Carsten H. Meyer

Intraocular Pharmacokinetics of Bevacizumab After a Single Intravitreal Injection in Humans

PURPOSE To investigate intraocular concentrations and pharmacokinetics of bevacizumab after a single intravitreal injection in humans. DESIGN Prospective, noncomparative, interventional case series. METHODS We included 30 nonvitrectomized eyes of 30 patients (age range, 43 to 93 years) diagnosed with clinically significant cataract and concurrent macular edema secondary to neovascular age-related macular degeneration, diabetic retinopathy, or retinal venous occlusion in the same eye. All patients received an intravitreal injection of 1.5 mg bevacizumab. Between one and 53 days after injection, an aqueous humor sample was obtained during elective cataract surgery. Concentrations of unbound bevacizumab in these samples were quantified by enzyme-linked immunosorbent assay. RESULTS Concentration of bevacizumab in aqueous humor peaked on the first day after injection with a mean concentration (c(max)) of 33.3 microg/ml (range, 16.6 to 42.5 microg/ml) and subsequently declined in a monoexponential fashion. Nonlinear regression analysis determined an elimination half-time (t(1/2)) of 9.82 days (R(2) = 0.81). No significant differences between diagnosis subgroups were noted. CONCLUSIONS In human nonvitrectomized eyes, the aqueous half-life of 1.5 mg intravitreally injected bevacizumab is 9.82 days.

Strategy for Safe Performance of Extrathoracic Magnetic Resonance Imaging at 1.5 Tesla in the Presence of Cardiac Pacemakers in Non–Pacemaker-Dependent Patients A Prospective Study With 115 Examinations

Background— The purpose of the present study was to evaluate a strategy for safe performance of extrathoracic magnetic resonance imaging (MRI) in non–pacemaker-dependent patients with cardiac pacemakers. Methods and Results— Inclusion criteria were presence of a cardiac pacemaker and urgent clinical need for an MRI examination. Pacemaker-dependent patients and those requiring examinations of the thoracic region were excluded. The study group consisted of 82 pacemaker patients who underwent a total of 115 MRI examinations at 1.5T. To minimize radiofrequency-related lead heating, the specific absorption rate was limited to 1.5 W/kg. All pacemakers were reprogrammed before MRI: If heart rate was <60 bpm, the asynchronous mode was programmed to avoid magnetic resonance (MR)–induced inhibition; if heart rate was >60 bpm, sense-only mode was used to avoid MR-induced competitive pacing and potential proarrhythmia. Patients were monitored with ECG and pulse oximetry. All pacemakers were interrogated immediately before and after the MRI examination and after 3 months, including measurement of pacing capture threshold (PCT) and serum troponin I levels. All MR examinations were completed safely. Inhibition of pacemaker output or induction of arrhythmias was not observed. PCT increased significantly from pre- to post-MRI (P=0.017). In 2 of 195 leads, an increase in PCT was only detected at follow-up. In 4 of 114 examinations, troponin increased from a normal baseline value to above normal after MRI, and in 1 case (troponin pre-MRI 0.02 ng/mL, post-MRI 0.16 ng/mL), this increase was associated with a significant increase in PCT. Conclusions— Extrathoracic MRI of non–pacemaker-dependent patients can be performed with an acceptable risk-benefit ratio under controlled conditions and by taking both MR- and pacemaker-related precautions.

Retinal pigment epithelial tears after intravitreal bevacizumab injection for neovascular age-related macular degeneration.

Purpose: To study retinal pigment epithelium (RPE) tears after off-label intravitreal bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) injection for neovascular age-related macular degeneration. Eyes with a vascularized pigment epithelial detachment (PED) that developed an RPE tear were compared with eyes with a vascularized PED but without an RPE tear. Methods: Nine retina specialists across the United States and in Europe participated in this retrospective case series. All eyes that received intravitreal bevacizumab injection for choroidal neovascularization (CNV) over 12 months (October 2005 to September 2006) were included. Eyes without all three confirmed tests (fluorescein angiography, fundus photography, and optical coherence tomography) were excluded from analysis. Statistical analyses were performed on multiple characteristics of eyes with a vascularized PED that did and did not develop an RPE tear. Results: Among 2,785 intravitreal bevacizumab injections for 1,064 eyes, RPE tears were found in 22 eyes in 22 patients (2.2%). A vascularized PED was present in 21 of 22 eyes that developed an RPE tear (17.1% of PED eyes; 15, 100% occult CNV; 6, predominantly occult CNV). Mean interval from bevacizumab injections to RPE tears was 37.3 days. Mean follow-up time was 124.9 days. Mean subfoveal PED size was larger for eyes with tears than for those without tears (13.97 mm2 vs 9.9 mm2, respectively; P = 0.01; odds ratio, 1.09). There was substantially smaller mean ratio of CNV size to PED size for eyes with tears than for those without tears (27.9% vs 67.6%, respectively; P = 0.005). Mean pre–bevacizumab injection best-corrected Snellen visual acuity was 20/162, and mean post–RPE tear best-corrected visual acuity was 20/160 (P = 0.48). Conclusion: Large PED size is a predictor for RPE tears, and a small ratio of CNV size to PED size (<50%) is more common in eyes with RPE tears. Vision may be preserved despite RPE tears.

Magnetic Resonance Imaging at 1.5-T in Patients With Implantable Cardioverter-Defibrillators

OBJECTIVES Our aim was to establish and evaluate a strategy for safe performance of magnetic resonance imaging (MRI) at 1.5-T in patients with implantable cardioverter-defibrillators (ICDs). BACKGROUND Expanding indications for ICD placement and MRI becoming the imaging modality of choice for many indications has created a growing demand for MRI in ICD patients, which is still considered an absolute contraindication. METHODS Non-pacemaker-dependent ICD patients with a clinical need for MRI were included in the study. To minimize radiofrequency-related lead heating, the specific absorption rate was limited to 2 W/kg. ICDs were reprogrammed pre-MRI to avoid competitive pacing and potential pro-arrhythmia: 1) the lower rate limit was programmed as low as reasonably achievable; and 2) arrhythmia detection was programmed on, but therapy delivery was programmed off. Patients were monitored using electrocardiography and pulse oximetry. All ICDs were interrogated before and after the MRI examination and after 3 months, including measurement of pacing capture threshold, lead impedance, battery voltage, and serum troponin I. RESULTS Eighteen ICD patients underwent a total of 18 MRI examinations at 1.5-T; all examinations were completed safely. All ICDs could be interrogated and reprogrammed normally post-MRI. No significant changes of pacing capture threshold, lead impedance, and serum troponin I were observed. Battery voltage decreased significantly from pre- to post-MRI. In 2 MRI examinations, oversensing of radiofrequency noise as ventricular fibrillation occurred. However, no attempt at therapy delivery was made. CONCLUSIONS MRI of non-pacemaker-dependent ICD patients can be performed with an acceptable risk/benefit ratio under controlled conditions by taking both MRI- and pacemaker-related precautions. (Implantable Cardioverter Defibrillators and Magnetic Resonance Imaging of the Heart at 1.5-Tesla; NCT00356239).

Acute retinal pigment epithelial tear following intravitreal bevacizumab (Avastin) injection for occult choroidal neovascularisation secondary to age related macular degeneration

Retinal pigment epithelium (RPE) tears are well recognised complications of pigment epithelial detachments (PED) in age related macular degeneration (AMD) and may arise spontaneously after trauma, photocoagulation, or photodynamic therapy (PDT).1 Rosenfeld et al recently reported favourable results after intravitreal (IV) bevacizumab (Avastin) injection in neovascular AMD.2 We present two patients, who developed an RPE tear after an intravitreal Avastin injection. The first case was a 64 year old man with an occult CNV with a PED in the right eye ( fig 1A–C). His visual acuity (VA) gradually declined from 20/30 to 20/60. Four days after an uneventful IV injection of 0.05 ml Avastin, the patient noted a sudden drop in VA. His VA was 20/80 while fluorescein angiography (FA) and optical coherence tomography revealed a large RPE tear (fig 2A–C). The second case was a 84 year old woman with an occult CNV with a PED. Her VA was 20/60 when she required an IV Avastin injection. When …

Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans

PURPOSE To investigate intraocular concentrations and pharmacokinetics of ranibizumab after a single intravitreal injection in humans. DESIGN Prospective, noncomparative, interventional case series. METHODS We included 18 nonvitrectomized eyes of 18 patients (age range, 61-85 years) that were diagnosed with both clinically significant cataract and macular edema secondary to either exudative age-related macular degeneration, diabetic maculopathy, or retinal vein occlusion. Each eye received a single intravitreal injection of 0.5 mg ranibizumab. An aqueous humor sample was obtained during cataract surgery between 1 and 37 days after injection. Concentrations of unbound ranibizumab in these samples were quantified by enzyme-linked immunosorbent assay. RESULTS Ranibizumab concentration in aqueous humor peaked the first day after injection (range, 36.9-66.1 μg/mL) and subsequently declined in a mono-exponential fashion. Nonlinear regression analysis determined an initial peak concentration (c(max)) of 56.1 μg/mL and an elimination half-life (t(1/2)) of 7.19 days with a coefficient of determination (R(2)) of 0.90. Correction of ranibizumab concentrations for ocular volume as calculated from axial length measurements did not alter regression analysis results significantly (t(1/2), 7.15 days; R(2), 0.89). CONCLUSIONS In human nonvitrectomized eyes, the aqueous half-life of 0.5 mg intravitreally injected ranibizumab is 7.19 days, slightly shorter than the half-life of 9.82 days previously determined for bevacizumab by comparable methods.

Clinical evaluation of simultaneous confocal scanning laser ophthalmoscopy imaging combined with high‐resolution, spectral‐domain optical coherence tomography

Acta Ophthalmol. 2010: 88: 842–849

Combined treatment of acute subretinal haemorrhages with intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot study

Purpose:  To assess the effectiveness of consecutive intravitreal injections of recombined tissue plasminogen activator (rtPA), expansile gas and bevacizumab in eyes with acute subretinal haemorrhage (SRH).

The Use of Vital Dyes in Ocular Surgery

Vital dyes have advanced diagnosis and surgical technique in various specialties, including oncology, gastroenterology, and ophthalmology. In ocular surgery vital dyes are widely used in cataract and vitreoretinal surgery. Worldwide, intra-operative use of trypan blue during cataract surgery has enhanced visualization of the anterior capsule during capsulorrhexis, and patent blue has been recently licensed in Europe for cataract surgery. For chromovitrectomy, the vital dyes indocyanine green, infracyanine green, and brilliant blue stain the internal limiting membrane, and trypan blue and triamcinolone acetonide help visualize epiretinal membranes and vitreous, respectively. Intra-operative vital dyes are finding uses in corneal, glaucoma, orbit, strabismus, and conjunctival surgery. We provide a summary of current knowledge of the use of vital dyes in ocular surgery. We review the properties of dyes, techniques of application, indications, and complications in ocular surgery. Vital dyes represent an expanding area of research, and novel dyes deserve further investigation.

Intraocular pharmacokinetics after a single intravitreal injection of 1.5 mg versus 3.0 mg of bevacizumab in humans.

Purpose: To compare the concentration of unbound bevacizumab in the anterior chamber of patients with macular edema, who received a single intravitreal injection of two different dosages. Methods: This was a comparative, interventional case series. Twenty-nine nonvitrectomized eyes of 29 patients with significant lens opacities and concurrent macular edema were included in the study. All patients were treated by a single dose of intravitreal injection of bevacizumab 1.5 mg (Group A, n = 13) or 3.0 mg (Group B, n = 16). Subsequent phacoemulsification and aspiration of an aqueous humor samples were performed at various intervals (1–60 days). The axial length of the globe was measured using the IOLMaster to calculate the total volume and corresponding globe size–corrected half-time. The concentration of unbound bevacizumab was measured by enzyme-linked immunosorbent assay and pharmacokinetic parameters including half-time of elimination. Results: The mean peak concentration was observed in both groups on the first day after intravitreal bevacizumab injection. The mean concentration of unbound bevacizumab ranged in Group A from 17.5 μg/mL at baseline to 0.66 μg/mL at Day 57 and in Group B from 28.3 μg/mL at baseline to 0.00 μg/mL at 54 days. The axial lengths of all injected eyes were not significantly different between Group A (mean values, 23.026 mm, SD 1.21) and Group B (mean, 23.313 mm, SD 1.00; P = 0.31). Regression analysis determined elimination half-time values of 7.85 days (R2 = 0.75) in Group A and 11.67 days (R2 = 0.91) in Group B. Similar half-times were calculated for globe size–corrected concentrations with 8.21 days (R2 = 0.81) in Group A and 11.17 days (R2 = 0.88) in Group B. Conclusion: Single- and double-dose injections have similar pharmacokinetic characteristics in a first-order exponential decay function. The globe size–corrected concentration and half-time did not affect the calculated half-time in both groups. Doubled dosing induced a higher peak concentration at baseline, but the presumed extended biologic active concentration was no longer statistically significant after 6 weeks. The application of twice the dosage does not double the duration of its efficacy; it rather appears to extend the pharmacological duration by 1 half-time or approximately 8 days to 11 days.