O R I G I N A L A R T I C L E

Characterization of cutaneous photosensitivity in healthy volunteers

receiving talaporfin sodiumElizabeth Bromley, Brittany Briggs, Llew Keltner & Sy-Shi Wang

Light Sciences Oncology Inc., Bellevue, WA, USA

Key words:NPe6; photosensitivity; photosensitizer;

talaporfin sodium

Correspondence:Dr Sy-Shi Wang, Light Sciences Oncology Inc.,

15405 SE 37th St, Suite 100, Bellevue, WA

98006, USA

Tel: 425 957 8977

Fax: 425 957 8976

e-mail: syshiw@lsoncology.com

Accepted for publication:1 December 2010

Conflicts of interest:The authors are employees of the study

sponsor, Light Sciences Oncology, Inc.

Summary

Purpose: Historically, cutaneous photosensitivity has been the most common side effect of

treatment with light-activated drugs. Talaporfin sodium is a water soluble photosensitizer in

commercial use and clinical development that is cleared from the body relatively rapidly. This

trial was conducted to determine the period of skin photosensitivity in healthy subjects given

talaporfin sodium and to determine the correlation between photosensitivity and plasma

levels of talaporfin sodium.

Methods: Twenty healthy volunteers were dosed with 0.25–1.0 mg/kg talaporfin sodium and

exposed at successive timepoints to a solar simulator applied to a small patch of skin on the

back. Photosensitivity was assessed at these sites 24 h later. Duration of photosensitivity and

correlation with plasma drug concentration were analyzed.

Results: Skin reactions were generally mild and were classified most commonly as asympto-

matic erythema. Photosensitivity subsided in each subject between 1 and 3 weeks after

dosing. Subjects no longer exhibited photosensitivity at plasma drug levels between 600 and

2900 ng/ml in each subject. Two subjects in the lowest dose group did not exhibit

photosensitivity despite plasma drug levels as high as 4000 ng/ml.

Conclusions: These results indicate that a clinically effective dose of talaporfin sodium was

well-tolerated and that cutaneous photosensitivity was mild and resolved relatively rapidly.

P hotosensitive molecules hold special appeal for clinical use

as they can be activated locally in order to limit harmful side

effects in parts of the body that are unaffected by disease.

Currently, photoactive drugs are being marketed or developed

for oncology, macular degeneration, benign prostatic hyper-

plasia, abnormal vasculature in the skin and other indications.

The safety profile of this class of drugs has generally been

favorable, with the most common side effect being lingering

photosensitivity in the skin of treated patients. Many photoactive

compounds are lipid soluble and are therefore slow to clear from

the epithelium, requiring patients to limit exposure to direct

sunlight or bright indoor lighting for 90 days or more after

treatment in the case of the most frequently used photosensitizer,

porfimer sodium (1, 2). Complying with light precautions for

that length of time is a hardship for many patients and a barrier to

increased use of such therapies.

Talaporfin sodium, (1)-tetrasodium (2S,3S)-18-carboxylato-

20-[N-(S)-1,2-dicarboxylatoethyl]-carbamoylmethyl-13-ethyl-

3,7,12,17-tetramethyl-8-vinylchlorin-2-propanoate (also known

as AptocineTM or NPe6) is a second-generation chlorin deri-

vative with regions of anionic charge that render it water soluble.

In addition, the molecule contains four carboxylate groups that

may enable it to be cleared from the body rapidly (3). Both of

these features may contribute to a shorter period of skin

photosensitivity relative to other drugs in this class. Talaporfin

sodium was approved in Japan for endobronchial cancer in 2003

and is currently being evaluated in Phase 3 clinical trials for

hepatocellular carcinoma and colorectal cancer metastatic to the

liver, as well as Phase 1 and 2 trials for benign prostatic

hyperplasia. The clinical dose of the drug used in each of these

trials is 1 mg/kg administered intravenously.

In a previous Phase 1 clinical trial of patients with refractory

solid tumors, no evidence of cutaneous photosensitivity was

observed in any patient (4). All clinical trials of talaporfin sodium

performed to date have included light precautions advising

subjects to remain indoors for the first 72 h post-treatment and

wear protective clothing and sunglasses outdoors for 2 weeks or

until a 10-min exposure to sunlight causes no reactions,

whichever comes first. The purpose of the present clinical study

was to evaluate the duration of photosensitivity generated by

talaporfin sodium in healthy volunteers in order to further refine

the period of recommended light precautions in patients treated

with this drug. In addition, plasma pharmacokinetic data were

correlated with the period of photosensitivity in each subject to

determine the range of concentrations over which subjects were

light sensitive.

85r 2011 John Wiley & Sons A/S � Photodermatology, Photoimmunology & Photomedicine 27, 85–89

Methods

Subjects

Subjects were healthy volunteers ranging in age from 20 to 73

years with an average age of 35.6 years. Twelve were male and

eight were female. A majority (60%) of subjects were white and

30% were Asian. One subject (5%) reported being both Asian

and white, and one subject (5%) was Native Hawaiian/Pacific

Islander. To be eligible for inclusion, subjects were required to be

18 years of age or older and in good health as determined by

medical history, laboratory results, physical examination and 12-

lead electrocardiogram. All subjects were required to be classified

as Fitzpatrick Skin Type 1, 2 or 3 (5). Concomitant use of other

drugs known to engender photosensitivity (tetracyclines,

sulfonamides, phenothiazines, sulfonylureas, thiazide diuretics

and griseofulvin) was not permitted. One subject (023) was lost

to follow-up after Day 5 due to a scheduling conflict.

Demographic criteria and Fitzpatrick Skin Type of the subjects

are shown in Table 1.

Study design

The protocol and all amendments for this study were reviewed

and approved by an Aspire (La Mesa, CA) independent review

board. This study was conducted between December 2007 and

July 2008. Just like the route of administration in other talaporfin

clinical trials, talaporfin sodium was administered intravenously

at 0.05, 0.1, 0.25, 0.5 and 1.0 mg/kg in healthy volunteers

across six randomized cohorts of five subjects each. Two cohorts

received 1.0 mg/kg. Each cohort contained one placebo subject

according to the randomization schedule. Because of a protocol

deviation, photosensitivity data were not collected from the 0.05

and 0.1 mg/kg dose groups (cohorts 1 and 2) and thus they are

not included in this analysis.

After taking baseline measurements, subjects received

intravenous drug and photosensitivity was tested used a

standardized method (6, 7). Briefly, a solar simulator was

applied to a 2 cm� 2 cm demarcated area on the subject’s back.

The simulator (Newport Oriel 300 W 91160 Solar Simulator,

Irvine, CA, USA) was applied for 10 min at a dose rate of

40 mW/cm2 (for a total dose of 2400 J/m2) with an Air Mass

1.5 Global filter in a spectrum intended to mimic that

of the sun at a zenith angle of 48.21 (350–2500 nm). The back

was chosen because it is typically covered with clothing and

therefore is an area sensitive to sunlight exposure. All skin

assessments in this study were performed by the Principal

Investigator and photographs were taken for the record. Skin

assessments at each simulator application site were conducted

24 h after exposure with the exception of the first post-dose

assessment, which was performed at 8 h. In addition, a safety

assessment was performed at 2–3 h after every exposure. These

safety assessments were all negative (scored as zero) for the 0.05

and 0.1 mg/kg dose groups when the described simulator

settings were used.

In cohort 3, 24 h assessments were performed daily

after dosing until the degree of redness was equal to that of a

baseline spot on two consecutive readings or until discharge

from the study on Day 8. In cohorts 4 and 5, the first post-dose

simulator exposure was performed on Day 4 and then daily until

discharge. In cohort 6, solar simulator exposure was performed

on Days 7, 15 and 22 to analyze longer term effects. All doses of

study drug were administered at the clinical site under

authorized supervision. Subjects were confined to the clinical

site until study discharge or 8 days after dosing, whichever came

first.

Table 1. Demographic criteria and Fitzpatrick Skin Type of healthy volunteer subjects

Subject number Age Sex Race Hispanic or Latino? (Y/N) Fitzpatrick skin type

016 49 Male Asian N 3

017 48 Male White N 1

018 36 Male White N 3019 73 Female White N 2

020 26 Female White N 3

021 21 Male White N 1

022 56 Male Asian N 3023 23 Female White N 2

024 26 Female White N 2

025 49 Female Asian N 2

026 33 Male Asian N 3027 20 Male White N 2

028 45 Male Asian N 2

029 28 Female White N 3

030 28 Female White N 3031 20 Male White N 3

032 40 Male Asian N 3

033 20 Male Other: Asian/White N 3034 28 Male White N 2

035 43 Female Native Hawaiian or Pacific Islander Y 2

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Bromley et al.

Application site assessments were judged using the following

photosensitization scale:

0 = None1 = Minimal, asymptomatic erythema

2 = Moderate erythema with pruritis or edema

3 = Severe erythema with moderate to severe edema

4 = Blisters associated with erythema5 = Ulceration

Pharmacokinetic analysis

Blood samples were collected from subjects predose and at solar

simulator exposure timepoints after dosing until the subject was

discharged from the study. Talaporfin sodium content in each

sample was analyzed using a validated method of HPLC with MS/

MS detection performed by Covance (Madison, WI, USA).

Results and discussion

Results of photosensitivity assessments are shown in Table 2.

Dosing was performed on Day 1. In cohorts 3–5, solar simulator

exposures were conducted on unique application sites at each

exposure and assessed 24 h later for the degree of

photosensitivity exhibited in the skin. For subjects in cohort 6,

exposures were performed on Days 7, 15 and 22 in order to

gauge longer term photosensitivity reactions.

Degree of photosensitivity

Fourteen of 16 subjects who received drug exhibited some

photosensitivity at the simulator exposure site. These reactions

were generally mild. Twelve of the 14 subjects never exhibited

reactions above a grade 1 on the photosensitization scale

(minimal, asymptomatic erythema). One subject in a 1.0 mg/

kg dose cohort (cohort 5) had a grade 2 reaction (characterized

as erythema with pruritis or edema) at the exposed site after solar

simulator exposure on Day 5. In addition, one subject in cohort 4

(0.5 mg/kg) had a reaction of hives (scored as grade 2) after

simulator exposure on Day 4 that persisted for several days. No

reactions more severe than grade 2 on the photosensitization

scale were recorded. No reactions were reported in placebo

subjects. None of the subjects experienced photosensitivity

outside the 2 cm� 2 cm simulator exposure site.

Two subjects in cohort 3 who received 0.25 mg/kg talaporfin

sodium did not exhibit any photosensitivity. One of these subjects

was classified as Fitzpatrick Skin Type 1 while the other was Type 3.

All subjects who received at least 0.5 mg/kg talaporfin sodium

experienced some skin photosensitization. Although the sample

size was small, Fitzpatrick Skin Type did not appear to correlate

with degree or duration of photosensitivity.

Duration of photosensitivity

Regardless of dose, every photosensitive subject still exhibited

minimal, asymptomatic erythema at Day 6 except for subject

Table 2. Degree of photosensitivity of study subjects over time

Subject Timepoint PredoseDay 1 (8 hourspostdose) Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 15 Day 22

Cohort 3 (0.25 mg/kg) 016 0 1 1 1 1 0 1 1

017 0 0 0018 0 0 0

019� 0 0 0

020 0 1 1 1 1 1 1

Cohort 4 (0.5 mg/kg) 021 0 1 1 1 1022 0 1 1 1

023 0 1 1

024 0 2w

025� 0 0 0

Cohort 5 (1.0 mg/kg) 026� 0 0 0

027 0 1 1 1 1

028 0 1 2 1 0029 0 1 1 1 1

030 0 1 1 1 1

Cohort 6 (1.0 mg/kg) 031 0 1 0 0

032� 0 0 0 0033 0 1 0 0

034 0 1 1 0

035 0 1 1 0

�Placebo subjects in each cohort. Skin reaction assessment scale: 0 = none; 1 = Minimal, asymptomatic erythema; 2 = Moderate erythema with

pruritis or edema; 3 = Severe erythema with moderate to severe edema; 4 = Blisters associated with erythema; 5 = Ulceration.wThis subject developed hives and was not subjected to solar simulator again. Readings from Day 4 spot were given scores of 2 on Days 5–8.

Subject 023 was lost to follow-up after Day 5.

Subjects were dosed on Day 1. All reactions were assessed 24 h after solar simulator exposure unless otherwise noted.

87r 2011 John Wiley & Sons A/S � Photodermatology, Photoimmunology & Photomedicine 27, 85–89

Talaporfin sodium photosensitivity in volunteers

023, who was lost to follow-up on Day 5 while still

photosensitive. Thus, the period of photosensitivity was

maintained at least this long, although the reactions exhibited

were very mild. Subjects in cohort 6, whose reactions were

assessed at more distant timepoints in order to capture the end of

the photosensitivity period, all displayed mild, asymptomatic

erythema in skin exposed to the solar simulator on Day 7.

Photosensitivity ceased in half of these subjects before their next

solar simulator exposure at Day 15. The remaining subjects were

no longer photosensitive at exposure on Day 22. Thus, the period

of photosensitivity in the 1.0 mg/kg dose group was o 3 weeks

for all subjects.

Relation of plasma concentration and photosensitivity

Blood was collected and drug concentration was assayed from

each subject at the same timepoints that the solar simulator was

applied. Photosensitivity reactions were then analyzed according

to plasma concentration of talaporfin sodium (Fig. 1). Subjects

differed significantly in the threshold of drug that induced skin

photosensitivity. Although they received drug, the two subjects

in cohort 3 who did not exhibit any photosensitivity had plasma

levels of talaporfin sodium (as high as 4000 ng/ml) that

surpassed concentrations at which other subjects were

photosensitive. No subject exhibited a photosensitive reaction at

plasma levels below 603 ng/ml. With the exception of subjects

017 and 018, all active drug recipients displayed photosensitive

reactions when their plasma levels were above 2900 ng/ml.

Thus, the threshold for photosensitization appears to reside

between 600 and 2900 ng/ml for most individuals, while

others may experience no skin reactions at the clinically relevant

doses assayed in this analysis.

Safety

No adverse events above a grade 2 (moderate) were reported

in any subject. Four grade 2 adverse events, all considered

not treatment related, were reported (headache, migraine

headache, hypotension and bradycardia). All treatment-related

adverse events were grade 1 (mild). Treatment-related adverse

events reported in more than one subject included erythema at

the exposure site (13 subjects) and pruritis (4 subjects), which

were recorded from the safety-related photosensitivity

assessments performed at 2–3 h post-exposure. Overall, safety

analysis is not significantly altered by inclusion of subjects from

cohorts 1 and 2 (0.05 and 0.1 mg/kg dose groups) who were

given the drug but not assessed for photosensitivity due to a

protocol deviation.

Limitations

The number of subjects in this study was very small and thus a

fully powered statistical analysis of the findings is not possible. In

combination with clinical experience, the data obtained in this

study provide support for the light exposure precautions in

current use. A study with greater power to detect atypical

reactions in subsets of patients would greatly inform these

precautions.

Conclusions

In healthy volunteers given a clinically relevant dose of talaporfin

sodium, cutaneous photosensitivity was generally mild and

ceased between 1 and 3 weeks of dosing. Cessation of photo-

sensitivity occurred at plasma drug levels between approximately

600 and 2900 ng/ml in individual subjects, although two

subjects did not exhibit any photosensitivity despite plasma

levels 4 4000 ng/ml.

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Photosensitivity Reactions As aFunction of Plasma Concentration of TS

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 220

2000

4000

6000

8000

Day

ng

/mL

Fig. 1. Photosensitivity reactions as a function of plasma drug concentra-

tion Plasma drug concentrations in each subject are plotted over time,

with unique symbols for each subject. A red symbol indicates that a

photosensitivity assessment of 1 or greater was recorded at this

timepoint. A black symbol indicates that a photosensitivity assessment of

zero was recorded at this timepoint.

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Talaporfin sodium photosensitivity in volunteers