Mycophenolate Mofetil Pharmacokinetics in Systemic Sclerosis

Drug of investigation: Mycophenolate mofetil (MMF), given orally as a tablet twice daily.

Dosage of drug: This study recruits patients who have been prescribed a steady dose of MMF in the range between 1000 and 3000 mg daily by their physician.

Design: This is an open-label PK study.

Disease studied: Systemic sclerosis (SSC, scleroderma).

Variables assessed: Estimated AUC0-12 for MMF. Gastrointestinal manifestations of SSc. Concomitant medication.

Study population:

Inclusion criteria: Diagnosis of SSC fulfilling the 2013 classification criteria for this disease. Participant should have been prescribed a stable dose of MMF tablets, taken twice daily, for at least 3 months prior to the study.

Exclusion criteria: Failure to comply with study protocol. Limited access to repeated venous puncture. Recipient of organ transplant. Pulmonary arterial hypertension.

Number of participants: The study aims at the inclusion of 35 subjects.

Primary objective: To investigate the PK of orally ingested MMF in SSC.

Secondary objectives:

1. To investigate how SSC manifested in the gastrointestinal (GI) tract may alter the PK of MMF.
2. To investigate how the PK of MMF in SSc is altered by medications often used in SSC, i.e. proton pump inhibitors (PPI), NSAID and calcium channel blockers.

DESIGN AND ASSESSMENT SCHEDULE Study participants will take their medication, including the study drug, as prescribed by their ordinary physician. Study participant will note what they had for breakfast.

The study-timespan for the individual study participant is estimated to maximum 8 hours.

Blood samples will be drawn from a subcutaneous venous port if available. If not available, subjects will be receive a peripheral venous catheter that is to be used for repeated blood sampling. If usage of such a catheter fails during the study day, blood samples will be drawn from repeated venipunctures.

VARIABLES STUDIED

The following variables will be studied:

Plasma-MMF-concentration: Will be measured by approved laboratory, Skåne UniversityHospital, using high performance liquid chromatography. AUC 0_12 will be calculated as suggested by de Winter, Neumann, van Hest et. al., Ther Drug Mon 2009;31(3):382-390.

Kidney and liver function: Serum samples will be analysed regarding kidney function and eGFR will be calculated from creatinin and cystatin C. Liver function will be assessed by AST, ALT, GT and ALP. Hematological characteristics will be noted.

GI manifestations of SSc: Fecal calprotectin, will be assayed by ELISA (Calpro, Lysaker, Norway) at University Hospital Lund. Malnutrition will evaluated in reference to the validated Malnutrition Universal Screening Tool (MUST). S-transthyretin, vitamin B12, folic acid, iron and zink and S-albumin will be assessed as markers of malnutrition. The intestinal flora will be assessed by microbiological analysis of fecal sampling (Genetic Analysis AS, Oslo, Norway).

Pregnancy: Will be evaluated by urine test.

Questionnaire: Regarding concomitant medication and the UCLA SCTC GIT 2.0 (Swedish version) will be given to each study participant.

Eligibility Criteria:
Inclusion Criteria:

* a confirmed diagnosis of SSC according to the 2013 ACR/EULAR classification criteria
* above 18 years of age
* fluent in Swedish and able to understand the study protocol and "Patient information"
* being prescribed and using a fixed dos (1000-3000 mg daily) of MMF tablet, Cellcept or substitutable medical product, twice daily since at least 3 months
* the study participant's written and informed consent
* women in child-bearing age should use contraception

Exclusion Criteria:

* Recipient of a solid organ transplant
* Pregnancy or lactation
* The presence of renal failure (defined as eGFR \< 30 ml/min)
* A history of complicated venipunctures defined as
* a history of any venipuncture within the last year that required three or more attempts in order to succeed or
* a decision has been made that the patient should receive a subcutaneous venous port because of complicated venipunctures.

If the patient has a functioning subcutaneous venous port, the above criteria does not apply if venous sampling has been uncomplicated from this port.

* A history of hypersensitivity reactions to MMF
* Patients diagnosed with any kind of acute infection during the one (1) week preceding the study day
* A history of gastrointestinal surgery that includes resection of any port of the ventricle, small intestine, large intestine or liver (except for surgery for appendicitis, gall bladder resection or hemorrhoids, which do not constitute reasons for exclusion)
* Pulmonary arterial hypertension
* Anemia, defined as Hb \< 100 g/L during the last 4 weeks The patient will be informed about the study and sign informed consent before study commences.