Interaction of Cyclosporin and Itraconazole

Kwan, Jonathan; Foxall, P.J.D.; Davidson, Dena; Bending, M. R.; Eisinger, A. J.

doi:10.1016/s0140-6736(87)90873-7

Cited by 76 publications

(17 citation statements)

References 2 publications

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“…43,44 These cases demonstrate that the addition of itraconazole to calcineurin inhibitor therapy increases the trough concentrations of the calcineurin inhibitors by two-to three-fold. In each of these case reports, additional factors could affect the outcome; so the frequency of occurrence and the magnitude of the drug interaction are not clear.…”

Section: Fluconazolementioning

confidence: 89%

Drug interactions in the hematopoietic stem cell transplant (HSCT) recipient: what every transplanter needs to know

Leather

2003

Bone Marrow Transplant

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Summary:Pharmacokinetic drug interactions among hematopoietic stem cell transplant recipients can result in either increases in serum concentrations of medications, which may lead to enhanced toxicity; or reduced serum concentrations, which can lead to treatment failure and the emergence of post transplant complications. The use of drugs that have a narrow therapeutic index, such as cyclosporine/tacrolimus (calcineurin inhibitors), increases the significance of these interactions when they occur. This report will review the clinical data evaluating the drug interactions of relevance to HSCT clinical practice, focusing on the pharmacokinetic interactions, and provides recommendations for managing these interactions to avoid both toxicity and treatment failure. Keywords: drug interactions; cytochrome P450; cyclosporine; tacrolimus; pharmacokinetic; CYP3A4; azoles A drug interaction is best defined as 'the possibility that one drug may alter the intensity of pharmacological effects of another drug that is given concurrently'. This results in either enhanced activity of the affected drug, which may lead to toxicity, or reduced activity of the affected drug, leading to therapeutic failure. It is also possible that there may be the appearance of a new effect that is not seen with either drug alone, for example, caspofungin and cyclosporine coadministration leading to elevated liver function tests. Drug interactions can be categorized as being either pharmacokinetic (PK) or pharmacodynamic in nature, and the remainder of this review will focus on PK interactions. Pharmacokinetic drug interactions -what are they?Pharmacokinetic drug interactions influence the disposition of the drug in the body. When drugs are ingested, they undergo several processes to produce an end effect, including absorption, distribution, metabolism, and excretion. Interactions between two or more drugs may affect any of these phases, including the modulation of hepatic drug biotransformation, renal clearance, altered distribution, or changes in plasma protein binding. The most clinically relevant mechanisms of PK drug interactions relate to metabolism and elimination of drugs from the body, and involve the cytochrome P450 (CYP) enzymes and the transporter P-glycoprotein at the hepatic and intestinal levels, and glomerular filtration and tubular secretion at the renal level. Cytochrome microsomal enzyme systemThe CYP microsomal enzyme system is a family of hemoproteins that is responsible for the oxidative biotransformation of endogenous substrates and xenobiotics. CYPs are expressed in several tissues, with the main drug metabolizing CYPs concentrated in the liver, with lower expression in the lungs, kidneys, intestines, and brain.1 Of the several different CYP isoforms identified, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 have the greatest involvement in drug metabolism. An extensive list of drugs metabolized by the various isoenzymes is outlined in Table 1. 2 The majority of oxidatively biotransformed drugs are metabolized, at least in part, ...

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Section: Fluconazolementioning

confidence: 89%

Drug interactions in the hematopoietic stem cell transplant (HSCT) recipient: what every transplanter needs to know

Leather

2003

Bone Marrow Transplant

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“…Case reports or small series of patients have also demonstrated this interaction in renal, heart, and lung transplant recipients, with an associated deterioration in renal function induced by CsA (15,16,26). However, one study failed to observe itraconazole and CsA interaction in patients with bone marrow transplantation during an average time of 4.4 weeks in which both drugs were administered together (19).…”

Section: Discussionmentioning

confidence: 99%

“…Itraconazole has not been compared with amphotericin B against invasive pulmonary aspergillosis in randomized clinical trials, although results of initial nonran-domized studies appear promising (6,7,30). However, among the concerns with antifungal azole derivatives, such as itraconazole, is their potential adverse interaction with CsA that may increase CsA levels, resulting also in nephrotoxicity (15,16,26), and their limited bioavailability in some patients that may lower concentrations in serum (6,25,27).…”

mentioning

confidence: 99%

Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma

Berenguer

Ali

Allende

et al. 1994

Antimicrob Agents Chemother

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Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (loglo CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 ,ug/ml; range, <0.5 to 16.8 ,g/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden ofA.fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden ofA.fumigatus.This model demonstrated that levels in plasma of greater than 6 ,ug/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 ,g/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis.

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“…Clinical interaction data are somewhat equivocal although the balance of evidence suggests that both itraconazole (Kwan et al, 1987;Trenk et al, 1987) and fluconazole, particularly at higher doses of 200 mg day-', (Graves et al, 1990;Lazar & Wilner, 1990;Sugar et al, 1989) will cause an elevation of blood CsA concentrations.…”

Section: Discussionmentioning

confidence: 99%

Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.

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Tjia

1991

Brit J Clinical Pharma

143

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Interaction of Cyclosporin and Itraconazole

Cited by 76 publications

References 2 publications

Drug interactions in the hematopoietic stem cell transplant (HSCT) recipient: what every transplanter needs to know

Drug interactions in the hematopoietic stem cell transplant (HSCT) recipient: what every transplanter needs to know

Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporin A, and correlation between therapeutic response and itraconazole concentrations in plasma

Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.

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