Pharmacokinetics Of Cyclosporine Research Articles

Effects of plasma lipid levels on blood distribution and pharmacokinetics of cyclosporin A.

The present study attempted to characterize the distribution of cyclosporin A (CsA) among the lipoprotein fractions, very-low-, intermediate-, low-, and high-density (VLDL, IDL, LDL, and HDL, respectively) in the plasma of patients awaiting heart transplantation and the influence of plasma lipid constituents on the pharmacokinetics of CsA. Major fractions of a therapeutic concentration of CsA were found in HDL and in LDL. In addition, plasma lipid concentrations (total cholesterol, triglycerides, phospholipids, VLDL-cholesterol--TC, TG, PL, VLDLc, respectively) are positively correlated with the CsA distribution within the LDL fraction, and negatively correlated with the CsA distribution within the HDL fraction. Thus, the percentage of CsA in each type of lipoproteins was shown to vary with the lipid levels among individuals. A significant negative correlation was found between apparent distribution volume at steady state (Vss) in plasma and TC, PL, and LDLc and between the area under the curve measured in blood (AUCB) for whole blood and PL.

Pharmacokinetics of Cyclosporine and Steady‐State Aspirin During Coadministration

Anecdotal reports from clinical trials assessing the use of cyclosporine in the treatment of rheumatoid arthritis suggest an association between enhanced renal impairment and combined use of cyclosporine with nonsteroidal anti-inflammatory drugs. To explore possible pharmacokinetic contributions to this phenomenon, a randomized, two-period crossover investigation was performed in 24 healthy volunteers in which a single oral dose of 300 mg cyclosporine was administered alone and on day 10 of multiple oral dosing of aspirin 960 mg three times daily. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a steady-state dosing interval for aspirin on day 9 (aspirin alone) and day 10 (coadministration of cyclosporine and aspirin). Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay and plasma concentrations of acetylsalicylic acid and metabolites by high-performance liquid chromatography. Lack of a pharmacokinetic interaction was conclusively demonstrated for the rate and extent of cyclosporine and acetylsalicylic acid absorption and for the rate and extent of salicylic acid formation after a single dose of cyclosporine was coadministered during steady-state aspirin dosing. If a clear association between enhanced renal impairment and the combined use of cyclosporine and aspirin is substantiated, the underlying mechanism appears to be pharmacodynamic rather than pharmacokinetic.

Pharmacokinetics of cyclosporine in heart and lung transplant candidates and recipients with cystic fibrosis and Eisenmenger's syndrome.

To compare the pharmacokinetics of cyclosporine in patients with either cystic fibrosis or Eisenmenger's syndrome. Patients in the study were heart and lung transplant candidates with either cystic fibrosis (n = 6) or Eisenmenger's syndrome (n = 5), as well as patients who received heart and lung transplantation for either cystic fibrosis (n = 13) or Eisenmenger's syndrome (n = 7). This was no experimental pharmacokinetic study in transplant candidates and an exploratory population pharmacokinetic study in transplant recipients. Patients with cystic fibrosis showed higher blood cyclosporine clearance, higher apparent oral clearance, shorter mean residence time, and more erratic absorption. The coefficient of variation of pharmacokinetic parameters was higher in patients with cystic fibrosis. There were no significant differences in metabolite indexes between the two groups of patients after either oral or intravenous administration. A significant negative correlation was found between cyclosporine clearance and hematocrit (r = 0.81 [95% confidence interval, -0.95 to -0.4.1]). Dose-normalized predose blood concentration measurements were lower in patients with cystic fibrosis after transplantation. There was a significant correlation between hematocrit and log dose-normalized cyclosporine concentration (r = 0.40 [95% confidence interval, 0.30 to 0.49]). The total daily dose per 100 ng/ml trough blood concentration required was estimated to be 2.36 times (95% confidence interval, 1.96 to 2.84) higher in patients with cystic fibrosis. Cyclosporine pharmacokinetics is more variable in patients with cystic fibrosis. The difference in cyclosporine clearance between the two groups is accounted for by differences in binding in blood rather than metabolism. The findings suggest that patients with cystic fibrosis could be conservatively given initial oral doses that are 1.5 times higher than those for patients who receive transplants because of Eisenmenger's syndrome.

The Pharmacokinetics of Oral Cyclosporine A in Stable Kidney Transplanted Patients

s Third International Congress of Therapeutic Drug Monitoring and Clinical Toxicology: PDF Only

On the intraindividual variability and chronobiology of cyclosporine pharmacokinetics in renal transplantation.

The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0-12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0-12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t1/2, tmax and Cmax were more variable than the AUC (0-12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng.ml-1 versus 223 ng.ml-1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.

Pharmacokinetics of cyclosporine A after intravenous and oral administration in liver transplant patients measured with high-performance liquid chromatography.

Cyclosporine A (CsA) bioavailability after i.v. and oral administration was studied in six stable liver transplant patients with open and clamped bile drain. CsA levels were determined by the high-performance liquid chromatography method (HPLC). External bile drainage decreased CsA absorption considerably. Clamping the bile drain resulted in higher and earlier peak CsA levels. Clamping the bile drain increased the bioavailability (9.6% vs. 7%, p < 0.05), but even then it was considerably lower than the value of approximately 30% generally reported in literature. It is recommended to continue i.v. CsA administration to obtain therapeutic plasma concentrations. Early bile drain clamping or bile refeeding will improve CsA absorption and may also result in continuously therapeutic CsA levels.

剤形が及ぼすＣｙｃｌｏｓｐｏｒｉｎｅ血中動態への影響

The effect of dosage form on the pharmacokinetics of cyclosporine (CYA) in steady state after oral administration as either a capsule or a solution was studied in 4 renal trans plant recipients.CYA (dose; 100-350mg/day) was administered orally to the patients (17-49 years old) every 12 hr. The whole blood levels were measured by fluorescence polarization immu noassay (FPIA) based on monoclonal antibody. The blood specimens were collected just before administration (0h) in the morning and at1 (1h), 2 (2h), (3h), 6 (6h), 8 (8h) hours after administration; specimens were also collected just before the evening administration (12h) and at1 (13h), 2 (14h), 3 (15h), 4 (16h), 7 (19h), 12 (24h) hours after administration in one day.There were no significant differences between capsule and solution the administrations in the area-under-the-curve (AUC), and in the maximal blood concentration (Cmax). There was a significant difference between the trough level of 0h and 24h, and between the time of maximum blood concentration (Tmax) after the administration of solution in the daytime and that at nighttime (p<0.05).These results suggest that the capsule is not only as applicable as solution in changeover patients but also very useful for trough blood level monitoring.

Pharmacokinetics of cyclosporin A during pregnancy; monitoring of treatment and specific assays of cyclosporin, based on five liver transplant patients.

Very little information is available concerning the pharmacokinetic behaviour and monitoring of cyclosporin A (CsA) during pregnancy, notably after liver transplant. Monitoring of blood levels of CsA is considered to be one of the best tools for evaluation of the efficacy of immunosuppressant treatment. The aim of this study was to bring together new information concerning pregnant women receiving immunosuppressant treatment with CsA and, in view of the special pathophysiological status of such patients, to compare pharmacokinetic profiles of changes in blood levels of CsA and of the combination of CsA plus metabolites. Specific (CsA-S kit) and a new non-specific (CsA-NS kit) assays of CsA were carried out in five hospitalized pregnant patients who had received liver transplants between the 6th and the 41st weeks of amenorrhea. The results of five cases investigated lead to the following conclusions: (1) The pharmacokinetic behaviour of native CsA in the pregnant woman between the 6th and 41st weeks of amenorrhea suggests no systemic accumulation nor any radical need for changes in dosage schedule as compared with a non-pregnant patient. (2) Monitoring based upon simultaneous use of the CsA-NS and CsA-S kits may be a source of analytical bias and hence confusion for the physician. (3) Determination of an experimental CsA-NS/CsA-S accumulation ratio (based upon analysis of single concentrations or processing of AUCs) is of interest only if specific assays involve not only CsA itself but also its principal metabolites. (4) Monitoring based upon single measurements of residual CsA levels only, is necessary and adequate. Furthermore, such an approach is less costly.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cyclosporin A after intravenous administration to rats in various disease states.

We examine the pharmacokinetic profile of cyclosporin A (CyA) after intravenous administration to rats prepared as models of various disease states found in patients who receive organ transplantations. After intravenous bolus administration to normal rats, the total blood clearance (CLt) of CyA showed a dose-dependent increase. The CLt was reduced in anemic (ANE) rats prepared by venesection, in carbon tetrachloride-induced acute hepatic failure (AHF) rats, and in glycerol-induced acute renal failure (ARF) rats. On the other hand, the volume of distribution at a steady state (Vss) of CyA increased significantly in ANE and aged (AGE) rats. CyA distribution was tissue-specific, and the tissue CyA concentration was disease state-dependent. Linear relationships between the CyA concentration in whole blood and various tissues (liver, kidney and heart) were found in AGE, ANE and AHF animals. However, in ARF rats, tissue concentration was not increased to a great extent in comparison with the other disease models, even though the whole blood CyA concentration was increased. The tissue per blood concentration ratio (Kb), which represented the CyA tissue transfer from systemic circulation, was influenced by the disease state. In the liver, in particular, the Kb increased in the AHF and AGE groups, whereas it decreased in the ANE and ARF rats. The CLt of CyA was negatively related to the erythrocyte per plasma concentration ratio (E/P), and the E/P exhibited disease state-dependent changes, suggesting that this ratio is a valuable indicator for predicting variations in CyA total blood clearance in organ transplant patients during episodes of anemia, nephrotoxicity and hepatotoxicity.

Lack of effect of isradipine on cyclosporin pharmacokinetics.

The influence of isradipine as a long acting form (IcazR LP 5 mg) on cyclosporin pharmacokinetics was studied in six hypertensive renal transplant patients (mean age 37 yrs; mean body weight 62 kg). These patients received a mean daily cyclosporin dose of 307 mg in two equal intakes. Isradipine was orally administered once a day at a dose of 5 mg before the morning cyclosporin intake. Cyclosporin kinetics was assessed over a 0-12-h period, the day before (D-1) and 13 days (D+13) after isradipine treatment. Whole blood concentrations of cyclosporin were determined by radioimmunoassay (RIA) using the SandimmuneR-RIA kit (specific and non-specific monoclonal antibodies). Area under the blood concentration-time curve (AUC), the maximum blood concentration (Cmax) and the time to reach Cmax (Tmax) on D-1 and D+13 were not significantly different whatever the specificity of the RIA method. For example, the mean AUC +/- sd values were 5,247 +/- 2,255 (D-1) vs 5,317 +/- 1,675 (D+13) microgram.1(-1).h for the specific and 20,905 +/- 8,317 vs 19,327 +/- 5,758 microgram.1(-1).h for the non-specific determinations. Therefore, the pharmacokinetics of cyclosporin is not influenced by co-administration of isradipine at a therapeutic dosage. Moreover, the clinical results show that isradipine treatment was effective after 13 days administration (mean systolic blood pressure 132 vs 158 mm Hg, P < 0.05 and mean diastolic blood pressure 77 vs 93 mm Hg, P < 0.05 in supine position), and well tolerated throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction.

The pharmacokinetics of cyclosporine was studied in six healthy volunteers after administration of the drug orally (10 mg/kg) and intravenously (3 mg/kg) with and without concomitant rifampin administration. Both blood and plasma (separated at 37 degrees C) samples were analyzed for cyclosporine concentration. For blood and plasma, respectively, clearances of cyclosporine were calculated to be 0.30 and 0.55 L/hr/kg, values for volume of distribution at steady state were 1.31 and 1.68 L/kg, and bioavailabilities were 27% and 33% during the pre-rifampin phase. Post-rifampin phase clearances of cyclosporine were 0.42 and 0.79 L/hr/kg, values for volume of distribution at steady state were 1.36 and 1.35 L/kg, and bioavailabilities were 10% and 9% for blood and plasma, respectively. Rifampin not only induces the hepatic metabolism of cyclosporine but also decreases its bioavailability to a greater extent than would be predicted by the increased metabolism. The decreased bioavailability most probably can be explained by an induction of intestinal cytochrome P450 enzymes, which appears to be markedly greater than the induction of hepatic metabolism.

Optimisation of immunosuppressive therapy using pharmacokinetic principles.

Clinical experience with immunosuppressive therapy is more extensive in the area of preventing the rejection of transplanted organs than in the treatment of autoimmune diseases. Among the many pharmacological agents presently in use, only prednisone (or methylprednisolone) and cyclosporin require dosage individualisation. Sources of interindividual variability in the pharmacokinetics of prednisone have been identified and are guiding the selection of individual dosage rates. As an alternative, a single timed concentration can determine an apparent value for prednisone clearance from which an individual dosage can be calculated. In contrast, numerous sources of inter- and intraindividual variability in cyclosporin pharmacokinetics prevent the easy selection of safe and effective starting dose rates. Indeed, test doses of cyclosporin followed by series of blood samples and the calculation of individual pharmacokinetic parameters are needed to assure successful immunosuppression right from the start. Furthermore, only continued monitoring sustains immunotherapy vis-à-vis intraindividual variability and a narrow therapeutic range of cyclosporin concentrations.

Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability.

The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the immunosuppressive drug cyclosporine were studied in 187 patients with uremia. All patients underwent a pharmacokinetic evaluation including a 3 mg/kg intravenous dose of cyclosporine and a 14 mg/kg oral dose of cyclosporine. Cyclosporine was analyzed by specific monoclonal radioimmunoassay on whole blood samples. Statistical analysis included univariate analyses and stepwise multiple regression analysis. Major findings were as follows: The bioavailability (F) of cyclosporine was significantly lower in black patients than in white patients (mean values of 30.9% +/- 12.3% and 39.5% +/- 16.5%, respectively; p < 0.001). This difference was noted both before transplant and at 1 week after kidney transplantation, at which time the corresponding mean values were 28.6% +/- 15.5% and 36.1% +/- 15.5%, respectively (p < 0.01). Other factors that correlated with F were serum triglyceride (positively) and blood hemoglobin concentrations (inversely). Patients with diabetes displayed a longer mean absorption time than other patients and a larger volume of distribution of cyclosporine at steady state (VSS). Other factors that correlated with VSS were serum albumin concentration and patient height. Cyclosporine clearance (CL) decreased with patient age and also with increasing concentrations of serum triglycerides and blood hemoglobin. It was lower in patients with the pretransplant diagnosis of nephrosclerosis than in patients with other diseases. Several pharmacokinetic parameters correlated with the level of substances that can potentially bind cyclosporine in the blood. Serum triglycerides correlated with maximum concentration, time to maximum concentration, F, and CL. Blood hemoglobin concentration and blood hematocrit correlated with F, CL, and intravenous mean residence time. Although several relationships were observed between demographic factors and cyclosporine pharmacokinetics, the racial difference in F is of great clinical significance and may contribute to the poorer outcome observed after kidney transplantation in black patients.

Pharmacokinetics of cyclosporine in psoriasic patients

Pharmacokinetics of cyclosporine in psoriasic patients

DAILY RENAL HYPOPERFUSION INDUCED BY CYCLOSPORINE IN PATIENTS WITH RENAL TRANSPLANTATION

A variety of side effects are associated with the use of cyclosporine, the most relevant of which remains the renal toxicity. We did parallel studies on cyclosporine pharmacokinetics and renal function in patients who had a recent kidney transplant and were given cyclosporine as a part of their immunosuppressive therapy. Seven consecutive renal transplant patients were studied at the end of a month of treatment while on different oral cyclosporine doses (5, 3.5, 2.5, or 1.5 mg/kg, twice a day, respectively). Cyclosporine pharmacokinetics profiles and renal function parameters (GFR and renal plasma flow [RPF], as inulin and p-amino hippurate clearances, respectively) were determined before and over a 12-hr period after each single dose of cyclosporine. Plasma levels and urinary excretion rate of endothelin were also studied before and after the highest cyclosporine dose (5 mg/kg). Mean trough levels, area under the curve values, and maximum concentration of blood cyclosporine were comparable after 5 and 3.5 mg/kg cyclosporine and decreased in a dose-dependent manner after the lower doses (2.5 and 1.5 mg/kg). In the same patients GFR declined on average 63%, 53%, 35%, and 18%, 2-4 hr after maximum cyclosporine concentration was reached. As blood levels of cyclosporine returned to trough, GFR progressively increased to baseline. Similar results were found for RPF; 5 mg/kg cyclosporine did not modify endothelin plasma levels. By contrast, urinary excretion of the peptide increased significantly (P less than 0.01) in the 6 hr that followed cyclosporine administration and returned within the normal range in the subsequent 6 hr. Following each oral administration of cyclosporine, 2-4 hr after peak blood concentration was reached, patients showed renal hypoperfusion, transient and rapidly reversible. This was associated with an increased urinary endothelin excretion rate that was also transient. It is speculated that an excessive renal synthesis of endothelin is the cause of the daily renal hypoperfusion observed in patients with renal transplants given cyclosporine.

Chronopharmacokinetics of Cyclosporine A in the Wistar rat following oral administration.

The pharmacokinetics of Cyclosporine A (CsA) was studied in male Wistar rats weighting 300 +/- 50 g trained to a 12:12 light-dark cycle. Oral administration (40 mg/kg) was performed at 1 of 4 different temporal stages: 09.00 h, 15.00 h, 21.00 h or 03.00 h (local time) i.e. 0200, 0800, 1400 or 2000 HALO (hours after light on). Blood samples were collected over 72-96 h after dosing, plasma was separated by centrifugation at 37 degrees C and stored frozen until assay, using radioimmunoassay (RIA). Two experiments were performed: the first with 4 groups of 48 rats and a non-specific polyclonal antibody (P-RIA); and the second with only 2 groups of 48 rats and a more specific monoclonal antibody (M-RIA). Plasma concentration data were evaluated with model-based linear pharmacokinetic concepts, with apparent zero-order or first-order absorption and n-exponential disposition (n = 1, 2 or 3): models MN0 or MN1. A compartment-independent approach was also conducted and led to area under the plasma concentration-time curve (AUC) and mean residence time (MRT) determinations. A comparison of the pharmacokinetic profiles across time of administration indicates that absorption, first-pass metabolism and tissue distribution of CsA in the rat are circadian-dosing stage dependent.

Pharmacokinetics of Cyclosporine in Bone Marrow Transplantation: Longitudinal Characterization of Drug in Lipoprotein Fractions

The pharmacokinetics of cyclosporine (CSA; 2 mg/kg given iv over a period of 2h every 12 h) in whole blood, plasma, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) were studied after single (n = 10) and multiple (31 days; n = 6) doses in patients receiving allogeneic bone marrow transplants. Whereas HDL-cholesterol levels decreased significantly, LDL-cholesterol levels increased from day 1 to day 31 of CSA dosing. The mean area under the concentration–time curve and half-life values of CSA in whole blood or total plasma did not differ after single or multiple doses. Greater amounts of CSA were contained in the HDL relative to the LDL fraction over the 24-h period after a single dose; the reverse was found after multiple dosing. Cyclosporine was not detectable in the very LDL fractions. The percentage of total plasma CSA contained in each lipoprotein fraction was independent of the concentration of CSA in total plasma or whole blood. The pharmacokinetics of CSA in the various biologic matrices were not associated with measurements of kidney and liver function. Taken together, the variability of CSA pharmacokinetics previously reported in whole blood or total plasma was also found in lipoprotein fractions. The relative changes in CSA content of lipoproteins may offer an explanation for differences in drug effect with multiple dosing.

Drug interactions with quinolone antibacterials.

The quinolone antibacterials are prone to many interactions with other drugs. Quinolone absorption is markedly reduced with antacids containing aluminium, magnesium and/or calcium and therapeutic failure may result. Other metallic ion-containing drugs, such as sucralfate, iron salts, and zinc salts, can also reduce absorption. Some of the newer quinolones inhibit the cytochrome P450 system, e.g. enoxacin, pefloxacin and ciprofloxacin. The toxicity of drugs that are metabolised by the cytochrome P450 system is enhanced by concomitant use of some quinolones. Ciprofloxacin, enoxacin and pefloxacin can increase theophylline concentrations to toxic values. The pharmacokinetics of warfarin and cyclosporin are unaffected. Ofloxacin, fleroxacin and temafloxacin have a low inhibitory effect on the cytochrome P450 system and a low interaction potential may result. The affinity of quinolones for the gamma-aminobutyric acid (GABA) receptor may induce CNS adverse effects; these effects are enhanced by some nonsteroidal anti-inflammatory drugs (NSAIDs).

Comparison of cyclosporin and FK506 pharmacokinetics in kidney transplant recipient candidates

Comparison of cyclosporin and FK506 pharmacokinetics in kidney transplant recipient candidates

Chronic cyclosporin A therapy in rats.

We investigated the pharmacokinetics of cyclosporin A (CsA) blood levels and drug toxicity in a chronic rat study in which long-term (30 weeks) CsA was administered. Ninety Lewis rats received subcutaneous CsA at 5 mg/kg/day for 12 weeks, at which time CsA injections were stopped in 50 animals. The remaining 40 rats were maintained on 5 mg/kg CsA daily until week 18 and then switched to an alternate day dosing until week 30. All rats were observed daily and weighed weekly. Whole blood CsA levels were determined by a commercially available radioimmunoassay kit. The daily dosing regimen resulted in greatly elevated trough CsA levels (greater than 1,600 micrograms/liter) and substantial chronic systemic toxicity, with weight loss and death in eight animals. Alternate day dosing reduced trough levels (mean 1,311 micrograms/liter) and decreased toxicity. Chronic administration by the subcutaneous route resulted in a considerable depot effect, with constancy of drug levels over a 48 hr dosing interval and a slow decline of drug levels (15 days) upon cessation of treatment. These results underscore the importance of monitoring both body weight and blood CsA levels in rodent studies when CsA is employed. Investigators should be aware of drug accumulation with chronic therapy and the consequent need to modify dosing to prevent toxicity.