Assessment of concentrations of belimumab in body fluids of patients with systemic lupus erythematosus

The biological agent belimumab (Benlysta®) has recently been introduced for the
treatment of severe systemic lupus erythematosus (SLE), a systemic autoimmune
disease affecting women and men aged 20 to 45 years, the period of life during
which pregnancies are usually planned. The introduction of belimumab for the
treatment of SLE has improved the disease course in many of these patients
importantly. Female patients treated with belimumab are advised against
pregnancy because insufficient data on the safety of its use during pregnancy
with regard to potential embryotoxic effects are available. Men treated with
belimumab are currently advised not to induce a pregnancy because no data on
belimumab concentrations in seminal fluid and on the safety of peri-conceptual
paternal exposure to belimumab with regard to pregnancy outcome and embryotoxic
effects are available. A study on belimumab concentrations in blood of healthy
subjects and SLE patients treated with belimumab demonstrated that steady state
levels of belimumab in blood are rapidly reached in intravenously treated
individuals, while a steady state level of belimumab in blood of subcutaneously
treated individuals is not achieved before 11 weeks of treatment (1). No data
are currently available on the distribution of belimumab to other body fluids.
In particular, it is unknown whether belimumab is detectable in the seminal
fluid of men treated with belimumab. Therefore, it is unknown whether men
treated with belimumab should indeed be adviced to avoid inducing a pregnancy.
Belimumab may be transported by body fluids (seminal fluid, saliva, blood) of
the man in the recipient woman. Previous studies on other chemical agents have
demonstrated that the concentration of those chemical agents in seminal fluid
is in general equal to or lower than the blood concentration of that particular
chemical agent (2). In addition, it is assumed that total absorption of a
seminal dose of a chemical with a high seminal fluid : blood concentration
ratio is at least three orders of magnitude lower than that in the man (2).
However, the seminal fluid : blood concentration ratio of belimumab is unknown.

The present study is designed to provide more insight in the distribution of
intravenously or subcutaneously administered belimumab to three body fluids by
assessment of belimumab concentrations in blood, saliva and seminal fluid, and
assessment of the seminal fluid : blood concentration ratio of belimumab in
males treated with belimumab. The results of this study will provide
information which is necessary for better counselling of male SLE patients
treated with belimumab in the future on safety issues regarding inducing a
pregnancy during belimumab therapy. Furthermore, the results of this study will
provide insight in sex differences in belimumab concentrations in blood and
saliva.


REFERENCES

1. Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper GS. Understanding
the epidemiology and progression of systemic lupus erythematosus. Semin
Arthritis Rheum. 2010;39(4):257-68.
2. Klemmt L, Scialli AR. The transport of chemicals in semen. Birth Defects Res
B Dev Reprod Toxicol. 2005;74(2):119-31.

To determine the concentration of belimumab in blood, saliva and seminal fluid
in patients with SLE, treated with intravenous or subcutaneous belimumab.

Study design: A single centre, cohort study in a maximum of 10 patients with
SLE, treated with belimumab

Intervention: For patients treated with intravenous belimumab at the day care
in our hospital: withdrawal of blood directly before (10 ml) and directly after
(10 ml) infusion of belimumab; withdrawal of saliva directly before (4 ml) and
directly after (4 ml) infusion of belimumab. This will be done during 3
separate visits to the day clinic for belimumab treatment. Men treated with
intravenous belimumab are asked if they can intercept seminal fluid at three
random time points at home (3 x 4 ml).

For patients treated with subcutaneous belimumab (self-administration at home):
withdrawal of blood (10 ml) and withdrawal of saliva (4 ml) at the day of a
visit at the outpatient clinic of the department of rheumatology. This will be
done during 3 separate visits to the outpatient clinic during belimumab
treatment. Men treated with subcutaneous belimumab are asked if they can
intercept seminal fluid at three random time points at home (3 x 4 ml).

Only in case of withdrawal of belimumab treatment, the withdrawal of blood and
saliva and (for male patients only) the interception of seminal fluid will be
done again during 3 separate visits to the outpatient clinic after cessation of
belimumab treatment.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: During treatment with belimumab, withdrawal of
blood (20 ml for patients treated with intravenous belimumab and 10 ml for
patients treated with subcutaneous belimumab), withdrawal of saliva (8 ml for
patients treated with intravenous belimumab and 4 ml for patients treated with
subcutaneous belimumab) and interception of seminal fluid (12 ml) will take
place up to three times. If treatment with belimumab is stopped, withdrawal of
blood, withdrawal of saliva and interception of seminal fluid will take place
up to three times.