Critical Ketoconazole Dosage Range for Ciclosporin Clearance Inhibition in the Dog

Abstract

Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p > 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p > 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p < 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p > 0.05). We conclude from these new observations that the KC-induced decrease in CsA C1(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5–10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.

The Effect of Ketoconazole on Whole Blood and Skin Ciclosporin Concentrations in Dogs

“…Additionally, inhibition of the CYP 450 enzymes by KTZ has been shown to be dose dependent, which was supported in the present study, with blood and skin CSA concentrations obtained in Treatment 3 being higher than those in Treatment 4. 18 As KTZ inhibition of CYP 450 can affect the metabolism of many other drugs and would be a lifelong therapeutic when paired with CSA for treatment of CAD, it may be important to use the lowest effective KTZ dose to limit the potential degree of interaction with other drugs. 9 Furthermore, it should be noted that in the present study, CSA and KTZ were administered for only 7 days, and the long-term effect of this drug combination on the whole blood and skin CSA concentrations is unknown.…”

“…8,9 Numerous in vitro and in vivo studies have demonstrated that co-administration of KTZ with CSA results in increased whole blood CSA concentrations in dogs. [13][14][15][16][17][18] The inhibitory effect of KTZ on CSA clearance from blood was determined to be dose dependent, with the critical KTZ dosage range identified as 2.5-10 mg ⁄ kg daily. 18 A study on normal research beagles investigating the dose of KTZ necessary to maintain whole blood CSA trough levels between 400 and 600 mg ⁄ mL showed that KTZ at 13.6 mg ⁄ kg daily enabled a 75% reduction of CSA dose, with estimated monetary savings of 57.8% at that time, and KTZ at 4.7mg ⁄ kg daily reduced CSA dose by 38% and thus reduced cost by 23.8%.…”

“…[13][14][15][16][17][18] The inhibitory effect of KTZ on CSA clearance from blood was determined to be dose dependent, with the critical KTZ dosage range identified as 2.5-10 mg ⁄ kg daily. 18 A study on normal research beagles investigating the dose of KTZ necessary to maintain whole blood CSA trough levels between 400 and 600 mg ⁄ mL showed that KTZ at 13.6 mg ⁄ kg daily enabled a 75% reduction of CSA dose, with estimated monetary savings of 57.8% at that time, and KTZ at 4.7mg ⁄ kg daily reduced CSA dose by 38% and thus reduced cost by 23.8%. 14 These results have been applied clinically in studies on the efficacy of combination KTZ and CSA for the treatment of canine perianal fistulas, with excellent short-term results and a significant decrease in the dose of CSA required for clinical efficacy.…”

Coadministration of Ketoconazole to Cyclosporin-Treated Kidney Transplant Recipients: A Prospective Randomized Study

“…Suppression of CsA metabolism may be associated with a decrease in the CsA parent:parent + metabolite ratio [12,19], and CsA metabolites are reported to be less immunosuppressive and more toxic than the parent com pound [20,21], In addition, ketoconazole has been re ported to have immunosuppressive activity [12,18,22]. For these reasons, we carried out this prospective ran domized study not only to study CsA dose reduction but also to explore the possible additional biological benefits, i.e.…”

Inhibitory Effects of Ketoconazole, Cimetidine and Erythromycin on Hepatic CYP3A Activities in Cats

“…Moreover, other researchers also reported drug interaction of KTZ with Table 1. cyclosporine in human [19] and dog [5,14] and with midazolam in human [3,7] and dog [10]. The extent of inhibitory effects of KTZ on MDZ1'H and MDZ4H seems to be quite different among animal species.…”