Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations.

This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) and cyclosporine (CsA) alone versus in combination to produce renal dysfunction, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0.4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GFR, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in whole blood versus liver or renal tissues were measured, and the median effect model was used to discern the type of drug interactions. Compared with vehicle controls (1.98 +/- 0.34 ml/min), GFR values were reduced only by large doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 +/- 0.02 ml/min or 6.4 mg/kg per d = 1.3 +/- 0.2 ml/min; both P < 0.01) or CsA (10.0 mg/kg per d = 1.2 +/- 0.1 ml/min or 20.0 mg/kg per d = 0.8 +/- 0.4 ml/min; both P < 0.01). In contrast, hosts that were treated with smaller doses of CsA/RAPA combinations showed more pronounced effects in reduction of GFR values: 2.5/0.4 mg/kg per d, modestly (1.5 +/- 0.5 ml/min; P < 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 +/- 0.01 ml/min; P < 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentrations in whole blood and, particularly, in kidney tissue. In contrast, the pharmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities-myelosuppression and increased serum cholesterol/low-density lipoprotein cholesterol-occurred independently of pharmacokinetic interactions. RAPA aggravates CsA-induced renal dysfunction owing to a pharmacokinetic interaction, whereas CsA produces a pharmacodynamic effect that augments RAPA-induced myelosuppression and hyperlipidemia.

[1]  B D Kahan,et al.  Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: Racial differences in bioavailability , 1992, Clinical pharmacology and therapeutics.

[2]  U. Ruegg,et al.  Cyclosporine A up-regulates angiotensin II receptors and calcium responses in human vascular smooth muscle cells. , 1999, Kidney international.

[3]  B D Kahan,et al.  INDIVIDUALIZATION OF CYCLOSPORINE THERAPY USING PHARMACOKINETIC AND PHARMACODYNAMIC PARAMETERS , 1985, Transplantation.

[4]  B. Kahan,et al.  Routine clinical monitoring of sirolimus (rapamycin) whole-blood concentrations by HPLC with ultraviolet detection. , 1996, Clinical chemistry.

[5]  A. Macdonald.  A WORLDWIDE, PHASE III, RANDOMIZED, CONTROLLED, SAFETY AND EFFICACY STUDY OF A SIROLIMUS/CYCLOSPORINE REGIMEN FOR PREVENTION OF ACUTE REJECTION IN RECIPIENTS OF PRIMARY MISMATCHED RENAL ALLOGRAFTS , 2001, Transplantation.

[6]  G. Maurer.  Metabolism of cyclosporine. , 1985, Transplantation proceedings.

[7]  P. Halloran,et al.  Calcineurin activity is only partially inhibited in leukocytes of cyclosporine-treated patients. , 1995, Transplantation.

[8]  E. Lakatta,et al.  Rapamycin inhibits alpha 1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes. Evidence for involvement of p70 S6 kinase. , 1997, Circulation research.

[9]  A. Vickers,et al.  Cyclosporin A metabolism in human liver, kidney, and intestine slices. Comparison to rat and dog slices and human cell lines. , 1992, Drug metabolism and disposition: the biological fate of chemicals.

[10]  B. Kahan.  Drug therapy: cyclosporine , 1989 .

[11]  W. Bennett,et al.  Chronic cyclosporine nephropathy: the Achilles' heel of immunosuppressive therapy. , 1996, Kidney international.

[12]  F. Heitz,et al.  Tissue distribution, disposition, and metabolism of cyclosporine in rats. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[13]  W. Bennett,et al.  Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. , 1996, Kidney international.

[14]  G. Tydén,et al.  Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). , 1998, Transplantation.

[15]  T. Meyer,et al.  The effects of blood pressure reduction on cyclosporine nephrotoxicity in the rat. , 1993, Journal of the American Society of Nephrology : JASN.

[16]  S. Jordan,et al.  The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. , 1996, Kidney international.

[17]  S. Stepkowski,et al.  Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney, and small bowel transplantation in the rat. , 1991, Transplantation.

[18]  E. Mervaala,et al.  Effects of ACE inhibition on cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on a high-sodium diet. , 1999, Blood pressure.

[19]  H. Meier‐Kriesche,et al.  Correlation between pretransplantation test dose cyclosporine pharmacokinetic profiles and posttransplantation sirolimus blood levels in renal transplant recipients. , 1999, Therapeutic drug monitoring.

[20]  T. Chou,et al.  A rigorous approach to the diagnosis of synergy among combination therapies of immunosuppressive agents , 2001 .

[21]  B D Kahan,et al.  Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro. , 1991, Transplantation.

[22]  H. Meier‐Kriesche,et al.  Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. , 1999, Transplantation.

[23]  B. Kahan,et al.  Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. , 2000, Transplantation.

[24]  A. Evan,et al.  Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function. , 1987, Transplantation.

[25]  B D Kahan,et al.  Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival in rats. , 1996, Transplantation.

[26]  H. Strobel,et al.  Oxygen radical formation by the cytochrome P450 system as a cellular mechanism for cyclosporine toxicity. , 1994, Transplantation proceedings.

[27]  M. Mihatsch,et al.  Influence of rat strain on rapamycin's kidney effects. , 1993, Transplantation proceedings.

[28]  D. S. Gordon,et al.  Cyclosporine , 1986, Transplantation proceedings.

[29]  B. Julian,et al.  Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. , 1999, Transplantation.

[30]  N. Perico,et al.  Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate. , 1995, Journal of the American Society of Nephrology : JASN.

[31]  H. Schiebel,et al.  Sensitive and specific quantification of sirolimus (rapamycin) and its metabolites in blood of kidney graft recipients by HPLC/electrospray-mass spectrometry. , 1996, Clinical chemistry.

[32]  H. Harris,et al.  The Rat , 1958, Nature.

[33]  E. Fluhler,et al.  Therapeutic blood levels of sirolimus (rapamycin) in the allografted rat. , 1996, Transplantation.

[34]  C. Lally,et al.  Apoptosis and necrosis: mechanisms of cell death induced by cyclosporine A in a renal proximal tubular cell line. , 1998, Kidney international.

[35]  R. Calne,et al.  Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. , 1999, Transplantation.

[36]  V. Quesniaux,et al.  The Immunosuppressant Rapamycin Blocks In Vitro Responses to Hematopoietic Cytokines and Inhibits Recovering But Not Steady-State Hematopoiesis In Vivo , 1994 .

[37]  N. Vaziri,et al.  Depressed renal and vascular nitric oxide synthase expression in cyclosporine-induced hypertension. , 1998, Kidney international.

[38]  B. Kahan,et al.  Sample clean-up and high-performance liquid chromatographic techniques for measurement of whole blood rapamycin concentrations. , 1994, Journal of chromatography. B, Biomedical applications.

[39]  W. Bennett,et al.  Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. , 1996, Transplantation.

[40]  M. Lagman,et al.  In vivo expression of transforming growth factor-beta1 in humans: stimulation by cyclosporine. , 1998, Transplantation.

[41]  K. Copeland,et al.  Abbott TDx monoclonal antibody assay evaluated for measuring cyclosporine in whole blood. , 1990, Clinical chemistry.

[42]  S. Stepkowski,et al.  Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic interactions. , 1998, Therapeutic drug monitoring.

[43]  H. Hellendoorn,et al.  Applications of statistics in clinical chemistry. A critical evaluation of regression lines. , 1975, Clinica chimica acta; international journal of clinical chemistry.

[44]  R. Ardaillou,et al.  Involvement of reactive oxygen species in kidney damage. , 1993, British medical bulletin.

[45]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.

[46]  A. Ortiz,et al.  Cyclosporine A induces apoptosis in murine tubular epithelial cells: role of caspases. , 1998, Kidney international. Supplement.

[47]  Barry D Kahan,et al.  Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study , 2000, The Lancet.