Ciclosporin pharmacokinetics

In an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, aciclovir altered ciclosporin pharmacokinetics (228). 

Following the observation that grapefruit juice ingestion can increase the systemic bioavailability of ciclosporin, there was considerable interest in its possible use to reduce ciclosporin doses (SEDA-19, 351). However, this has been strongly criticized and considered hazardous because of large interindividual variability and the commercial availability of different formulations of grapefruit juice with potentially different effects on ciclosporin pharmacokinetics (250). 

The available data on a possible interaction between histamine H2 receptor antagonists and ciclosporin are inconclusive. Whereas neither cimetidine nor ranitidine significantly altered ciclosporin pharmacokinetics, there was an increase in serum creatinine concentration in patients taking both ciclosporin and cimetidine, but not ranitidine. The clinical significance of this interaction is probably limited, and it has been attributed to competition of cimetidine with creatinine for tubular secretion (251). 

Fluvoxamine and fluoxetine have been involved in isolated cases of increased blood ciclosporin concentrations, but fluoxetine was not confirmed to affect ciclosporin concentrations significantly in 13 patients (SEDA-20, 345) (SEDA-22, 385-386). In an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, sertraline altered ciclosporin pharmacokinetics (228). 

Ciclosporin pharmacokinetics vary considerably between patients, and even in an individual patient from time to time, with changes in the chnical condition and treatment, particularly with administration of other drugs (301). Inadequate exposure to ciclosporin is a key factor in acute rejection and contributes to the development of chronic rejection and graft failure. Monitoring of ciclosporin concentrations is widely adopted as an accurate and practical measure of drug exposure (302). 

A study in animals found that pretreatment with oral ciclosporin had no effect on the pharmacokinetics of alcohol or acetaldehyde. This suggests that any difference in the alcohol consumption of patients taking ciclosporin is unlikely to have a pharmacokinetic basis. The mechanism by which red wine exerts its effect is not known. White wine does not appear to affect ciclosporin pharmacokinetics," so the interaction is not believed to be an effect of alcohol. Antioxidants in red wine such as resveratrol may inactivate the cytochrome P450 isoenzyme CYP3A4 and this would also be expected to increase ciclosporin levels. The solubility of ciclosporin is decreased in red wine and it is possible that substances in red wine bind ciclosporin in the gastrointestinal tract and reduce its bioavailability. Another study by the same authors suggested that ciclosporin absorption is possibly impaired by P-glycoprotein induction. ... 

Food and milk can increase the bioavailability of ciclosporin. Lipid admixtures for parenteral nutrition appear not to affect ciclosporin pharmacokinetics. 

A study in 10 patients undergoing bone-marrow transplantation and given isocaloric and isonitrogenous parenteral nutrition with or without lipids found that ciclosporin pharmacokinetics are not affected by lipid-enriched admixtures. ... 

The food and milk interactions are established, clinically important, and result in an increase in the bioavailability of ciclosporin. The situation should therefore be monitored if any changes are made to the diet of patients taking ciclosporin. Patients should be warned because increased ciclosporin levels are associated with increased nephrotoxicity. Lipid admixtures in parenteral nutrition do not appear to affect ciclosporin pharmacokinetics and it is speculated that they may protect against ciclosporin-induced nephrotoxicity. Close supervision and monitoring is required. There is insufficient evidence to allow extrapolation of the results to bone-marrow transplant recipients with risk factors such as dysli-pidaemia, liver, or renal impairment. ... 

A study in 12 healthy subjects given a single 200-mg dose of ciclosporin found that pomelo juice significantly increased the AUC and maximum level of ciclosporin by about 19% and 12%, respectively, whereas cranberry juice did not have any significant effects on ciclosporin pharmacokinetics. ... 

On the basis of an experimental study in 9 patients it was concluded that the dosage of midazolam needs no adjustment in those taking ciclosporin. Midazolam also appears to have no effect on ciclosporin pharmacokinetics. ... 

The addition of mycophenolate mofetil to ciclosporin has been found to reduce the incidence of rejection episodes in kidney transplant patients and it is licensed for combined use. From the studies above, ciclosporin appears to reduce the levels of the active metabolite, mycophenolic acid, and increase the levels of the glucuronide metabolite (which is associated with mycophenolate adverse effects). The UK manufacturers point out that as efficacy studies were conducted in patients using ciclosporin, mycophenolate and corticosteroids, the finding that ciclosporin reduces the mycophenolic acid AUC by 19% to 38% does not affect the recommended dose requirements. They also state that ciclosporin pharmacokinetics are not affected by mycophenolate. However, this is in contrast to the studies... 

Stass H, Delesen H, Kubitza D, Mai I, Bauer S, Roots I. Moxifloxacin does not alter ciclosporin pharmacokinetics in transplant patients a multiple-dose, uncontrolled, single-centre study. Clin Drug Investig 2010 30(5) 279-87. 

The macrolide antibacterials (including erythromycin, clarithromycin and telithromycin) are often implicated in interactions, most frequently as a result of inhibition of the CYP3A4 enzyme system in the liver and enterocytes. Erythromycin inhibits the metabolism of carbamazepine, ciclosporin and theophylline significant increases in serum levels and features of toxicity have been documented. Careful clinical and pharmacokinetic monitoring are required in a patient taking any of these drugs who requires concomitant erythromycin. 

Tang-Liu, D. D., and Acheampong, A. (2005), Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye, Clin. Pharmacokinet.,44,247-261. 

Pharmacokinetics. Ciclosporin is about 40% absorbed from the gastrointestinal tract and is extensively metabolised in the liver mainly by the cytochrome P450 3A system the tis 27 h. 

However, some calcium channel blockers have pharmacokinetic interactions diltiazem, verapamil, nicardipine, and amlodipine increase ciclosporin concentrations, whereas nifedipine, felodipine, and isradipine do not (SED-14, 604) (SEDA-21, 210) (SEDA-21, 212)... 

St. John s wort contains an enzyme inducer that can reduce the plasma concentrations of drugs that are substrates of CYP3A4, such as indinavir and ciclosporin. However, in eight healthy volunteers aged 24-43 years, St. John s wort 300 mg/day (0.3% hypericin standardized tablet) for 14 days had no effect on the pharmacokinetics of carbamazepine (110). 

There was at least one episode of hepatotoxicity in 228 of 466 patients (49%) with renal transplants who took ciclosporin 110 (48%) had hyperalbuminemia, 108 (47%) a raised aspartate transaminase, and 167 (59%) a raised alkaline phosphatase (84). Ciclosporin dosage reduction resulted in resolution of hepatotoxicity in 185 patients (81%), while 32 (14%) had recurrent or persistent liver function abnormalities. Eleven (2.4%) developed biliary calculous disease. The serum ciclosporin concentration was high among the patients with hepatotoxicity. Pharmacokinetic studies showed an increased AUC in the patients with hepatotoxicity, probably due to reduced drug clearance. 

There was a dramatic increase in the systemic availability of paclitaxel when ciclosporin was administered concomitantly (241) and in a phase I study of the pharmacokinetics of twice-daily oral paclitaxel 60-160 mg/m in 15 patients in combination with ciclosporin (15 mg/kg) there was a seven-fold increase in the systemic exposure to paclitaxel the plasma concentration increased from negligible to therapeutic concentrations (242). The inhibitory effect of ciclosporin on the gastrointestinal multidrug transporter P-glycoprotein was suggested to account for these interactions. 

Dosages of statins should be reduced in patients taking ciclosporin, because of pharmacodynamic and pharmacokinetic interactions. 

Ciclosporin is absorbed to a variable extent from the gastrointestinal tract and almost completely metabolized in both the liver and small intestine by CYP3A, which metabolizes a large number of drugs. Inducers, inhibitors, or substrates of CYP3A therefore have the potential to interact with ciclosporin. In addition, ciclosporin has wide pharmacokinetic variability and a narrow therapeutic index. Conversely, ciclosporin can inhibit the hepatic metabolism of other drugs that share the same CYP3A metabolic pathway. 

Although there was no interaction between ciclosporin and ticlopidine in a pharmacokinetic study, a 64-year-old patient with a renal transplant had a reduction in the concentrationrdose ratio of ciclosporin after each of two successive courses of ticlopidine (298). 

The risk of ciclosporin-induced nephrotoxicity can be increased when NSAIDs are also used (44,45). Diclofenac in particular should be avoided, because it is more likely to cause deterioration of renal function in patients taking ciclosporin (SEDA-15, 100) (SEDA-17, 107). There is also a pharmacokinetic interaction, which may be caused by inhibition by ciclosporin of the first-pass metabolism of diclofenac (SEDA-21,104). 

In 16 healthy volunteers there were no important pharmacokinetic changes when a single dose of ciclosporin was taken during steady-state administration of aspirin, indometacin, or piroxicam, but there was an interaction with diclofenac, whose AUC was doubled in the presence of ciclosporin (46). 

Diltiazem abolishes the acute renal hypoperfusion and vasoconstriction induced by ciclosporin in renal transplant patients. Plasma endotheUn-1 may be a mediator of ciclosporin-induced renal hypoperfusion, but is not affected by diltiazem (26). This interaction has been confirmed with a new microemulsion formulation of ciclosporin in nine patients with renal transplants who took diltiazem 90-120 mg bd for 4 weeks (27). Diltiazem caused a 51% increase in the AUC of ciclosporin and a 34% increase in peak concentration, without altering the time to peak concentration. However, the ciclosporin microemulsion did not significantly affect the pharmacokinetics of diltiazem. 

Everolimus is an immunosuppressive macrolide that also has synergistic actions with ciclosporin and interrupts the proliferative responses of vascular and bronchial smooth muscle cells. In a phase I trial, its safety profile and pharmacokinetics were assessed during a 4-week course of once-daUy sequential ascending doses (0.75, 2.5, or... 

Both everohmus and ciclosporin are extensively biotransformed by CYP3A and are substrates for P-glycoprotein. However, in a multicenter randomized double-bhnd study in 101 patients, 1 year after kidney transplantation, who were randomly assigned to receive everolimus 0.5,1, and 2 mg bd plus ciclosporin and prednisone, the pharmacokinetics of ciclosporin were similar to pubhshed values in patients not taking everohmus (2). 

The pharmacokinetics of ciclosporin can be altered by macrolides. Commonly observed changes include increases... 

Cibulskyte D, Pedersen M, Fijelm-Poulsen J, Fiansen FiE, Madsen M, Mortensen J.The pharmacokinetics and acute renal effects of oral microemulslon ciclosporin A in normal pigs. Int Immunopharmacol. 2006 6 627-634. 

Single-dose ciclosporin slightly increased the absorption of sitagliptin, although this was not considered clinically relevant. Sitagliptin does not have a clinically relevant effect on the pharmacokinetics of digoxin, oral contraceptives, simvastatin or warfarin. 

The pharmacokinetics of mitoxantrone 10 mg/m daily were compared with mitoxantrone 6 mg/m (a 40% reduction in dose) with high-dose ciclosporin in children. The ciclosporin recipients had a 42% reduction in mitoxantrone clearance, a 12% inerease in mitoxantrone AUC, and similar toxicity. ... 

An established and clinically important interaction. Ciclosporin alters the pharmacokinetics of the anthracyclines resulting in increased serum levels. This pharmacokinetic interaction has complicated study into the value of using ciclosporin to modulate multidrug resistance in tumours and thereby improve the response to chemotherapy. In the case of anthracyclines and etoposide , (p.630), any benefit could just be attributed to dose intensification. Consequently, some have suggested reducing the dose of the anthracycline. The use of high-dose ciclosporin for multidrug resistant tumour modulation remains experimental and should only be used in clinical studies. Concurrent use should be very well monitored. More study is needed to find out the possible effects of low-dose ciclosporin. 

---