Padeliporfin

Padeliporfin is a photosensitiser that acts only when it is lit. It stays inside the blood vessels, and when laser light at 753 nm is shone on the prostate it sets off a chain of events in the tumour’s blood vessels that shuts them down and leads to focal tumour necrosis within a few days. The treatment is called vascular-targeted photodynamic therapy (VTP).

Mechanism of Action

• Vascular retention: padeliporfin remains within the circulation even at high doses, with minimal leakage into other tissues, so the reactive species produced on activation are contained in the vessels.
• Light activation: in the illuminated tumour vasculature it generates oxygen radicals (hydroxyl and superoxide), which cause local hypoxia. This induces release of nitric oxide radicals, causing a transient widening of the arteries and then release of the vasoconstrictor endothelin-1.
• Vascular shutdown: nitric oxide is rapidly consumed by oxygen radicals, forming reactive nitrogen species such as peroxynitrite, while the arteries constrict. Reduced deformability of red cells is thought to increase their aggregation and clot formation where the feeding arteries meet the tumour microcirculation, which blocks the tumour’s vessels. Reactive nitrogen species also trigger endothelial cell apoptosis and self-propagating tumour cell necrosis through peroxidation of cell membranes.
• Effect seen in patients: in men with localised prostate cancer treated with VTP, necrosis was visible on MRI at day 7, and the volume of necrosis correlated with the total light energy delivered. The Light Density Index (LDI), the cumulative length of illuminated fibre tips in cm per cc of the targeted zone (the lobe containing the positive biopsies), must reach at least 1.

Pharmacokinetics

• Distribution: in healthy men the mean volume of distribution was 0.064–0.279 L/kg at doses of 1.25–15 mg/kg, indicating distribution into extracellular fluid; in patients it was similar (0.09–0.10 L/kg at 2 and 4 mg/kg). Padeliporfin is 99% bound to plasma proteins. In vitro, it is unlikely to be a substrate of OATP1B1, OATP1B3, OCT1, OATP2B1, P-gp, BCRP, MRP2 or BSEP.
• Metabolism: minimal in human liver microsomes and S9 fractions, with no metabolites seen in vitro. No radiolabelled study has been done, so some metabolism in the body cannot be fully excluded. In vitro it is unlikely to inhibit cytochrome P450 enzymes.
• Elimination: clearance was 0.0245–0.088 L/h/kg in healthy men (1.25–15 mg/kg) and 0.04–0.06 L/h/kg in patients (4 and 2 mg/kg). The estimated half-life is 1.19 ± 0.08 hours at 4 mg/kg. Urinary excretion is very low (below 0.2% of the dose), so faecal elimination is the most probable route.
• Special populations: very few patients over 75 years took part in pharmacokinetic studies, so it is not known whether exposure differs in them. There are no data in hepatic impairment, where exposure is expected to be higher or longer. Renal excretion is minimal.

Tookad is used as monotherapy in adults with previously untreated, unilateral, low-risk adenocarcinoma of the prostate with a life expectancy of at least 10 years, and all of the following:

• Clinical stage T1c or T2a.
• Gleason score ≤ 6, based on high-resolution biopsy strategies.
• PSA ≤ 10 ng/mL.
• One of: 3 positive cancer cores with a maximum cancer core length of 5 mm in any one core; 1–2 positive cores with ≥ 50% cancer involvement in any one core; or a PSA density ≥ 0.15 ng/mL/cm³.

• Hypersensitivity to the active substance or to mannitol.
• Any previous prostatic intervention in which the internal urinary sphincter may have been damaged, including transurethral resection of the prostate (TURP) for benign prostatic hypertrophy.
• Current or prior treatment for prostate cancer.
• Cholestasis.
• Current exacerbation of rectal inflammatory bowel disease.
• Any medical condition that rules out general anaesthesia or invasive procedures.

The most frequent reactions in the phase II and III studies were urinary and reproductive: dysuria (25.1%), erectile dysfunction (21.1%), haematuria (19.6%), perineal pain or haematoma (15.3%), urinary retention (13.3%), micturition urgency (9.0%), pollakiuria (7.3%), urinary tract infection (5.5%), incontinence (5.3%) and ejaculation failure (5.0%). Non-specific events probably linked to general anaesthesia were also seen, such as transient global amnesia, bradycardia, sinus arrhythmia, atrial fibrillation, hypotension, bronchospasm, nausea, vomiting, constipation and pyrexia. Some cases of hepatotoxicity (1.5%), such as raised transaminases, were all mild. The groups below summarise reactions considered related to Tookad, the device or the procedure in a pooled analysis of 398 patients.

Very common (≥1/10): urinary retention; haematuria; dysuria (including bladder pain, bladder spasm and urinary tract pain); micturition disorders (urgency, pollakiuria, nocturia, reduced urine flow, straining); perineal pain (including pelvic pain); male sexual dysfunction (erectile dysfunction, ejaculation failure, ejaculation disorders, painful or retrograde ejaculation, reduced semen volume, dyspareunia).

Common (≥1/100 to <1/10): genito-urinary infection (urinary tract infection, orchitis, epididymitis, cystitis); haematoma; hypertension; haemorrhoids; anorectal discomfort; abdominal pain; rectal haemorrhage; hepatotoxicity (raised alanine and aspartate aminotransferase); ecchymosis; back pain; urethral stenosis; urinary incontinence; prostatitis; genital pain; prostatic pain; haematospermia; fatigue; abnormal clotting tests; perineal injury (including perineal and pelvic haematoma and necrosis).

Uncommon (≥1/1,000 to <1/100): prostatic abscess; decreased libido, affective disorder, encopresis; headache, dizziness, sciatica, sensory disturbance, formication; eye irritation, photophobia; exertional dyspnoea; abdominal discomfort, abnormal faeces, diarrhoea; rash, erythema, dry skin, pruritus, skin depigmentation, skin reaction; groin pain, muscle haemorrhage, haemarthrosis, musculoskeletal pain, pain in an extremity; ureteric and urethral haemorrhage, urinary tract disorders; genital haemorrhage, penile swelling, prostatic haemorrhage, testicular swelling; asthenia, catheter site pain, laser device failure, infusion site bruising, nodule, pain, application site erythema; raised lactate dehydrogenase, triglycerides, gamma-glutamyltransferase, cholesterol, creatine phosphokinase, LDL, neutrophils, white blood cells and PSA, lower blood potassium, weight loss; repeat surgical procedure, contusion, post-procedural urine leak, procedural pain, post-procedural discharge, fall.

Selected findings from the controlled phase III European study: erectile dysfunction in 30.5% of patients (26.9% for more than 6 months, 17.3% unresolved at the end of the study) and ejaculation failure in 8.1%; urinary retention in 15.2% (median onset 3 days, median duration 10 days); genito-urinary infection in 10.2% (serious in 2.5%); urinary incontinence in 12.7% (one severe case); moderate or severe urethral stenosis in 1.0%, needing dilatation; perineal injury and pain in 23.4%; prostatitis in 3.6%. In earlier studies there were two cases of excessive extraprostatic necrosis from incorrect laser calibration, one external urethral fistula from misplaced fibres, one case of grade 3 ischaemic optic neuropathy 33 days after treatment (at 2 mg/kg, resolved with a small visual field defect) and one prostatic abscess.

• OATP1B1 and OATP1B3 substrates (repaglinide, atorvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, bosentan, glibenclamide): padeliporfin could inhibit these transporters, and a transient rise in the substrates’ plasma concentration cannot be ruled out. Where concentration-dependent serious adverse reactions have been seen, avoid these medicines on the day of the infusion and for at least 24 hours after it; otherwise co-administer with caution and close monitoring.
• Photosensitising medicines (tetracyclines, sulphonamides, quinolones, phenothiazines, sulfonylurea hypoglycaemic agents, thiazide diuretics, griseofulvin, amiodarone): stop at least 10 days before the procedure and for at least 3 days after, or replace with medicines without photosensitising properties. If one cannot be stopped (for example amiodarone), warn the patient that sensitivity to sunlight may be increased and that protection from direct light may be needed for longer.
• Anticoagulants and antiplatelet agents (for example acetylsalicylic acid): stop at least 10 days before the procedure. Medicines that prevent or reduce platelet aggregation should not be started for at least 3 days after it.
• Systemic VEGF inhibitors: concomitant use is not recommended. After intra-ocular anti-VEGF therapy there may be an added risk of eye photosensitivity.
• Cytochrome P450 enzymes: in vitro, padeliporfin is unlikely to inhibit them.

Tookad is restricted to hospital use and must be used only by personnel trained in the vascular-targeted photodynamic therapy (VTP) procedure. It is given as part of focal VTP, performed under general anaesthesia after rectal preparation. Prophylactic antibiotics and alpha-blockers may be prescribed at the physician’s discretion.

Recommended Dose

• One single dose of 3.66 mg/kg of padeliporfin, by intravenous injection over 10 minutes.
• The prostate is then illuminated immediately for 22 minutes 15 seconds with laser light at 753 nm, delivered through interstitial optical fibres from a laser device at 150 mW per cm of fibre, giving 200 J/cm.
• Reconstitution before use is described in section 6.6 of the SmPC; the reconstituted solution contains 9.15 mg of padeliporfin per mL.
• Retreatment of the same lobe, or sequential treatment of the opposite lobe, is not recommended.

Fibre Placement

Fibre positions are planned at the start of the procedure with the treatment guidance software. The number and length of the fibres depend on the shape and size of the prostate, and the fibres are placed through the perineum into the gland under ultrasound guidance so as to reach an LDI of at least 1 in the targeted tissue. Treatment must not be undertaken if an LDI of at least 1 cannot be achieved.

Special Populations

• Hepatic impairment: no data. Exposure is expected to be increased or prolonged, and no specific dose recommendation can be given. Use with caution in severe hepatic impairment; Tookad is contraindicated in cholestasis.
• Renal impairment: renal excretion is minimal, so no dose adjustment is needed. The product contains potassium (see Special Instructions).
• Elderly: no specific adjustment.
• Children and adolescents: no relevant use in low-risk localised prostate cancer.
• Women: Tookad is not indicated for the treatment of women.

Patient Selection and Tumour Location

Before treatment the tumour must be accurately located and confirmed as unilateral with high-resolution biopsy strategies, such as multi-parametric MRI-based strategies or template-based biopsies. Treating both prostate lobes at once was associated with an inferior outcome and must not be done. Too few patients were retreated to establish the efficacy and safety of a second procedure.

Light Precautions for 48 Hours

There is a risk of skin and eye photosensitivity after VTP. For 48 hours patients must avoid direct sunlight (including through windows) and all bright light sources, indoors and outdoors, including sunbeds, bright computer screens and medical examination lights such as ophthalmoscopes, otoscopes and endoscopy equipment. Sunscreen does not protect against near infra-red light.

• First 12 hours: protective goggles, and medical surveillance for at least 6 hours in a room with dimmed light. The patient may be discharged the same evening at the physician’s discretion. At home, no direct exposure of skin or eyes to daylight; only incandescent bulbs up to 60 watts or equivalent (6 watts for LED lights, 12 watts for low-energy fluorescent lights). Television is allowed from a distance of 2 metres, and from 6 hours onwards smartphones, tablets and computers. Anyone who must go outdoors in daylight needs protective clothes and high-protection goggles.
• 12 to 48 hours: outdoors in daylight only in shaded areas or when overcast, wearing dark clothes and taking care with exposed hands and face.
• After 48 hours: normal activity and direct sunlight can be tolerated.
• Patients with photosensitive dermatitis, porphyria or a history of sensitivity to sunlight were not included in the clinical studies; the risk is expected to be low if they follow the precautions strictly. Patients who have had VEGF therapy should take particular care to protect the eyes.

Follow-up and Later Treatment

Long-term efficacy has not been determined: biopsy data beyond 2 years are limited, and residual tumour has been found on follow-up biopsy at 12 and 24 months, usually outside the treated volume. VTP has been shown to defer the need for radical therapy; longer follow-up is needed to show whether it is curative in some patients. After VTP, digital rectal examination should be done at least once a year, and PSA tested every 3 months for the first 2 years and every 6 months afterwards, including PSA doubling time and velocity. Routine biopsy is recommended at 2–4 years and at 7 years, with extra biopsies guided by clinical and PSA findings. A positive biopsy above the low-risk threshold (Gleason score above 6, more than 3 positive cores or any core longer than 5 mm) should lead to a recommendation for radical therapy. The safety and efficacy of radical surgery or radiotherapy after VTP are uncertain.

Procedure-related Risks

• Erectile dysfunction: it may occur even if radical prostatectomy is avoided, can appear soon after the procedure and may last more than 6 months.
• Extraprostatic necrosis: necrosis in the peri-prostatic fat without symptoms can occur. Excessive necrosis, from incorrect laser calibration or fibre placement, risks damage to the bladder or rectum and a recto-urethral or external fistula. Calibrate the equipment carefully and use the treatment guidance software.
• Urinary retention and urethral stricture: patients with a history of urethral stricture or poor urinary flow are at higher risk. Retention just after the procedure was attributed to temporary prostatic oedema and usually needed only short recatheterisation; urethral stenosis can develop months later.
• Urinary incontinence: careful fibre planning reduces the risk of sphincter damage. Severe long-term incontinence occurred in a patient with earlier TURP.
• Inflammatory bowel disease: give VTP only after careful clinical evaluation to patients with a history of active rectal inflammatory bowel disease or any condition that raises the risk of a recto-urethral fistula.
• Abnormal clotting: bleeding, bruising, haematuria or local pain from the needles may be excessive. Medicines that affect clotting should be stopped before the procedure and for the immediate period after it.

Potassium

The dose of 3.66 mg/kg contains less than 1 mmol (39 mg) of potassium in general, so the product is essentially potassium-free, but this is exceeded in patients heavier than 115 kg. Take this into account in patients with reduced kidney function or on a controlled potassium diet.

Pregnancy, Breastfeeding and Fertility

• Tookad is not indicated for women.
• Contraception: a patient who is sexually active with a woman who could become pregnant should use effective birth control, with his partner, for 90 days after the procedure.
• Fertility: padeliporfin has not been tested for reproductive toxicity and fertility. All stages of spermatogenesis were seen in animals, and minimal seminiferous epithelial degeneration in one high-dose male was considered incidental and probably related to the intravenous administration procedure.

Effect on Driving

Tookad has no influence on the ability to drive or use machines. Because the procedure includes general anaesthesia, patients should not drive or perform complex tasks until 24 hours after the anaesthetic.

Store unopened vials in a refrigerator at 2–8 °C, in the outer carton to protect them from light, and keep the cold chain during transport. After reconstitution with 5% glucose solution, stability in the vial has been shown for 8 hours at 15–25 °C and at 5 ± 3 °C; from a microbiological point of view the solution should be used immediately, and if it is not, in-use storage times and conditions are the responsibility of the user. Each pack holds one amber glass vial (183 mg with a blue flip-off cap; 366 mg with a white one).

5 years for the unopened vial. After reconstitution, see Storage Conditions.

Prescription only (Rx), under restricted medical prescription (Annex II B). Tookad is restricted to hospital use and is given only by personnel trained in the VTP procedure, under general anaesthesia and with laser illumination. It is supplied to the hospital that administers it, with cold-chain delivery at 2–8 °C.