James J. Zimmerman

Pharmacokinetics of Sirolimus in Stable Renal Transplant Patients after Multiple Oral Dose Administration

In this 2‐week, ascending dose study, the pharmacokinetic activity of sirolimus was examined in 40 stable renal transplant patients treated with cyclosporine and prednisone. Nine dose levels (range, 0.5–6.5 mg/m2/12 hr) of sirolimus were studied in a parallel design. Mean values for the pharmacokinetic parameters of sirolimus calculated in all dose groups were as follows: time to peak blood concentration, 1.4 ± 1.2 hours; terminal half‐life, 62 ± 16 hours; oral dose clearance, 208 ± 95 mL/h/kg; apparent oral steady‐state volume of distribution, 12 ± 5 L/kg; and blood/plasma ratio, 38 ± 13. The intersubject variabilities in dose clearance, steady‐state volume of distribution, and blood/plasma ratio were 4.5‐fold. Preliminary assessments suggested linear dose proportionality. An excellent correlation existed between area under the concentration—time curve and trough blood concentration at steady state. Sirolimus did not produce any significant changes in area under the concentration—time curve of cyclosporine. Preliminary analysis suggested that values for the pharmacokinetic parameters of sirolimus vary among races (black versus nonblack) but not among genders.

The Effect of a High‐Fat Meal on the Oral Bioavailability of the Immunosuppressant Sirolimus (Rapamycin)

The bioavailability of an oral nonaqueous solution of sirolimus was compared under fasting conditions and after a high‐fat meal in a randomized, two‐way crossover pharmacokinetic study. Healthy volunteers were administered a 15 mg single dose of sirolimus on two occasions, once while fasting and once after consumption of a high‐fat breakfast. Whole blood concentrations of sirolimus were assayed by using a validated method with high‐performance liquid chromatography/tandem mass spectrometric detection. Sirolimus was absorbed more slowly when administered after a high‐fat meal than when administered after fasting, as shown by statistically significant reductions in peak concentration (Cmax) and the ratio of Cmax to the area under the curve (AUC), and lengthening of the time to peak concentration. The oral availability of sirolimus was increased to a modest extent (35%) and in a uniform manner when administered with a high‐fat meal; the geometric mean ratio of the fed/fasting AUC values was 1.35, with a 90% confidence interval of 1.26 to 1.46. Food had no effect on the terminal half‐life of sirolimus (mean values of 67 to 68 hours). The 35% increase in AUC obtained after a high‐fat meal appears small relative to the intersubject and intra‐subject variabilities observed in clinical trials. However, to minimize unnecessary fluctuations in trough whole blood sirolimus concentrations, it is advisable that sirolimus be administered consistently in individual patients, either with or without meals.

Pharmacokinetic interaction between single oral doses of ditiazem and sirolimus in healthy volunteers

The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists.

Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers.

Sirolimus (RAPA) and cyclosporine (CsA) are immunosuppressive compounds that are being used concomitantly in renal transplant patients. Both drugs are dosed orally, have common intestinal and hepatic metabolism and intestinal transport mechanisms, and thus offer potential for pharmacokinetic drug interactions. A single‐dose, open‐label, four‐period, four‐treatment, randomized crossover study was completed in 15 male and 6 female volunteers. Each subject received a 10‐mg oral dose of RAPA alone (Rapamune Oral Solution), a 300‐mg oral dose of CsA alone (3 × 100‐mg Neoral Soft Gelatin Capsules), RAPA and CsA jointly, and CsA followed by RAPA delayed by 4 hours. Blood samples were collected for either 144 hours (RAPA) or 48 hours (CsA) and analyzed by either liquid chromatography/tandem mass spectrometry (RAPA) or radioimmunoassay (CsA). RAPA bioavailability was markedly increased by CsA when given jointly, with Cmax, tmax, and AUC being increased 116%, 92%, and 230%, respectively. However, when RAPA was administered 4 hours after CsA, increases in RAPA Cmax, tmax, and AUC were only 37%, 58%, and 80%, respectively. CsA did not affect t1/2 or mean residence time (MRT) by either mode of combined administration. RAPA did not significantly affect CsA bioavailability after either joint or delayed combined administrations. It was concluded that CsA markedly increases the bioavailability of RAPA, which may be attributed to a large intestinal and hepatic first‐pass effect, rather than altered elimination. RAPA did not affect the bioavailability of CsA.

Pharmacokinetics of Prednisolone During Administration of Sirolimus in Patients with Renal Transplants

The pharmacokinetic interaction of multiple oral doses of sirolimus (rapamycin) and prednisone were evaluated in 40 stable patients with renal transplants receiving concomitant multiple doses of cyclosporine. Nine sirolimus dosage levels from 1 mg/m2/ day to 13 mg/m2/day were studied and compared with placebo. Plasma concentrations of prednisone, prednisolone, and cortisol were measured by high‐performance liquid chromatography and analyzed by noncompartmental methods. Mean pharmacokinetic values of prednisolone found before sirolimus administration were as follows: peak plasma concentration (Cmax) was 187 ng/mL; time to peak plasma concentration (tmax) was 2.03 hours; rate of reaching peak plasma concentration (Cmax divided by the area under the concentration‐time curve [AUC]) was 0.149 hour−1; terminal half‐life (t1/2) was 3.60 hours; AUC was 1206 ng · hour/mL; and apparent clearance (Cl/F) was 0.094 L/hour/kg. During the 2 weeks of concomitant administration, prednisolone elimination decreased in relation to sirolimus dosages. These changes were modest, with mean increases of 18% in Cmax and 27% in t1/2 and mean decreases of 27% in Cl/F for the groups receiving 6 mg/m2/day to 13 mg/m2/day. Most patients initially had plasma cortisol concentrations indicative of adrenal suppression. With sirolimus treatment, the Cmax of cortisol did not decrease further, but the AUC (8:00 am‐8.00 pm) values were significantly lower, independent of sirolimus exposure. The AUC for cyclosporine did not correlate with sirolimus and prednisolone exposure. A 2‐week course of sirolimus showed a slight pharmacokinetic interaction between sirolimus and prednisolone/prednisone/cortisol in stable patients with renal transplants.

Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Mild to Moderate Hepatic Impairment

Eighteen adult subjects with mild to moderate hepatic impairment and 18 healthy control subjects were given a single 15‐mg dose of sirolimus by oral solution. Mean whole‐blood sirolimus weight‐normalized oral‐dose clearances (CL/F) were significantly decreased (P = .02) in subjects with mild to moderate hepatic impairment by −31.8% and −36.0%, respectively, compared with controls. There were no significant differences in mean sirolimus Cmax and tmax values among groups. The observed decreases in CL/F may be relevant in renal transplant patients with mild to moderate hepatic impairment, based on the close similarity of sirolimus CL/F in controls and previously studied stable renal transplant patients receiving multiple‐dose administration of sirolimus and cyclosporine. There was considerable overlap in the CL/F values of hepatic‐impaired subjects and controls, suggesting that whole‐blood sirolimus trough concentrations in renal transplant patients exhibiting mild to moderate hepatic impairment be initially monitored to assess the need for dose adjustments.

Population Pharmacokinetics of Intravenous Amiodarone and Comparison with Two‐Stage Pharmacokinetic Analysis

The disposition of amiodarone, an antiarrhythmic agent was evaluated after a single intravenous infusion (5 mg/kg over 15 minutes) in patients of various ages and with various degrees of renal function and left ventricular function. The plasma concentration—time data were obtained from three clinical studies with similar protocols. The data were analyzed by nonlinear mixed‐effects modeling (NONMEM) to estimate the population pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters. The pharmacokinetic parameters of amiodarone (weight‐corrected) also were calculated using two‐stage analysis and were compared with the results obtained from the mixed‐effects analysis. The population plasma concentration—time profile of amiodarone was best described by a four‐compartment model. Demographic covariates (i.e., creatinine clearance and ejection fraction) did not improve the final pharmacostatistical model significantly. The results from the two‐stage analysis showed no significant relationship between amiodarone pharmacokinetic parameters and age, gender, renal function, or ejection fraction. The results from one study, however, demonstrated that advanced age (≥65 years) resulted in reduced amiodarone clearance coupled with a prolonged elimination half‐life. No such correlation was detected with NONMEM analysis, which may be partly attributable to the small number of elderly patients. Overall, the results from NONMEM analysis validated the results obtained from the two‐stage analysis.

A comparative study of sirolimus tablet versus oral solution for prophylaxis of acute renal allograft rejection.

This multicenter, open‐label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24‐hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy‐confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady‐state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus tmax after tablet administration. Multivariate logistic regression analysis indicated that low sirolimus Cmin, TN and more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.

Evaluation of a Potential Tigecycline‐Warfarin Drug Interaction

Study Objective. To evaluate the potential for a clinically significant drug interaction between tigecycline and warfarin by using pharmacokinetic and anticoagulant assessments.

Absence of an interaction between tigecycline and digoxin in healthy men.

Study Objective. To evaluate a potential interaction between tigecycline and digoxin using pharmacokinetic and pharmacodynamic assessments.