Concurrent administration of sirolimus and voriconazole: a pilot study assessing safety and approaches to appropriate management

STUDY OBJECTIVES: To assess the use and safety of concurrent administration of voriconazole and sirolimus-which is contraindicated-and to determine approaches for appropriately managing patients who receive both drugs. DESIGN: Retrospective medical record review. SETTING: University-affiliated medical center. PATIENTS: Thirty-one cases in 23 inpatients who received at least one dose of voriconazole and sirolimus concomitantly within a 24-hour period. MEASUREMENTS AND MAIN RESULTS: Data on sirolimus and voriconazole indications, doses, routes, frequencies, and administration times; number of days of coadministration; and sirolimus dosage adjustments were collected. In addition, data on laboratory values, adverse events, sirolimus concentrations, and concomitant drugs, including cytochrome P450 (CYP) 3A isoenzyme and P-glycoprotein inhibitors and inducers, were collected for 7 days before, during, and for 14 days after coadministration. No cases of elevated sirolimus concentrations (>20 mg/ml) occurred in patients stabilized with voriconazole before starting low-dose sirolimus 0.5-1 mg/day, or in those stabilized with sirolimus 0.5-2 mg/day who had baseline sirolimus concentrations of 12 ng/ml or lower and whose sirolimus dose was decreased by 50% before the addition of voriconazole. In contrast, elevated sirolimus concentrations were experienced in patients receiving sirolimus doses of 4 mg/day or higher who had sirolimus concentrations of 12 ng/ml or higher and whose sirolimus dose was not decreased before addition of voriconazole. In a patient who received sirolimus with itraconazole, a strong CYP3A isoenzyme inhibitor, one case of only a minimal increase in the sirolimus concentration occurred after the addition of voriconazole. CONCLUSIONS: Sirolimus and voriconazole can be safely coadministered as long as consideration is given to which agent the patient receives first, the sirolimus dosage, sirolimus concentrations, and concurrent disease states and CYP3A isoenzyme inhibitors. Sirolimus concentrations should be closely and routinely monitored before, during, and after coadministration of voriconazole and other CYP3A isoenzyme inhibitors. Based on the results of this pilot study, a protocol on the management of this drug combination will be implemented and prospectively evaluated for efficacy and safety.     

Possible interaction between intravenous azithromycin and oral cyclosporine.

A 42-year-old man who had received a cadaveric kidney transplant 9 years earlier was admitted to the hospital with pneumonia. His oral cyclosporine dosage for the past 2 years was stabilized at 100 mg twice/day; his cyclosporine whole blood trough levels 15 days earlier and on the day he was admitted were both 178 ng/ml. The patient was treated with intravenous ceftriaxone and intravenous azithromycin and continued to receive the same dosage of oral cyclosporine. On hospital day 3, his cyclosporine trough level rose to 400 ng/ml and his dosage was reduced by 50%. Trough levels were 181 ng/ml and 175 ng/ml on hospital days 6 and 9, respectively On hospital day 9, the patient stopped receiving azithromycin. On hospital day 14, his cyclosporine trough level dropped to 76 ng/ml, and his cyclosporine dosage was increased back to 100 mg twice/day. The dosage produced trough levels consistent with those before he had been admitted. The patient was discharged on day 20, and a follow-up cyclosporine trough level determined 3 weeks later was 175 ng/ml. Administration of azithromycin may have caused the increased cyclosporine concentrations in this patient through p-glycoprotein inhibition and/or competition for biliary excretion. Azithromycin's interference may be inferred by the increase in cyclosporine levels after administration of this drug and the decrease in cyclosporine levels after its discontinuation-both consistent with the pharmacokinetic properties of cyclosporine. Ceftriaxone and acute-phase reactant activation during infection, however, also may have interfered with the patient's cyclosporine elimination. Azithromycin generally is considered unlikely to interact with cyclosporine. Nonetheless, practitioners should be aware of this possibility and should monitor cyclosporine levels closely, especially in critically ill patients who have other complications.     

Effects of calcineurin inhibitors on sirolimus pharmacokinetics during staggered administration in renal transplant recipients

STUDY OBJECTIVE: To compare the effects of different calcineurin inhibitors on sirolimus pharmacokinetics during long-term, staggered administration in kidney transplant recipients. Design. Randomized, open-label, parallel-group trial. SETTING: A medical center and one of its teaching hospitals in Taiwan. PATIENTS: Twenty-two de novo kidney transplant recipients. INTERVENTION: Patients received cyclosporine microemulsion or tacrolimus capsules twice/day in combination with once-daily sirolimus solution and corticosteroids. Sirolimus was administered 6 hours after the morning dose of cyclosporine or tacrolimus. After receiving a 6-mg loading dose of sirolimus, participants received sirolimus 2 mg/day for at least 7 days. Neither the cyclosporine nor the tacrolimus dosage was adjusted for at least 3 days before and during blood sampling for pharmacokinetic profiling. MEASUREMENTS AND MAIN RESULTS: One patient dropped out because of trimethoprim-sulfamethoxazole-related hepatotoxicity. We observed no differences between the two patient groups in terms of their demographic data, renal and liver function, or dosage of sirolimus during the study. During multiple-dose administration, the area under the whole-blood concentration-time curve and the peak and trough concentrations of sirolimus in the cyclosporine group were, respectively, 1.46 (95% confidence interval [CI] 1.21-1.71), 1.42 (95% CI 1.08-1.76), and 1.42 (95% CI 1.09-1.76) times higher than those of the tacrolimus group, even though sirolimus was administered 6 hours after the other agents. CONCLUSION: Sirolimus pharmacokinetics may change significantly when calcineurin inhibitors are switched, even with staggered administration, which may not completely prevent a drug interaction between cyclosporine and sirolimus solution.     

Sirolimus: the evidence for clinical pharmacokinetic monitoring

This review seeks to apply a decision-making algorithm to establish whether clinical pharmacokinetic monitoring (CPM) of sirolimus (rapamycin) in solid organ transplantation is indicated in specific patient populations. The need for CPM of sirolimus, although a regulatory requirement in Europe, has not yet been firmly established in North America and other parts of the world.Sirolimus has demonstrated immunosuppressive efficacy in renal, pancreatic islet cell, liver and heart transplant recipients. The pharmacological response of immunosuppressive therapy with sirolimus cannot be readily evaluated; however, a relationship between trough blood sirolimus concentrations, area under the plasma concentration-time curve (AUC) and the incidence of rejection has been proposed. Furthermore, sirolimus can be measured in whole blood by several assays--high-performance liquid chromatography with detection by tandem mass spectrometry, or with ultraviolet detection, radioreceptor assay or microparticle enzyme immunoassay.Both experimental animal and clinical data suggest that adverse events and their associated severity are correlated with blood concentrations. To prevent rejection and minimise toxicity, a therapeutic range of 4-12 microg/L (measured via chromatographic assays) is recommended when sirolimus is used in conjunction with ciclosporin. If ciclosporin therapy is discontinued, a target trough range of 12-20 microg/L is recommended. Sirolimus pharmacokinetics display large inter- and intrapatient variability, which may change in specific patient populations due to disease states or concurrent immunosuppressants or other interacting drugs. Due to the long half-life of sirolimus, dosage adjustments would ideally be based on trough levels obtained more than 5-7 days after initiation of therapy or dosage change. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. After the first 2 months of dose titration, routine CPM of sirolimus is not necessary in all patients, but may be warranted to achieve target concentrations in certain populations of patients, but the frequency of further monitoring remains to be determined and should be individualised.     

Clinical pharmacokinetics of sirolimus

Sirolimus (previously known as rapamycin), a macrocyclic lactone, is a potent immunosuppressive agent. Sirolimus was recently approved by the US Food and Drug Administration, on the basis of 2 large, double-blind, prospective clinical trials, for use in kidney transplant recipients at a fixed dosage of 2 or 5 mg/day in addition to full dosages of cyclosporin and prednisone. However, despite the fixed dosage regimens used in these pivotal trials, pharmacokinetic and clinical data show that sirolimus is a critical-dose drug requiring therapeutic drug monitoring to minimise drug-related toxicities and maximise efficacy. Assays using high performance liquid chromatography coupled to mass spectrometry, although cumbersome, are the gold standard for evaluating other commonly used assays, such as liquid chromatography with ultraviolet detection, radioreceptor assay and microparticle enzyme immunoassay. Sirolimus is available in oral solution and tablet form. It has poor oral absorption and distributes widely in tissues, displaying not only a wide inter- and intrapatient variability in drug clearance, but also less than optimal correlations between whole blood concentrations and drug dose, demographic features or patient characteristics. Furthermore, the critical role of the cytochrome P450 3A4 system for sirolimus biotransformation leads to extensive drug-drug interactions, among which are increases in cyclosporin concentrations. Thus, sirolimus is now being used to reduce or eliminate exposure to cyclosporin or corticosteroids. The long elimination half-life of sirolimus necessitates a loading dose but allows once daily administration, which is more convenient and thereby could help to improve patient compliance. This review emphasises the importance of blood concentration monitoring in optimising the use of sirolimus. The excellent correlation between steady-state trough concentration (at least 4 days after inception of, or change in, therapy) and area under the concentration-time curve makes the former a simple and reliable index for monitoring sirolimus exposure. Target trough concentration ranges depend on the concomitant immunosuppressive regimen, but a range of 5 to 15 microg/L is appropriate if cyclosporin is being used at trough concentrations of 75 to 150 microg/L. Weekly monitoring is recommended for the first month and bi-weekly for the next month; thereafter,concentration measurements are necessary only if warranted clinically.     

Reccurence of Kaposi's sarcoma after increased exposure to sirolimus

The conversion to sirolimus treatment is recently indicated as an effective therapy of Kaposi's sarcoma (KS) in transplant patients. We present two treatment modalities in patients with KS and recurrence of the disease after increasing sirolimus dose. Among 1034 renal transplants performed at our center, three (0.3%) suffered from KS. Initial immunosuppression consisted of cyclosporine, azathioprine and prednisone in one patient; and tacrolimus, mycophenolate mofetil and prednisone in two patients. KS symptoms appeared within one year post-transplantation. Two patients developed cutaneous tumor; one disseminated disease, including the skin, mediastinal lymph nodes and both lungs. After histological confirmation of KS immunosuppression was minimized: Two were converted to sirolimus (1-2 mg/day, level 5-8 ng/ml) treatment; the third patient discontinued tacrolimus and was administered 1 g/day mycophenolate mofetil. Gradual regression of KS was observed in all the patients. In one patient, 8 months after regression of lung KS, the dose of sirolimus was increased to 2 mg/day (level raised to 13.8 ng/ml). Recurrent disease developed afterwards involving diffuse interstitial infiltrates with nodular changes in both lungs. For the second time the dose of sirolimus was reduced to 1 mg/day (level 4-5 ng/ml) and lung lesions regressed 5 months later. Renal function was stable (creatinine 1.3-1.9 mg/dl) in all patients, 24 months from KS onset. In conclusion: treatment by low sirolimus or mycophenolate mofetil doses caused regression of KS. Recurrence of KS after increasing sirolimus dose suggests that regression of KS is a result of diminished immunosuppression, not the direct antineoplastic effect of sirolimus. Careful maintenance of low sirolimus levels is suggested.     

Sirolimus steady-state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients

AIMS: To determine whether bolus doses of methylprednisolone affect the steady-state trough concentrations of sirolimus. METHODS: Fourteen renal transplant recipients received concentration-controlled sirolimus therapy in combination with azathioprine and steroids (n=8) or mycophenolate mofetil and steroids (n=6). Bolus doses of methylprednisolone (mean total dose over 1-5 days, 1694 mg; range, 500-3000 mg) were given for the treatment of acute rejection. For each patient, the sirolimus dose (mean, 24.1 mg; range, 3.3-52.5 mg) was the same before and during methylprednisolone therapy. RESULTS: Mean sirolimus whole blood trough concentrations before and after treatment with methylprednisolone were 28.8 ng ml-1 (range, 13.9-45.3 ng ml-1), and 28.5 ng ml-1 (range, 13.0-47.9 ng ml-1), respectively (P=0.85; 95% confidence interval on the difference -3.3, 4.0 ng ml-1). CONCLUSIONS: Bolus methylprednisolone treatment does not affect steady-state sirolimus trough concentrations.     

Pharmacokinetics of intravenous itraconazole followed by itraconazole oral solution in patients with human immunodeficiency virus infection.

This randomized, open-label, comparative study assessed the pharmacokinetics and safety of intravenous and oral hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions of itraconazole in patients with advanced human immunodeficiency virus (HIV) infection. All patients received 1-hour intravenous infusions of itraconazole 200 mg twice dailyfor 2 days, then once dailyfor 5 days. Patients were then randomized to receive itraconazole oral solution, 200 mg twice daily or 200 mg once daily, for a further 28 days. Itraconazole was solubilized by HP-beta-CD in both intravenous and oral solutions, so HP-beta-CD concentration in plasma was measured. Thirty-two patients were enrolled and analyzed (n = 32 for intravenous treatment, 32 completed; n = 16 for oral once daily, 15 completed; n = 16 for oral twice daily, 12 completed). Steady-state plasma concentrations of itraconazole and hydroxyitraconazole were reached by days 3 and 6, respectively. After intravenous dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were 906 ng/ml and 1,690 ng/ml, respectively. During oral dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were maintained or increased in the 200 mg twice-dailygroup but fell with the 200 mg once-daily oral dose. Itraconazole was generally well tolerated and had a favorable safetyprofile; minor changes in hematology variables were noted during the intravenous phase, and HP-beta-CD was cleared rapidly, mostly in urine. Twenty-eight patients (88%) experienced at least one adverse event; no adverse event was severe, and only seven were definitely related to itraconazole. In conclusion, itraconazole 200 mg given intravenously twice daily for 2 days, then once daily for 5 days, rapidly achieves amean steady-state trough concentration of itraconazole of over 250 ng/ml, which is associated with clinic outcome and is effectively maintained with itraconazole oral solution 200 mg twice daily in patients with advanced HIV infection.     

Center experience in liver transplantation (LTX): management of dermal side effects caused by sirolimus

INTRODUCTION: Sirolimus improves post transplant maintenance therapy in LTX. Dermal side effects causing pain and discomfort can limit patients' compliance. The package insert mentions such skin disorders as acne and rash. One case of sirolimus-induced leucocytoclastic vasculitis is reported in the literature. METHODS: From July 1998 to October 2003, Sirolimus was implemented in the immunosuppressive protocol in 23 out of 60 liver recipients. Sirolimus target levels are between 3 and <10 ng/dl. Combination with a calcineurinblocker and/or MMF (mycophenolate mofetil) depending on liver function and creatinine is standard. Weekly patient monitoring in the first month after discharge included physical examination, blood samples and immunosuppresant trough levels. Biopsies were taken from untypical efflorescences. RESULTS: Three patients with non-specific effloresces were reported: one with leucocytoclastic vasculitis and one with exfoliate forearm dermatitis required change of medication while one perivascular lymphocytic eosinophilic dermatitis subsided after dose reduction. In three cases of mouth ulcer, trough levels exceeded 10 ng/dl and in six patients acne diminished after dose reduction. Eighteen out of 23 patients are still receiving sirolimus. Reasons for removal from the study were incompliance and incompatibility. Two patients died. DISCUSSION: Immunosuppressants inevitably produce side effects in TX recipients. The positive management of troublesome side effects contributes importantly to compliance and patient survival.     

Alinidine pharmacokinetics following acute and chronic dosing.

1 Alinidine (N-allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax -- 166.5 +/- 18.5 ng/ml at 1.8 +/- 0.7 h (mean +/- s.d., n = 5); AUC -- 1122.9 ng ml-1 h; VdSS -- 190.71 and T1/2 -- 4.2 h, and after i.v. administration: AUC -- 1046.7 ng ml-1 h; VdSS -- 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/- 0.06 ng/ml at 8.4 +/- 2.2 h and 0.5 +/- 0.2 ng/ml at 4.8 +/- 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/- 123.9 and 9.03 +/- 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/- 92.0 and 80.0 +/- 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/- 0.18 and 0.84 +/- 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2-8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine.     

Trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant recipients

AIMS: The influence of the trimethoprim-sulphamethoxazole combination on the steady-state pharmacokinetics of sirolimus, a potent macrocyclic immunosuppressant, was studied in renal transplant recipients. METHODS: Fifteen kidney transplant recipients were treated with sirolimus 8-23 mg m(-2) in combination with azathioprine and prednisolone from the day of transplantation. Whole blood sirolimus AUC and C(max) were determined on days 6 and 7 after transplantation. On day 7, sirolimus was coadministered with the first dose of trimethoprim (80 mg) and sulphamethoxazole (400 mg). RESULTS: On day 6, the mean (95% confidence interval) whole blood sirolimus AUC((0-24 h)) was 1040 (846, 1234) ng ml(-1) and mean C(max) was 109 (88, 129) ng ml(-1). Corresponding values on day 7 were AUC((0-24 h)) 1060 (826, 1293) ng ml(-1) and C(max) mean 107 (87, 127) ng ml(-1). The mean difference in the dose-corrected AUC((0-24 h)) was 0.40% (-9.4, +10). CONCLUSIONS: A single dose of trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant patients.     

Diltiazem increases steady state digoxin serum levels in patients with cardiac disease

Diltiazem has been reported to decrease or not to affect digoxin elimination. The effects of diltiazem on steady state concentrations of digoxin was evaluated in eleven patients with congestive heart failure receiving this drug for at least two weeks. The mean trough digoxin was 1.11 +/- 0.18 ng/ml before the coadministration of diltiazem (180 mg/day). This concentration increased to 1.54 +/- 0.22 ng/ml after three days and to 1.54 +/- 0.23 ng/ml after seven days of coadministration (P less than 0.01). Clinically, no patient showed signs of digitalis toxicity. Creatinine clearance was unchanged. The present results show that when diltiazem is added to a regimen that includes digoxin, steady state concentrations of this glycoside may increase.     

Clinical pharmacokinetics of tacrolimus in heart transplant recipients

We report pharmacokinetic data on tacrolimus in 14 heart transplant patients (2 women, 12 men). The median age and the median body weight were 55.5 years (range, 23-61 years) and 67.0 kg (55-79 kg), respectively. All patients were maintained on a triple-drug protocol (tacrolimus, azathioprine, and prednisone), with a 7-day antithymocyte globuline induction. The first tacrolimus dose, administered orally 1 to 5 days posttransplant, ranged from 0.03 to 0.4 mg/kg (median = 0.052 mg/kg). The maintenance dose ranged from 0.03 to 0.13 mg/kg/day (administered in two equal doses) to achieve blood levels of 5 of 20 ng/ml, as determined by a microparticle enzyme immunoassay (MEIA). Whole blood samples were drawn just before, at 0.5 hour, and at 1, 2, 3, 4, 6, 8, 10, and 12 hours after the administration of the first dose; trough levels were measured thereafter.The mean oral clearance (CL/F) and apparent volume of distribution (Vd/F) averaged 0.21+/-0.08 L/hour/kg and 2.4+/-0.8 L/kg while the half-life averaged 8.7+/-3.5 hours. Tacrolimus accumulation index during chronic therapy (Rac = Cmin(steady state)/Cmin(first dose) normalized to the same dose) averaged 1.3. Eighty-eight percent of the trough blood levels measured in our patients were within 5 and 20 ng/ml. The incidence of rejection in the study population was extremely low: a prevalence of grade 2 rejection or more, of 0.4+/-0.8 episodes/ patient was observed after a follow-up period of 8.8+/-2.2 months. Only one patient experienced severe renal toxicity, probably because of his preoperative precarious hemodynamic status. Pharmacokinetic data suggest that maintenance tacrolimus daily dose should be equal to 0.1 mg/kg/day to obtain trough blood concentrations of approximately 10 ng/ml. Inter- and intra-patient variability of tacrolimus blood concentration should be expected and justify careful monitoring.     

Sudden hearing loss associated with tacrolimus in a kidney-pancreas allograft recipient.

A 38-year-old woman with type 1 diabetes underwent kidney-pancreas transplantation. Her postoperative course was complicated due to recurrent acute graft rejections and pancreatitis. After initial immunosuppression with microemulsion cyclosporine, mycophenolate mofetil, and prednisone with muromonab-CD3 induction, cyclosporine was switched to tacrolimus on day 44. The initial dosage was 5 mg twice/day, but it was gradually increased to 10 mg twice/day, aiming at 15-20 ng/ml. On day 17 of tacrolimus therapy the woman developed sudden hearing loss with tinnitus. The serum tacrolimus level was 28.3 ng/ml (therapeutic range 10-20 ng/ml) on day 20 of tacrolimus therapy, and peaked at 34.9 ng/ml on day 28. Two audiograms performed on days 28 and 29 confirmed bilateral hearing loss of 80% for speech perception, characterized as mild to moderate sensorineural hearing loss with speech reception threshold of 35 dB (normal < 20 dB) in both ears. The tacrolimus dosage was gradually reduced to 6 mg twice/day by day 36, with drug level 9.7 ng/ml, after which her hearing gradually recovered.     

Sirolimus/cyclosporine/tacrolimus interactions on bile flow and biliary excretion of immunosuppressants in a subchronic bile fistula rat model

The new immunosuppressive agent sirolimus generally is combined in transplant patients with cyclosporine and tacrolimus which both exhibit cholestatic effects. Nothing is known about possible cholestatic effects of these combinations which might be important for biliary excretion of endogenous compounds as well as of immunosuppressants. Rats were daily treated with sirolimus (1 mg kg(-1) p.o.), cyclosporine (10 mg kg(-1) i.p.), tacrolimus (1 mg kg(-1) i.p.), or a combination of sirolimus with cyclosporine or tacrolimus. After 14 days a bile fistula was installed to investigate the effects of the immunosuppressants and their combinations on bile flow and on biliary excretion of bile salts, cholesterol, and immunosuppressants. Cyclosporine as well as tacrolimus reduced bile flow (-22%; -18%), biliary excretion of bile salts (-15%;-36%) and cholesterol (-15%; -47%). Sirolimus decreased bile flow by 10%, but had no effect on cholesterol or bile salt excretion. Combination of sirolimus/cyclosporine decreased bile flow and biliary bile salt excretion to the same extent as cyclosporine alone, but led to a 2 fold increase of biliary cholesterol excretion. Combination of sirolimus/tacrolimus reduced bile flow only by 7.5% and did not change biliary bile salt and cholesterol excretion. Sirolimus enhanced blood concentrations of cyclosporine (+40%) and tacrolimus (+57%). Sirolimus blood concentration was increased by cyclosporine (+400%), but was not affected by tacrolimus. We conclude that a combination of sirolimus/tacrolimus could be the better alternative to the cotreatment of sirolimus/cyclosporine in cholestatic patients and in those facing difficulties in reaching therapeutic ranges of sirolimus blood concentration.     

An assessment of the contribution of clonidine metabolised from alinidine to the cardiovascular effects of alinidine.

Five healthy volunteers (mean age 20.6 years, mean weight 71 kg) received in random order on day 1 and day 8 a single dose of alinidine 40 mg, clonidine 0.1 mg or placebo and on days 2-7 alinidine 40 mg, clonidine 0.1 mg or placebo given three times a day with 1 week between treatment periods. Blood samples were taken for measurement of concentrations of alinidine and clonidine during alinidine administration and of clonidine during clonidine dosing. Heart rate and blood pressure were recorded in supine and standing positions and heart rate after 3 min exercise. Plasma concentrations of alinidine reached a maximum of 163.6 +/- 10.0 ng/ml 2 h after alinidine administration on day 1 and during chronic administration similar concentrations were achieved. Clonidine plasma concentrations reached 0.3 +/- 0.11 ng/ml 6 h after alinidine 40 mg on day 1, and during chronic administration of alinidine, increased to a steady state on day 5 with trough and 2 h values of 0.73 +/- 0.15 and 0.86 +/- 0.14 ng/ml respectively. After the first dose of clonidine on day 1, the maximum plasma concentration of clonidine was 0.32 +/- 0.1 ng/ml at 4 h, during chronic administration clonidine plasma concentration rose to 1.04 +/- 0.14 ng/ml 2 h after a dose on day 5. Alinidine produced a greater reduction in the exercise tachycardia than clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacology of continuous infusion doxorubicin

Fifteen patients were studied during short-term (5 days at 10-15 mg/m2/day) or long-term (5-104 days at 3 mg/m2/day) doxorubicin infusion. Levels of doxorubicin and metabolites in serum and 24-h timed urine collections were determined by high-performance liquid chromatography. Quantifiable anthracycline levels were identified in serum of 5 of 6 patients (6 courses) receiving drug at 10 mg/m2/day. In 5 courses, total anthracycline levels were 10-80 ng/ml, whereas levels as high as 370 ng/ml were observed in a patient with hepatorenal failure. No detectable serum levels of anthracycline were seen in patients receiving long-term doxorubicin therapy. Although analysis of 24-h timed urine collections revealed that doxorubicin was the predominant anthracycline, the extent of urinary elimination showed considerable interpatient variation (1.0-52.5% of the infused dose/24-h period on the short-term protocol and 5.3-57.2%/24-h period on the long-term protocol). Metabolic processing of doxorubicin administered by continuous infusion was found to be similar to that of drug given by bolus administration and showed no change in pattern with time. However, a greater variability in serum and urinary anthracycline levels was seen among patients on infusion schedules than has been noted with bolus drug treatment.     

Cimetidine increases steady state plasma levels of propranolol.

1 The influence of cimetidine (1000 mg daily) on propranolol steady state plasma levels has been studied in seven normal volunteers. Cimetidine was used as a 200 mg normal release tablet whereas propranolol was given as a 160 mg slow release formulation once daily. 2 After 1 day of cimetidine treatment (day 9 of the study) the mean (Css) and minimal (Css min) propranolol steady state plasma levels increased significantly from 24.1 +/- 14.9 ng/ml (mean +/- s.d.) to 39.2 +/- 27.7 ng/ml (P = 0.01) and from 14.8 +/- 9.3 ng/ml to 27.1 +/- 21.2 ng/ml (P = 0.03), respectively. The apparent oral clearance (Clo) was reduced from 6.7 +/- 4.3 l/min to 4.6 +/- 3.11/min (P = 0.006). 3 A prolongation of cimetidine administration to 5 days (day 13 of the study) intensified this effect significantly (P = 0.02): Css of propranolol was elevated from 23.2 +/- 14.4 ng/ml to 44.9 +/- 26.7 ng/ml (P = 0.003); Css min was increased from 14.1 +/- 10.2 ng/ml to 28.4 +/- 17.9 ng/ml (P = 0.02) while Clo decreased from 6.9 +/- 4.1 1/min to 3.3 +/- 1.61/min (P = 0.006). 4 We conclude that the drug interaction between propranolol and cimetidine leads to significant elevations of propranolol steady state plasma concentrations which may cause a clinically relevant enhancement of the effect of a given dosage. This requires careful observation of patients under concomitant treatment with propranolol and cimetidine.     

Long-term pharmacokinetics of doxorubicin HCl stealth liposomes in patients after polychemotherapy with vinorelbine, cyclophosphamide and prednisone (CCVP).

The concentration-time profiles of Doxorubicin (DOXO) from day 0 to day 21 after i.v. infusion of 25 or 30 mg/m2 doxorubicin HCI stealth liposomes (Caelyx) were investigated in 9 patients receiving combination polychemotherapy with cyclophosphamide, vinorelbine and prednisone. Peak serum concentrations occurred from 0.04 to 4.0 days after infusion (mean tmax = 1.79 +/- 1.55 d) with a mean cmax of 4,595 +/- 2,849 ng/ml. A total amount of 12.84 +/- 2.47 mg liposomal DOXO in the plasma volume (Vp = 2,794 + 537 ml) could be estimated at tmax (= 27 % of the mean dose of 47.6 mg). Stealth liposomes were eliminated slowly from the blood with a mean t 1/2el of 1.9 + 0.5 days (MRT was 4.6 + 2.5 days). AUClast values ranged from 8,070 to 33,446 ng/ml*d (mean 10,987 +/- 9,339 ng/ml*d). The low plasma clearance (Cltot = 4,681 +/- 2,835 ml/day) and the small volume of distribution (Vz = 11.7 +/- 6.31) suggested that stealth-liposomes were stable in the blood at least for 14 days. Polychemotherapy with Hyper-CCVP schedule did not alter the stability of stealth liposomes, but peak levels of DOXO seemed to be somewhat lower compared to regression analysis of literature data (cmax versus dosage range from 20 to 60 mg/m2). Due to clast occurring between day 12 to 18, no indices for an accumulation of the drug in the blood could be found, when liposomes were given every four weeks.     

Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers.

A possible interaction of itraconazole, a potent inhibitor of CYP3A4, with intravenously administered methylprednisolone, was examined. In this double-blind, randomized, two-phase cross-over study, 9 healthy volunteers received either 200 mg itraconazole or matched placebo orally once a day for 4 days. On day 4, a dose of 16 mg methylprednisolone as sodium succinate was administered intravenously. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined up to 24 hr. Itraconazole increased the total area under the plasma methylprednisolone concentration-time curve (AUC(0-infinity) 2.6-fold) (P<0.001), while the AUC (12-24) of methylprednisolone was increased 12.2-fold (P<0.001). The systemic clearance of methylprednisolone during the itraconazole phase was 40% of that during the placebo phase (P<0.01). The volume of distribution of methylprednisolone was not affected by itraconazole. The mean elimination half-life of methylprednisolone was increased from 2.1+/-0.3 hr to 4.8+/-0.8 hr (P<0.001) by itraconazole. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hr after the administration of methylprednisolone, was only about 9% of that during the placebo phase (11.0+/-9.0 ng/ml versus 117+/-49.2 ng/ml; P<0.001). In conclusion, itraconazole decreases the clearance and increases the elimination half-life of intravenously administered methylprednisolone, resulting in greatly increased exposure to methylprednisolone during the night time and in enhanced adrenal suppression. Care should be taken when itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with methylprednisolone.