Orlistat and Cyclosporine Injection: Interaction Details

a) A multiple-dose study in patients receiving cycloSPORINE 50 mg twice daily and orlistat 120 mg three times daily found that coadministration of these drugs led to decreases of 31% and 25% in AUC and Cmax, respectively; however, when cycloSPORINE was administered 3 hours after orlistat, the AUC and Cmax decreased only by 17% and 4%, respectively ³.

b) A 61-year-old male heart transplant recipient was stabilized on cycloSPORINE liquid 100 mg twice daily, azaTHIOprine 12.5 mg daily, aspirin 100 mg daily, calcium 500 mg daily, furosemide 40 mg daily, xipamide 10 mg daily, allopurinol 150 mg daily, pravastatin 20 mg daily, and losartan 50 mg daily for six months. Because of obesity, his general practitioner started him on orlistat 120 mg three times daily. Two weeks later, during routine cycloSPORINE monitoring, it was found that his cycloSPORINE level had fallen from 101 ng/mL to 50 ng/mL. His dose of cycloSPORINE was increased to 110 mg twice daily, but another blood level one week later showed no increase in the cycloSPORINE level. Orlistat was discontinued, and his cycloSPORINE level increased to 104 ng/mL. The patient was rechallenged with orlistat 120 mg three times daily so that pharmacokinetic parameters could be measured. CycloSPORINE trough blood levels decreased from 98 ng/mL to 52 ng/mL, maximum concentration (Cmax) decreased from 532 ng/mL to 74 ng/mL, and the area under the concentration-time curve (AUC) from 0 to 12 hours fell from 2832 ng/h/mL to 700 ng/h/mL. Upon discontinuation of orlistat, cycloSPORINE levels increased to 104 ng/ml. Because the resorption and systemic appearance of orlistat is negligible, the postulated mechanism of this interaction is an interference with cycloSPORINE absorption in the small intestine ⁴.

c) Some authors recommend that transplant recipients should take cycloSPORINE at least two hours before or after orlistat. Plasma cycloSPORINE levels should also be measured to reduce the risk of inadequate immunosuppression and organ rejection. It is likely that the reported reductions in blood cycloSPORINE concentrations in patients concomitantly taking orlistat are due to a decrease in cycloSPORINE absorption ⁵.

d) A pharmacokinetic interaction occurs between cycloSPORINE and orlistat leading to decreased blood concentrations of cycloSPORINE. One case report describes a patient who underwent heart transplantation with a nonsignificant acute rejection episode. Orlistat was initiated 24 days before this episode for obesity. The cycloSPORINE level was 38 mcg/L. Orlistat was discontinued and cycloSPORINE levels returned to baseline (90-110 mcg/L). Orlistat may have decreased cycloSPORINE trough levels by impairing its intestinal absorption ⁶.

e) A pharmacokinetic interaction between cycloSPORINE and orlistat leads to decreased blood concentrations of cycloSPORINE. Another case report describes a 65-year-old heart transplant recipient who was given cycloSPORINE therapy and predniSONE. Whole blood cycloSPORINE trough levels were stable over 9 months (150 +/- 20 ng/mL). A decrease in blood cycloSPORINE concentration from 150 to 50 ng/mL without clinical consequences occurred six months after starting concomitant therapy with orlistat (3 X 120 mg/d). CycloSPORINE (SANDIMMUNE®) dosage was increased to 300 mg/day. CycloSPORINE whole blood concentrations remained at 65 ng/mL. Seven days after switching to Neoral(R) (NEO), a microemulsion form of cycloSPORINE, the whole blood concentrations reached 125 ng/mL. NEO dose was increased to 375 mg/d. Two hours after NEO intake, whole blood concentrations were 975 ng/mL, indicating that cycloSPORINE impregnation was adequate. Subtherapeutic blood cycloSPORINE concentrations may occur after orlistat therapy is initiated. The microemulsion formulation of cycloSPORINE may overcome this interaction, however, therapeutic drug monitoring is required during coadministration of cycloSPORINE and orlistat. The author does not rule out underdosage of cycloSPORINE causing acute rejection ⁷.

f) Reduction in plasma cycloSPORINE levels by orlistat occurred in two renal transplant patients. A 25-year-old female who received a cadaver renal transplant (CRT) was taking CyA-neoral 175 mg/d and azaTHIOprine 50 mg/d for maintenance immunosuppression. Orlistat 120 mg twice a day was initiated and after 49 days of therapy her cycloSPORINE levels decreased from previous values of 157 ng/mL to 76 ng/mL (51.6%). Orlistat was discontinued and the cycloSPORINE levels rose to 122, 134, and 151 ng/mL. The cycloSPORINE dose remain unchanged. A 50-year-old female CRT patient received induction immunosuppression with Simulect (basiliximab-Novartis), CyA-neoral 10 mg/kg, azaTHIOprine 3 mg/kg, and methylPREDNISolone 5 mg/kg. Orlistat was initiated and her CyA plasma concentration had fallen from 132 ng/mL to 76 ng/mL (42.4%). Orlistat was discontinued after 5 days of therapy and the dose of cycloSPORINE had been increased to 275 mg/day. CycloSPORINE plasma levels increased to 186 ng/mL. Orlistat interferes with cycloSPORINE absorption in the small intestine, leading to increased excretion with fatty stools. To avoid immunosuppression, the author recommends that orlistat not be used in combination with cycloSPORINE ⁸.

g) CycloSPORINE levels are decreased with concomitant orlistat administration. A 56-year-old overweight male with advanced renal failure caused by diabetic nephropathy was prescribed orlistat three months before he was to receive a kidney transplant. He also suffered from diabetic retinopathy, mild diabetic neuropathy, hypertension, dyslipidemia, and coronary artery disease. Orlistat was administered until the day of his renal transplant operation. He started standard CyA-Neoral by mouth 48 hours before surgery. Other medications were basiliximab, prednisoLONE, azaTHIOprine, raNITIdine, cotrimoxazole, and insulin. The transplanted kidney functioned immediately, and the plasma creatinine fell over the next 7 days. The patient did not have a normal bowel movement until day 7. CyA levels measured 3 days after engraftment were extremely low (C0 was undetectable (desirable C0 300-400 ng/mL); C2 was 306 ng/mL (desirable C2 1,500 to 1,700 ng/mL). The oral dose was increased rapidly to 30 mg/kg/d, but the achieved blood levels were not adequate. CyA was then administered intravenously (4 mg/kd/d as a bolus over 120 minutes) after a drug interaction was suspected. This led immediately to adequate CyA blood levels. After 3 days the patient was given oral CyA at conventional doses with predictable and stable blood CyA concentrations. At 3 months, plasma creatinine level was 2.1 mg/dL (183 mcmol/L), C0 was 208 ng/mL, and C2 was 1,728 ng/mL. The author suggests that most of the infested CyA was "lost" in the orlistat that was residing in the small bowel. More predictable pharmacokinetics were restored once the patient had evacuated the orlistat-CyA conglomerate from the bowels ⁹.