Author: Jordi Monés (Spain)
Co-authors: Shamika Gune, Mauricio Maia, Han Ting Ding, Merce Morral, Matts Kagedal, Katie Maass
Purpose
The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system that includes a pars plana implant for continuous delivery of ranibizumab into the vitreous. In the phase 3 Archway trial in patients with neovascular age-related macular degeneration (nAMD), serum and aqueous humor samples were collected to characterize the pharmacokinetic profile of ranibizumab delivered via the PDS with fixed refill-exchanges every 24 weeks (PDS Q24W).
Setting/Venue
Archway (NCT03677934) was a phase 3, randomized, active treatment–controlled trial for the treatment of nAMD, conducted at 77 study locations in the United States (N = 415).
Methods
In the PDS with ranibizumab 100 mg/mL Q24W and intravitreal ranibizumab 0.5 mg injections every 4 weeks (Q4W; monthly ranibizumab) arms, serum pharmacokinetic samples were collected at randomization and at weeks 4, 24, 36, and 96 from all patients. At selected sites, samples were taken at days 2 and 7 and at weeks 12, 48, and 72 in the PDS Q24W arm, and 1–5 days after an injection in the monthly ranibizumab arm. Optional aqueous humor samples were collected from patients in either arm at randomization and at weeks 24, 28, 48, 52, 72, 76, and 96; serum samples were also collected at this time. The pharmacokinetic-evaluable population included patients who did not receive ranibizumab as supplemental treatment in the study eye after implant insertion or in the fellow eye, or patients with prior intravitreal bevacizumab treatment. Ranibizumab concentrations were measured using a validated enzyme-linked immunosorbent assay with lower limits of quantitation of 15 pg/mL for serum and 20,000 pg/mL for aqueous humor. Vitreous concentrations were predicted using a population pharmacokinetic model with a compartmental structure, including compartments for the implant, vitreous, and serum, where the dose was either administered into the vitreous or into the implant.
Results
In the PDS Q24W arm (n = 94), geometric mean (CV%) serum ranibizumab concentrations ranged from 419 (54%) pg/mL at week 4 to 340 (94%) pg/mL at week 24. In the monthly ranibizumab arm (n = 79), the geometric mean serum ranibizumab concentrations ranged from 1880 (57%) pg/mL at 1–5 days after injection (Cmax) to 58.1 (171%) pg/mL at week 4 (Ctrough). The aqueous humor pharmacokinetic profile reflected the same trends seen in serum, with PDS Q24W (n = 42) maintaining concentrations above monthly ranibizumab Ctrough (n = 46). Using a population pharmacokinetic model, in both serum and vitreous, the total ranibizumab exposure (as summarized by area under the concentration curve) with PDS 100 mg/mL Q24W was predicted to be ~40% of the total ranibizumab exposure with intravitreal ranibizumab 0.5 mg Q4W injections. The predicted vitreous humor concentrations of ranibizumab were estimated to decrease by half by 170 days after a refill-exchange procedure.
Conlusions
The PDS continuously released ranibizumab over the Q24W refill-exchange interval, achieving steady concentrations. Ranibizumab concentrations with PDS Q24W were within the range experienced with monthly ranibizumab injections. The aqueous humor pharmacokinetic profile was consistent with the serum pharmacokinetic profile.
Financial Disclosure
Financial Disclosures: Jordi Monés: Cell Cure Neurosciences (A,C,SP); Lineage Cell Therapeutics (A,C,SP); Genentech (A,C,I,SP); Novartis (A, C, I, SP); Iveric Bio (A, C, I, SP, SH); Reneuron (A, C, I, SP); Roche (A, I, SP); Apellis (A, C, I, SP); Kodiak (A, I); Maculogix (C); Notal Vision (SH) Mauricio Maia, Han Ting Ding, Matts Kagedal and Katie Maass: Genentech (EM) Merce Morral: F. Hoffmann-La Roche (EM).................. • Advisory Board (A) • Board of Directors (B) • Consultant (C) • Employee (EM) • Founder (F) • Investigator (I) • Speaker (SP) • Stockholder (SH) • Other (O)
Comments
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