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Metvixia

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Metvixia

Metvixia

CLINICAL PHARMACOLOGY

Mechanism of Action

Photosensitization following application of Metvixia (methyl aminolevulinate cream) Cream occurs through the metabolic conversion of methyl aminolevulinate (prodrug) to photoactive porphyrins (PAPs), which accumulate in the skin lesions to which Metvixia (methyl aminolevulinate cream) Cream has been applied. When exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a photodynamic reaction, resulting in a cytotoxic process dependent upon the simultaneous presence of oxygen. The absorption of light results in an excited state of porphyrin molecules, and subsequent spin transfer from photoactive porphyrins to molecular oxygen generates singlet oxygen. Metvixia (methyl aminolevulinate cream) photodynamic therapy (PDT) of actinic (solar) ketatosis lesions is the combination of photosensitization by topical application of Metvixia (methyl aminolevulinate cream) cream to the lesions and subsequent illumination with red light of narrow spectrum using a light dose of 37 J/cm² delivered by the Aktilite CL128 lamp.

Pharmacokinetics

The time-course of Protoporphyrin IX in actinic keratosis lesions and surrounding skin after application of Metvixia (methyl aminolevulinate cream) Cream has been monitored by means of fluorescence. The optimum concentration of methyl aminolevulinate cream (16.8 %) and duration of application (3 h) were derived from such studies of pharmacokinetics in skin using a range of concentrations (1.6%, 8% and 16.8%) and cream application times (up to 28 h). Three hours after the application of Metvixia (methyl aminolevulinate cream) Cream fluorescence in the treated lesions was significantly greater than that seen in both treated and untreated normal skin, and after application of vehicle cream (not containing methyl aminolevulinate) to normal skin. In a fluorescence study of 8 patients with actinic keratoses using Metvixia (methyl aminolevulinate cream) Cream 16.8% applied for 3 h and illumination with the Aktilite CL128 lamp, 88 % photodegradation of Protoporphyrin IX was observed immediately after illumination, followed by a transient small secondary increase in fluorescence 2 hours after illumination. At 24 and 48 hours, 94% and 96 % degradation of Protoporphyrin IX, respectively from baseline, was observed.

Reproductive Toxicology

Development toxicity studies have been performed in pregnant rats with intravenous doses of methyl aminolevulinate hydrochloride up to 700 mg/kg/day on Days 6 to 16 of gestation. There were no treatment-related effects on fetal body weight, sex ratio, external malformations and variations, and skeletal abnormalities and ossification extent. Only a slight, non-significant increase in early embryonic death was noted in the 700 mg/kg/day group, compared to the control group. The fetal NOAEL (No Adverse Effect Level) was 350 mg/kg/day methyl aminolevulinate hydrochloride in pregnant rats (2100 mg/m², 811 times the MTHD based on mg/m² comparisons and an estimated maximum systemic uptake of 1%).

Development toxicity studies have also been performed in pregnant rabbits with intravenous doses of methyl aminolevulinate hydrochloride up to 200 mg/kg/day on Days 6 to 18 of gestation. Slightly lower fetal body weights and increased incidences of fetuses with jugals connected/fused to maxilla, supernumerary ribs, incompletely ossified cranial bones and other ossification irregularities were noted in the high dose (200 mg/kg/day) group, compared to the control group. The fetal NOAEL was 100 mg/kg/day methyl aminolevulinate hydrochloride in pregnant rabbits (1200 mg/m², 463 times the MTHD based on mg/m² comparisons and an estimated maximum systemic uptake of 1%).

In the prenatal and postnatal development toxicity study in rats treated with intravenous doses of methyl aminolevulinate hydrochloride up to 500 mg/kg/day from Day 6 of gestation to Day 24 of lactation, there were no treatment-related effects on litter size, pup mortality, pup weights, and post weaning performance of the F1 animals including development and reproductive capacity. Only a slightly longer duration of gestation and a slight delay in pup physical development were noted in the 250 and 500 mg/kg/day groups. The NOAEL was 125 mg/kg/day methyl aminolevulinate hydrochloride (750 mg/m², 290 times the MTHD based on mg/m² comparisons and an estimated maximum systemic uptake of 1%).

Clinical Studies

Metvixia (methyl aminolevulinate cream) Cream 16.8 % for photodynamic therapy (PDT) by illumination using the Aktilite CL128 lamp was studied in 211 randomized subjects with a total of 1555 nonhyperkeratotic actinic keratoses in two multicenter, randomized, double-blind vehiclecontrolled clinical trials. One study was conducted in the USA and the other in the USA and Germany.

Each subject had 4 to 10 previously untreated, non-pigmented, grade 1 (thin) or 2 (moderate) actinic keratoses on the face and or scalp. Grade 3 (very thick and obvious) actinic keratoses were not treated in the studies.

Two sessions of PDT were administered at an interval of one week with patients randomized 1:1 to receive Metvixia (methyl aminolevulinate cream) -PDT or Vehicle-PDT on both occasions. Each session comprised lesion preparation (debridement with sharp curette) to roughen the surface, application of cream with subsequent maintenance for 3 hours under occlusion using an adhesive, non-absorbent dressing, removal of residual cream followed immediately by light activation. Red light illumination (630 nm) was provided by the Aktilite CL128 lamp and the light dose was 37 J/cm².

The subject complete response rate was assessed 3 months after the last treatment. Lesion clinical complete response was defined as complete disappearance of a lesion upon visual inspection and palpation. If all treated lesions within a subject were in clinical complete response 3 months after treatment, the subject was assessed as a complete responder. The subject complete response rates are shown in Table 2 for each of the two studies.

Table 2: Subject Complete Response after Lesion Debridement followed by Aktilite PDT with Metvixia (methyl aminolevulinate cream) vs. Vehicle - Studies 1 and 2

  Study 1 Study 2
Metvixia
n = 49
Vehicle
n = 47
Metvixia
n = 57
Vehicle
n = 58
Subjects with Complete 29 7 39 4
Response 59.2% 14.9% 68.4% 6.9%

The overall lesion complete response rates and the response rates by lesion grade and location are shown in Table 3 for the two studies.

Table 3: Lesion Complete Response Rate by Grade and Location - Studies 1 and 2 conducted with Aktilite photodynamic therapy

 
  Study 1 Study 2
Metvixia
n = 3 63
Vehicle
n = 3 60
Metvixia
n = 4 18
Vehicle
n = 4 14
Lesions with Complete response 313 (86%) 188 (52%) 348 (83%) 119(29%)
Grade 1 25 9 267 182 161
Face Total 191 20 1 9 9 88
CR 167(87%) 121(60%) 90(91%) 33(38%)
Scalp Total 6 8 6 6 7 6 73
CR 63(93%) 29(44%) 66(87%) 31(42%)
Grade 2 10 4 93 23 6 25 3
Face Total 7 6 6 8 11 9 15 7
  CR 65(86%) 29(43%) 103(87%) 35(22%)
Scalp Total 2 8 2 5 11 5 96
  CR 18(64%) 9(36%) 89(77%) 20(21%)

There was no difference between response rates to Metvixia (methyl aminolevulinate cream) Aktilite PDT for Grade 1 lesions on the face and scalp (CR rates of 89 % and 90 % respectively). For Grade 2 lesions, the corresponding CR rates to Metvixia (methyl aminolevulinate cream) Aktilite PDT were 86 % and 75 % respectively.

Metvixia (methyl aminolevulinate cream) Cream has not been studied for more than one course which consists of two treatment sessions one week apart. There is no information available regarding the recurrence rate for lesions treated with this therapy. Clinical studies did not follow patients beyond 3 months, and the recurrence rate of treated lesions is unknown.

Last reviewed on RxList: 8/1/2008
This monograph has been modified to include the generic and brand name in many instances.

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