Effect of Metabolic Inhibitors on Cyclosporine Pharmacokinetics Using a Population Approach

Abstract

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Css(trough)) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Css(trough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) ratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered concomitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.

Severe Human Traumatic Brain Injury, but Not Cyclosporin A Treatment, Depresses Activated T Lymphocytes Early after Injury

“…Eight patients received a 24-h infusion of 5 mg/kg of CsA, followed by a second 24-h infusion of 5 mg/kg of CsA (with ketoconazole 200 mg given by feeding tube, to increase the bioavailability of the CsA), after a washout period of 24 h. The rationale for the administration of ketoconazole, an antifungal agent, is because CsA undergoes significant metabolism mediated by cytochrome P4503A4 (CYP3A4) isozyme and P glycoprotein (PgP) efflux in the gut wall, liver, and blood-brain barrier (Lown et al, 1997), with significantly reduced oral bioavailability. Several investigators have, therefore, used inhibitors of CYP3A4 and/or PgP, such as ketoconazole, to improve bioavailability of the drug and decrease the cost of therapy (McLachlan and Tett, 1998;Foradori et al, 1998;Jones, 1997). Since a high brain concentration of CsA was an aim of our study, ketoconazole seemed to be a rational addition to our trial design.…”

Population‐Based Assessments of Clinical Drug‐Drug Interactions: Qualitative Indices or Quantitative Measures?

“…Coadministration of valproic acid and more than 1 enzyme‐inducer, for example, typically results in a greater decrease in valproic acid concentrations. McLachlan and Tett 63 similarly found that treatment with 2 CYP3A4 inhibitors (ie, ketoconazole and diltiazem) inhibited the dose‐rate‐ C ss trough ratio of cyclosporine, a CYP3A4 substrate, more potently than did treatment with 1 inhibitor (eg, ketoconazole) alone (84.1% vs 76.9%, respectively).…”

“…Several of the studies listed in Table III revealed additional unique characteristics of the population‐based approach. For example, McLachlan and Tett 63 evaluated the impact of different CYP3A4 inhibitors on dose‐rate‐ C ss trough ratio for cyclosporine using the population‐based approach. These researchers identified a rank order of interactions in which ketoconazole plus diltiazem inhibited the dose‐rate‐ C ss trough ratio most potently, followed by ketoconazole alone, itraconazole alone, and diltiazem alone.…”

Beneficial Pharmacokinetic Drug Interactions

“…Itraconazole and diltiazem have subsequently been shown to be effective for cyclosporine dose-sparing as well. Florea et al [8] reported a 48% decrease in the total daily dose of cyclosporine when administered with itraconazole while another study found that cyclosporine dose could be reduced by 23%, 40%, 75% and 80% when combined with diltiazem, itraconazole, ketoconazole or ketoconazole plus diltiazem, respectively [9]. Gerntholtz et al [5] reported an 85% reduction in cyclosporine dose with ketoconazole and suggested that this combination was critical in making transplantation more affordable in developing countries.…”