Interaction Between Rimonabant and Cyclosporine and Tacrolimus

Official Title: “The Effect of Rimonabant Treatment on Cardiovascular Risk Factors in Renal Transplant Recipients -- Pilot Safety Study”

The major cause of premature death in renal transplant recipients is cardio-vascular disease. In addition, obesity is becoming a major problem in this patient population.

Rimonabant does not only seem to have weight reducing properties but also weight reduction independent effects on insulin sensitivity and endothelial function, two important cardio-vascular risk factors. Rimonabant therefore is an interesting drug for the treatment of transplanted patients. Present data also indicate that rimonabant does not interact with essential immunosuppressive drugs (CsA and Tac) indicating that it most probably is safe to administer to this patient population. However this needs to be investigated in a proper manner.

Renal transplant recipients are treated with life-long immunosuppressive therapy in order to prevent acute rejection episodes. The calcineurin inhibitors (CsA and Tac) are the back-bones in the immunosuppressive treatment and they have a very narrow therapeutic index.

It is therefore essential to assure that new drug to be used in transplanted patients do not interact with CsA and Tac. Even though rimonabant is metabolized via the same enzyme as CsA and Tac (CYP3A4) previous in vitro and in vivo studies with relevant probe drugs in healthy volunteers do not indicate the presence of any relevant pharmacokinetic interaction.

However, to be absolutely sure that it is safe to administer rimonabant in transplanted patients a 12-hour pharmacokinetic interaction investigation is included for 16 patients in the present pilot study (8 patients on CsA and 8 patients on Tac).

Intervention(s) in this Clinical Trial

• Drug: cyclosporine A
  • Cyclosporine is dosed twice daily and is individualized as per center practice and kept stable during the study.
• Drug: tacrolimus
  • Dosing of tacrolimus is given twice daily and individualized as per center practice.

Arms, Groups and Cohorts in this Clinical Trial

• Other: CsA
  • Investigation of systemic exposure of cyclosporine before and after 2 moths of co-adminiastration of rimonabant.
• Other: Tac
  • Investigation of systemic exposure of tacrolimus before and after 2 moths of co-adminiastration of rimonabant.

Primary Measures

• Effect of rimonabant on cylosporine/tacrolimus bioavailablility
  • Time Frame: 2 months
    

Secondary Measures

• Effect of rimonabant on insulin sensitivity
  • Time Frame: 2 months
    

Inclusion Criteria:

• Renal transplant recipient with stable renal function (less than 20% deviation in serum creatinine the last 2 months).
• Renal transplant recipient currently on CsA or Tac and prednisolone based immunosuppression.
• BMI > 30 kg/m2 or >27 kg/m2 in combination with one or more cardio-vascular risk factors.
• > 18 years of age.
• Male patient, or female patient without childbearing potential (surgically sterilized or postmenopausal) or, if female of childbearing potential, is not lactating, has a negative pregnancy test at screening and is willing to utilize an effective method of contraception throughout the study period and for 90 Days following discontinuation of the Study Drugs.
• Signed informed consent.

Exclusion Criteria:

• Diabetes mellitus
• Severe liver disease.
• Depressive-, anxiety- or sleeping disorders.
• Estimated GFR < 25 ml/min.
• Epilepsy.
• Skin disorders that may influence laser Doppler flowmetry investigations.
• Pregnant or nursing mothers.
• Concomitant treatment with CYP3A4 inhibitors (www.cyp450.no) with interaction potential according to the investigator.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: University of Oslo School of Pharmacy Other

Overall Clinical Trial Officials and Contacts

Anders Åsberg, Ph.D. Study Chair Scholl of Pharmacy, University of Oslo  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00525681

Study ID Number: RIMONA-PILOT

ClinicalTrials.gov Identifier: NCT00525681

Health Authority: Norway: Norwegian Medicines Agency