Cysview

CLINICAL PHARMACOLOGY

Mechanism of Action

Cysview (hexaminolevulinate hydrochloride intravesical solution) is an ester of the heme precursor, aminolevulinic acid. After bladder instillation, Cysview (hexaminolevulinate hydrochloride intravesical solution) enters the bladder mucosa and is proposed to enter the intracellular space of mucosal cells where it is used as a precursor in the formation of the photoactive intermediate protoporphyrin IX (PpIX) and other photoactive porphyrins (PAPs). PpIX and PAPs are reported to accumulate preferentially in neoplastic cells as compared to normal urothelium, partly due to altered enzymatic activity in the neoplastic cells. After excitation with light at wavelengths between 360 and 450 nm, PpIX and other PAPs return to a lower energy level by fluorescing, which can be detected and used for cystoscopic detection of lesions. The fluorescence from tumor tissue appears bright red and demarcated, whereas the background normal tissue appears dark blue. Similar processes may occur in inflamed cells.

Pharmacodynamics

In vitro studies have shown increased porphyrin fluorescence in normal urothelium after exposure to Cysview (hexaminolevulinate hydrochloride intravesical solution) . In the human bladder, a greater accumulation of porphyrins is proposed in neoplastic or inflamed cells, compared to normal urothelium. After bladder instillation of Cysview (hexaminolevulinate hydrochloride intravesical solution) for approximately 1 hour and subsequent illumination with blue light at wavelengths 360 – 450nm, the porphyrins will fluoresce red [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics

After bladder instillation of [14C]-labeled Cysview (hexaminolevulinate hydrochloride intravesical solution) (100 mg) for approximately 1 hour in healthy volunteers, absolute bioavailability of Cysview (hexaminolevulinate hydrochloride intravesical solution) was 7% (90% confidence interval [CI]: 5%-10%). The [14C]-labeled substance(s) showed biphasic elimination, with an initial elimination half-life of 39 minutes, followed by a terminal half-life of approximately 76 hours. Whole blood analysis showed no evidence of significant binding of Cysview (hexaminolevulinate hydrochloride intravesical solution) to erythrocytes. An in vitro study showed that Cysview (hexaminolevulinate hydrochloride intravesical solution) underwent rapid metabolism in human blood.

Animal Toxicology and/or Pharmacology

Dose dependent neurological effects such as tremor, increased motor activity, and increased startle and touch escape responses were observed immediately after dosing at doses ≥ 30 mg/kg (24 times human systemic exposure based on the body surface area, using 10% as the upper level of 90% confidence interval of bioavailability) in a single dose rat study. The animals recovered to normal status by 60 min after dosing. Adverse neurological effects were also noted in other single or repeat dose toxicity studies.

Hexaminolevulinate hydrochloride had moderate to strong potential to cause skin sensitization based on a local lymph node assay in mouse.

Clinical Studies

The safety and efficacy of Cysview (hexaminolevulinate hydrochloride intravesical solution) when used with photodynamic cystoscopy were studied in a prospective, multicenter, controlled clinical trial. Adult patients with known or suspected bladder cancer were randomized to either white light (WL) cystoscopy (control group, n = 384) or WL followed by blue light (BL) cystoscopy (study drug group, n = 395). Only the study drug group patients received Cysview (hexaminolevulinate hydrochloride intravesical solution) by bladder instillation prior to cystoscopy. After bladder evacuation of Cysview (hexaminolevulinate hydrochloride intravesical solution) , bladder lesion mapping was performed initially using the Karl Storz PDD system in the WL mode followed by lesion mapping in the BL mode. Control group patients underwent only WL cystoscopy with lesion mapping. The average age of the randomized patients was 69 years (range 24 to 96); 78% were male and 94% were Caucasian. All patients had previously undergone cystoscopy.

The main diagnostic efficacy outcome was assessed within the study drug group. This assessment compared lesions detected during an initial cystoscopic examination to their centralized histologic findings (the standard of truth). Following the initial diagnostic cystoscopy, patients within both study groups who had histologically confirmed Ta and/or T1 lesions underwent follow-up WL cystoscopy at 3, 6 and 9 months; these histologic evaluations were based upon the site assessments at both the initial and follow-up cystoscopy.

Diagnostic efficacy assessed the number of patients within the study drug group who had at least one additional Ta or T1 bladder cancer detected only by BL; the proportion of these patients was compared to a proposed threshold proportion of 10%. Within the study drug group, 286 patients had at least one Ta and/or T1 lesion, including 47 patients who had at least one of the lesions detected only by BL (see Table 1).

Table 1: BL Cystoscopic Ta and/or T1 Lesion Detection within the Study Drug Group

Number of patients with any Ta and/or T1 lesion detected with either WL or BL 286
Number (%) of patients with any Ta and/or T1 lesion detected only with BL 47 (16%)
p-value* 0.001
*exact test comparison of the proportion to a threshold value of 10% Some malignant lesions were detected only by WL or BL (see Table 2).

Table 2: Bladder Tumor Detection within the Study Drug Group by WL and/or BL Cystoscopy

Number of lesions Detected by Both
WL & BL
Detected by
WL Only
Detected by
BL Only
CIS, n = 66 33 6 27
Ta, n = 580 472 52 56
T1, n = 95 76 10 9
T2 – T4, n = 47 38 8 1

Among the lesions detected only by BL, 23% were negative for any carcinoma-related pathology, including dysplasia. Among the lesions detected only by WL, 17% were negative for any carcinoma-related pathology, including dysplasia.

Last reviewed on RxList: 6/29/2010
This monograph has been modified to include the generic and brand name in many instances.

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