as OTX-TKI
Manufacturer
Ocular Therapeutix
Last updated
309 sources

Product information and disease descriptionProduct descriptionProduct informationPharmacology

Pharmacokinetics

12 evidence topics · 9 sources

Designed release duration

“AXPAXLI is delivered by intravitreal injection and is designed for a duration of six months or longer.” (opens the source at this quote in a new tab)

“Our prolonged constant rate of axitinib delivery over a nine-to-twelve-month period could make it possible to reduce patients’ treatment burden by reducing the frequency of treatment for wet AMD.” (opens the source at this quote in a new tab)

Implant bioresorption in humans

“Implant observed to bioresorb consistently at about eight to nine months in trial, informing potential redosing timeline” (opens the source at this quote in a new tab)

“In addition, the AXPAXLI doses in cohort 1 (200 µg single dose) were observed to have biodegraded in all subjects within nine to 10.5 months of injection.” (opens the source at this quote in a new tab)

Systemic exposure in humans: Australian phase 1 trial

“Plasma levels of the active drug, axitinib, were below the limit of quantification at all doses, indicating that systemic exposure to intravitreal delivery of axitinib by AXPAXLI up to 600 μg was negligible.” (opens the source at this quote in a new tab)

Ocular tissue concentrations in non-human primates: first-generation implants

“Median axitinib concentrations in the retina and choroid/RPE were substantially greater than the inhibitory concentration (IC50) of VEGF receptor-2 (0.08 ng/mL) from after Month 3” (opens the source at this quote in a new tab)

“Hydrogel degradation was observed at approximately 5 to 6 months with released axitinib particles visible in the vitreous at Month 9 and localized at Month 12” (opens the source at this quote in a new tab)

“Plasma samples showed axitinib levels were below the lower limit of quantification (LLOQ=0.1 ng/mL) up to Month 3, then slightly above LLOQ (0.1 – 0.2 ng/mL) in Month 6 samples and returned to below LLOQ at Month 9” (opens the source at this quote in a new tab)

Ocular tissue concentrations through 12 months in non-human primates: sponsor summary

“That data showed that clinically representative formulations of AXPAXLI delivered sustained axitinib concentrations through 12 months that were well above the IC50 for VEGFR-2 (vascular endothelial growth factor receptor) in cynomolgus monkey retina tissue and choroid/RPE tissues.” (opens the source at this quote in a new tab)

First-generation versus second-generation implant pharmacokinetics in monkeys and rabbits

“Rapidly achieved higher initial axitinib concentrations in the target tissues, suggesting a potential earlier onset of action” (opens the source at this quote in a new tab)

“Maintained steady-state concentrations better than OTX-TKI due to drug left behind following hydrogel bioresorption at 6 months” (opens the source at this quote in a new tab)

Interspecies scaling of implant bioresorption

“Implant bioresorption at ~5-6 months in NHPs is equivalent to ~8-9 months in humans” (opens the source at this quote in a new tab)

Terminal release after bioresorption

“Hydrogel remains intact until final resorption event, which occurs over a span of about 3-4 weeks. In humans, the resorption occurs 8-9 months after implantation.” (opens the source at this quote in a new tab)

Release kinetics: independent review

“Axitinib concentrations were above the half-maximum inhibitory concentration of VEGF receptor 2 in the retina, choroid, and retinal pigment epithelium consistently through 9 months.” (opens the source at this quote in a new tab)

“Axpaxli is an investigational intravitreal, hydrogel implant that delivers axitinib with 0-order kinetics for 6–12 months, reducing the need for frequent intravitreal injections.” (opens the source at this quote in a new tab)

Class context: oral axitinib (INLYTA) absorption, distribution, and half-life

“The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.” (opens the source at this quote in a new tab)

“Axitinib is highly bound (>99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein.” (opens the source at this quote in a new tab)

“The plasma half-life of INLYTA ranges from 2.5 to 6.1 hours.” (opens the source at this quote in a new tab)

Class context: oral axitinib (INLYTA) metabolism and excretion

“Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.” (opens the source at this quote in a new tab)

“Following oral administration of a 5-mg radioactive dose of axitinib, approximately 41% of the radioactivity was recovered in feces and approximately 23% was recovered in urine.” (opens the source at this quote in a new tab)

Vitreous and plasma concentrations of the 450 µg implant in humans

No evidence found.

Vitreous clearance of tyrosine kinase inhibitors and the rationale for sustained release: independent review

“Rapid vitreous clearance of existing VEGF inhibitors limits durability to 1-4 months.” (opens the source at this quote in a new tab)

“Combining TKIs with sustained release platforms, such as hydrogel or polyvinyl alcohol, allow for the sustained release of the molecules and the potential for extended durability.” (opens the source at this quote in a new tab)

“OTX-TKI is administered via a 25-gauge intravitreal injection and is designed to be completely bioresorbable and have biologic activity over 9-12 months.” (opens the source at this quote in a new tab)