PubMed Health⌕ Search

Biomedical subjects

John M Kovarik

Publications and source records attributed to John M Kovarik.

At least 19 recordsLinked to original sources
PubMed2007

Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects.

OBJECTIVE: The pharmacokinetics and lymphocyte responses to the immunomodulator fingolimod (FTY720) were characterized after oral and intravenous administration. METHODS: In this randomized, two-period crossover study 11 evaluable healthy subjects received single doses of fingolimod 1.25 mg orally and 1 mg intravenously infused over 2 h. The pharmacokinetics of fingolimod, blood lymphocyte counts and heart rate were characterized for 28 days after each dose. RESULTS: After oral administration, Cmax was 1.1+/-0.2 ng/ml occurring at 12 h postdose and the AUC was 201+/-31 ng.h/ml. After intravenous infusion, Cmax was 4.9+/-0.8 ng/ml, AUC was 175+/-50 ng. h/ml, clearance was 6.3+/-2.3 l/h and distribution volume was 1199+/-260 l. The oral/intravenous ratio of dose-normalized AUCs was 0.94 (95%CI: 0.78-1.12). The pharmacologically active metabolite fingolimod-phosphate was quantifiable near its peak after oral administration but not after intravenous administration. The mean lymphocyte nadir occurred on day 1 and was 35% lower after oral (0.74x10(9)/l) than after intravenous (1.15x10(9)/l) administration. Lymphocytes recovered to the normal range by day 15 for both treatments. The mean heart rate nadir occurred 3-4 h postdose and was 11% lower after oral administration (47 bpm) versus intravenous administration (53 bpm). CONCLUSIONS: Average systemic exposure to fingolimod was similar after oral and intravenous administration. However, the acute decrease in lymphocyte counts was weaker after intravenous administration, likely because of lower blood levels of the active metabolite fingolimod-phosphate compared with oral administration.

Administration, Oral↗
PubMed2006

Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus.

OBJECTIVE: Both sirolimus and cyclosporine are immunosuppressants used in a combined regimen after organ transplantation. When coadministered with the innovator formulation of cyclosporine, sirolimus blood levels increase 3.3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine. METHODS: In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing. RESULTS: Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77-0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83-0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%. CONCLUSIONS: Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.

Adult↗
PubMed2006

Everolimus drug interactions: application of a classification system for clinical decision making.

INTRODUCTION: More than half of all drugs used in medical practice are metabolized by cytochrome CYP3A. Coadministration of drugs that share this elimination pathway may lead to pharmacokinetic drug interactions. Efforts are underway by clinical, drug development and regulatory scientists to classify CYP3A-related drug interactions with the ultimate goal of improving guidance for clinical intervention. The CYP3A inhibitory classification system ranks inhibitors according to the fold-increase in area-under-the-curve (AUC) of a probe substrate as: strong (> or =5-fold), moderate (>2.0- to 4.9-fold), or weak (< or =2.0-fold). This classification system was applied to characterize everolimus as a CYP3A substrate.Methods. Five open-label crossover drug interaction studies were performed in 12-16 healthy subjects each. Subjects received a single 2 mg dose of everolimus alone and again during single- or multiple-dose treatment with the probe inhibitors ketoconazole, erythromycin, verapamil, cyclosporine and atorvastatin.Results. The fold-increase in everolimus AUC was: 15.0 with the strong inhibitor ketoconazole; 4.4, 3.5 and 2.7 with the moderate inhibitors erythromycin, verapamil and cyclosporine; and no change with the weak inhibitor atorvastatin. Subjects with low baseline AUCs when everolimus was given alone tended to have AUC increases of a higher magnitude (more potent interaction) in the presence of an inhibitor.Conclusions. Strong CYP3A inhibitors should be avoided when possible during everolimus treatment as compensatory everolimus dose reductions could be difficult to manage. Everolimus therapeutic drug monitoring should be used to guide individualized dose adjustments when moderate CYP3A inhibitors are added to or withdrawn from the regimen. Routine everolimus therapeutic drug monitoring should be sufficient to determine whether dose adjustments are needed when weak CYP3A inhibitors are coadministered. This rational and systematic approach to drug interactions on everolimus yielded clinically useful, structured guidelines for dose adjustment.

Area Under Curve↗
PubMed2006

Everolimus in pulmonary transplantation: pharmacokinetics and exposure-response relationships.

BACKGROUND: In this study we evaluated exposure, safety and efficacy data from an international trial of everolimus. We sought to identify a tolerated and efficacious range for blood levels of this agent in maintenance lung transplant recipients. METHODS: In a randomized, double-blind, multicenter trial, 213 maintenance lung transplant recipients received either everolimus 1.5 mg twice daily (n = 101) or azathioprine 1 to 3 mg/kg/day (n = 112) with cyclosporine and corticosteroids. At 15 visits over the first 2 years of the trial, we obtained 826 everolimus trough (C0) blood samples. We used median-effect analysis to assess relationships between everolimus C0 vs efficacy and safety responses. RESULTS: Everolimus administration began at 1.5 mg twice daily and was progressively lowered over the first 2 months to an average of 1.2 +/- 0.4 mg twice daily, which was maintained thereafter. This dose yielded median C0 levels of 6.6 ng/ml (10th to 90th percentiles: 2.8 to 11.8 ng/ml). Over this range of everolimus C0, freedom from a decline in pulmonary function with bronchiolitis obliterans syndrome and freedom from biopsy-proven acute rejection were both > or = 88%. The incidence of increased cholesterol (> 6.5 mmol/liter), increased triglycerides (> 2.9 mmol/liter) and transiently decreased platelet count (< 100 x 10(9)/liter) rose significantly with increasing C0. Infections and drug-related adverse events were not significantly related to exposure. CONCLUSIONS: A tolerated and efficacious concentration range for everolimus in maintenance lung transplantation appears to be 3 to 12 ng/ml when used in conjunction with cyclosporine and corticosteroids. This range should be prospectively assessed with possible refinement as more clinical experience is gained.

Adult↗
PubMed2006

Fingolimod (FTY720) in severe hepatic impairment: pharmacokinetics and relationship to markers of liver function.

The authors assessed the impact of severe hepatic impairment on the disposition of fingolimod--a sphingosine-1-phosphate receptor immunomodulator primarily metabolized by CYP4F2--in 6 patients and 6 matched healthy controls who received a single 5-mg oral dose. Compared with healthy controls, severe hepatic-impaired subjects had a doubled area under the concentration time curve (AUC) and 50% prolonged elimination half-life but a similar peak blood concentration. When these data were combined with those from a previous study in mild and moderate hepatic-impaired subjects, there were significant positive correlations between fingolimod AUC versus bilirubin (r = 0.683) and prothrombin time (r = 0.777) and a significant negative correlation versus albumin (r = 0.578), confirming the importance of liver function for fingolimod clearance. For patients with severe hepatic impairment (Child-Pugh class C), a standard first dose of fingolimod could be given followed by a maintenance dose that is reduced by half from the normal maintenance dose.

Adult↗
PubMed2006

FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects.

The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) were randomized to FTY720 1.25 mg or 5 mg or placebo administered once daily for 7 days. Continuous telemetry revealed an acute, dose-dependent decrease in mean heart rate (10-bpm decrease vs placebo) following the first dose of FTY720, with a nadir generally 4 hours postdose. Although a persistent FTY720-related decrease in heart rate was measured from day 2 to day 7, additional doses of FTY720 after day 2 resulted in no further incremental decreases. Mean PR interval increased by approximately 8 to 10 msec in FTY720-treated subjects on day 1. FTY720 did not increase the QRS or QT interval. These results confirm that the first dose of FTY720 has a mild to moderate negative chronotropic effect.

Adolescent↗
PubMed2004

FTY720 and cyclosporine: evaluation for a pharmacokinetic interaction.

BACKGROUND: FTY720 is a sphingosine-1-phosphate receptor agonist intended for use in immunoprophylaxis regimens to prevent acute rejection after organ transplantation. OBJECTIVE: To evaluate the potential for a pharmacokinetic drug interaction between the immunomodulator FTY720 and cyclosporine to support the use of this drug combination in organ transplantation. METHODS: In this open-label, randomized crossover study, 12 subjects with psoriasis received a single dose of FTY720 1 mg alone and on day 5 of an 8-day course of cyclosporine 200 mg twice daily. The single-dose pharmacokinetics of FTY720 and the steady-state pharmacokinetics of cyclosporine were characterized when given alone and during coadministration. Routine safety data were collected, with special attention to total blood lymphocyte counts and heart rate. RESULTS: Cyclosporine coadministration compared with FTY720 given alone did not significantly alter FTY720 maximum concentration (C(max)) (0.57 +/- 0.17 vs 0.58 +/- 0.19. ng/mL, respectively) or AUC(0-t) (41 +/- 13 vs 41 +/- 13 ng. h/mL, respectively). Likewise for cyclosporine, FTY720 coadministration did not alter the steady-state Cmax compared with cyclosporine given alone (1452 +/- 308 vs 1376 +/- 149 ng/mL, respectively) or AUC(tau) (6385 +/- 1578 vs 6031 +/- 1051 ng. h/mL, respectively). Mean lymphocyte counts decreased from baseline by an average of 35% over the first 2 days after FTY720 administration and thereafter increased to prestudy values by day 5 similarly in the absence and presence of cyclosporine. The morning mean supine heart rate decreased approximately 10% and returned to prestudy rates by day 5 after administration of FTY720 alone and with cyclosporine. Heart rate changes were asymptomatic in all study participants. One subject experienced asymptomatic second-degree type 1 atrioventricular (Wenckebach) block. CONCLUSIONS: The pharmacokinetics of single-dose FTY720 and steady-state cyclosporine were not altered during coadministration.

Adult↗
PubMed2004

Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling.

Everolimus, a proliferation signal inhibitor, is an immunosuppressant that targets the primary causes of progressive allograft dysfunction, thus improving the long-term outcome after heart transplantation. The present study investigated whether therapeutic drug monitoring (TDM) of everolimus would benefit heart transplant patients. Data from a twelve-month phase III trial comparing everolimus (1.5 or 3 mg daily) with azathioprine were used to evaluate everolimus pharmacokinetics, exposure-efficacy/safety and TDM prognostic simulations. Everolimus trough levels were stable in the first year post-transplant and averaged 5.2 +/- 3.8 and 9.4 +/- 6.3 ng/mL in patients treated with 1.5 and 3 mg/day, respectively. Cyclosporine trough levels were similar in all treatment groups. Biopsy-proven acute rejection (BPAR) was reduced with everolimus trough levels > or =3 ng/mL. Intravascular ultrasound (IVUS) analysis showed evidence of reduced vasculopathy at 12 months with increasing everolimus exposure. Unlike cyclosporine, increasing everolimus exposure was not related to a higher rate of renal dysfunction. The TDM simulation, which was based on two everolimus dose adjustments and an initial starting dose of 1.5 mg/day, showed that the simulated BPAR rate (with TDM) was 21% versus 26% in the group with fixed dosing. Therefore, TDM in heart transplantation could optimize immunosuppressive efficacy and reduce treatment-related toxicity.

Azathioprine↗
PubMed2004

Everolimus therapeutic concentration range defined from a prospective trial with reduced-exposure cyclosporine in de novo kidney transplantation.

Prospective therapeutic drug monitoring of everolimus was performed in a 1-year multicenter trial in 237 de novo kidney transplant patients. Trough blood levels, rejection episodes, and safety parameters were evaluated to define an appropriate therapeutic concentration range for everolimus in this setting. Patients were randomized to everolimus starting doses of 0.75 mg bid (n = 112) or 1.5 mg bid (n = 125). Doses were then individualized based on everolimus trough blood levels (C0) in an attempt to maintain troughs > or = 3 ng/mL; no upper limit was specified. The regimen also contained corticosteroids and cyclosporine with an early dose reduction in months 2-3 posttransplant based on concentrations 2 hours postdose (C2). Cyclosporine C0 levels were also collected. Prospective therapeutic drug monitoring of everolimus C0 in patients starting at 0.75 mg bid led to dose adjustments in 52% of patients to an average long-term dose of 0.93 +/- 0.36 mg bid. This gave median (10th to 90th percentile) C0 levels of 5.3 (3.4-7.9) ng/mL. In patients starting at 1.5 mg bid, 55% had dose adjustments leading to an average long-term dose of 1.24 +/- 0.35 mg bid. This yielded C0 levels of 7.2 (4.4-11.6) ng/mL. Cyclosporine dosing began on average at 274 +/- 78 mg bid, was down-titrated in months 2-3 from 181 +/- 80 mg to 81 +/- 33 mg bid, and stabilized at 70 +/- 26 mg bid thereafter. This yielded median C2 levels of 1165 ng/mL in month 1, a down-titration with levels of 853 and 630 ng/mL in months 2 and 3, and a posttitration level of 472 ng/mL. The corresponding median cyclosporine C0 was 242 ng/mL initially and 70 ng/mL in the posttitration phase. In patients starting at 0.75 mg bid everolimus and an early down-titration of cyclosporine, everolimus C0 between 3 and 8 ng/mL was an effective and safe concentration range. Concentrations up to 12 ng/mL were tolerated over the first year posttransplant. This trial demonstrated that therapeutic monitoring of everolimus can be prospectively performed for dose individualization. Maintaining everolimus troughs in the range 3 to 8 ng/mL in the first posttransplant year with reduced-exposure cyclosporine is associated with good efficacy and safety profiles.

Adrenal Cortex Hormones↗
PubMed2004

Overview of FTY720 clinical pharmacokinetics and pharmacology.

Drug discovery programs are actively exploring for therapeutic agents targeting enzymes and receptors regulating sphingolipid metabolism and biologic functions. FTY720 is a close structural analogue of sphingosine with immunomodulatory properties. After oral administration, FTY720 is phosphorylated by sphingosine kinase to form the active moiety FTY720-phosphate, which subsequently binds to the sphingosine-1-phosphate receptor. In characterizing the safety and pharmacological effects of FTY720, detailed clinical pharmacology studies in healthy subjects and renal transplant recipients have focused on cardiac responses and lymphocyte trafficking. After the first dose, FTY720 causes a mild, transient decrease in heart rate that returns to baseline in approximately 1 to 2 weeks despite continued administration of the drug. FTY720 elicits a prompt and dose-dependent decrease in peripheral blood lymphocytes by redirecting them from the circulation to the lymph nodes without impairing lymphocyte functions. An association among FTY720 blood concentration, decrease in lymphocyte counts, and freedom from acute rejection episodes has been observed in early clinical development trials in de novo kidney transplantation.

Animals↗
PubMed2004

Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects.

AIMS: FTY720 is a sphingosine-1-phosphate receptor agonist that redirects lymphocytes from the circulation to lymph nodes without impairing lymphocyte function. It is being developed as an immunomodulator for the prevention of acute rejection after organ transplantation. This study was performed to provide guidance on administration with respect to meals and to measure pharmacologic responses in healthy subjects. METHODS: In this randomized, two-period, crossover study, 14 healthy subjects received placebo on day -1 of each period with baseline circadian measurements of lymphocyte count and heart rate. Subjects subsequently received a single 1 mg oral dose of FTY720 on day 1 under fasting conditions and after a high fat meal. Blood FTY720 concentrations, lymphocyte count, and supine heart rate were assessed over an 8 day period after each FTY720 dose. The effect of food on FTY720 pharmacokinetics was assessed by standard bioequivalence testing. RESULTS: Both the peak concentration (0.65 +/- 0.17 vs 0.64 +/- 0.18 ng ml(-1)) and total exposure (AUC 149 +/- 65 vs 139 +/- 43 ng ml(-1) h) did not differ significantly between fasting and fed states, respectively. The corresponding fed/fasting ratios and 90% confidence intervals were 1.00 (0.86, 1.17) for Cmax and 0.98 (0.86, 1.11) for AUC. Under both treatment conditions peripheral blood lymphocyte count decreased from baseline by 38 +/- 9% over the first 2 days postdose and then increased towards predose values over the subsequent week. Whereas a circadian rhythm in supine heart rate was preserved in the presence of FTY720, the heart rate vs time curve was shifted downwards by 10% over the first day postdose and then recovered to prestudy values by days 3-5 postdose. These changes were asymptomatic. CONCLUSIONS: Single 1 mg doses of FTY720 were well tolerated in healthy subjects and elicited a moderate decrease in peripheral blood lymphocyte count and a transient decrease in heart rate consistent with its pharmacological mode of action. FTY720 may be administered without regard to the timing of meals or their fat content.

Administration, Oral↗
PubMed2004

Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects.

FTY720 is a sphingosine-1-phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple-dose FTY720. In this randomized, double-blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month-long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory E(max) model. First-dose exposure was consistent with dose proportionality between the low- and high-dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for C(max) (5.0 +/- 1.0 vs. 18.2 +/- 4.1 ng/mL) and for AUC (109 +/- 24 vs. 399 +/- 85 ng.h/mL). Washout pharmacokinetics after the last dose indicated an elimination half-life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 +/- 0.1 x 10(9)/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 +/- 0.1 x 10(9)/L. Descriptive exposure-response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end-of-study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low- and high-dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose-proportionality after both single- and multiple-dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure-response modeling provided evidence that 5 mg/day FTY720 resulted in a near-maximal dynamic effect of this drug on lymphocytes.

Administration, Oral↗
PubMed2004

Everolimus: a proliferation signal inhibitor targeting primary causes of allograft dysfunction.

Allograft dysfunction remains a major problem for long-term graft survival after kidney and heart transplantation. Current immunosuppressive regimens do not completely address the causes of allograft dysfunction which include acute rejection episodes, complications of immunodeficiency (for example, cytomegalovirus infection), nephrotoxicity from calcineurin inhibitors (cyclosporine and tacrolimus) and vascular remodeling and vasculopathy. Everolimus is a potent immunosuppressor that inhibits growth factor-stimulated proliferation of hematopoietic and nonhematopoietic cells, including vascular smooth muscle. Everolimus is indicated for the prophylaxis of acute rejection in kidney and heart transplant patients in a combined regimen with cyclosporine microemulsion and corticosteroids. Everolimus is formulated as both a tablet and a tablet for oral solution. It is rapidly absorbed and displays dose-proportional, stable pharmacokinetics. Everolimus has equivalent efficacy to mycophenolate mofetil in reducing the incidence of acute rejection after renal transplantation and superior efficacy to azathioprine after heart transplantation. Combination of everolimus with cyclosporine allows dose-reduction of cyclosporine while maintaining efficacy due to the synergistic immunosuppressive effects of the combination. Everolimus reduces intimal thickening of blood vessels to the graft and the incidence of allograft vasculopathy in heart transplantation. In both kidney and heart transplantation, the incidence of cytomegalovirus infection was lower in everolimus-treated patients compared with patients receiving the control treatment. Everolimus-related adverse events include elevated cholesterol and triglycerides, which respond to treatment, and decreased platelet count, which is transient. Nephrotoxicity may result from the combination of everolimus with full-dose cyclosporine but is mitigated by reducing the dose of cyclosporine. Everolimus is initiated at 0.75 mg b.i.d. with dose adjustments guided by therapeutic drug monitoring of predose blood levels. In clinical development trials, everolimus has demonstrated the ability to reduce the incidence of acute rejection episodes, cytomegalovirus infection and cardiac vasculopathy, thus addressing the primary causes of allograft dysfunction.

Animals↗
PubMed2003

Cyclosporine pharmacokinetics and dose monitoring after lung transplantation: comparison between cystic fibrosis and other conditions.

BACKGROUND: In cystic fibrosis (CF), absorption of cyclosporine A (CsA) through the gastrointestinal tract is often impaired because of fat malabsorption. The aim of this study was to compare the steady-state pharmacokinetics of CsA and the inter- and intrasubject variability of CsA exposure in stable lung transplant recipients with and without CF and to determine the best single-time predictors of the area under the curve (AUC). METHODS: Ten lung transplant recipients without CF and 10 lung transplant recipients with CF were studied. All patients received Neoral twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h postdose on three separate days within a 5-day period. RESULTS: CsA exposure and pharmacokinetic variables were similar in the two groups, although exposure-per-milligram-per-dose was approximately 25% lower in CF patients. Coefficients of intersubject variability were numerically higher in CF patients, but the difference between groups did not reach significance. On the other hand, the maximum concentration (Cmax), the concentration 2 hours after administration (C2), AUC0-12, and AUC0-4 showed a twofold greater intrasubject variability in CF patients. CsA trough concentration did not predict accurately the AUC, but C2 was a good predictor of the AUC0-4 in both CF (r2=0.90) and non-CF (r2=0.78) patients. CONCLUSION: Compared to patients without CF, patients with CF show a lower bioavailability of CsA and a greater intrasubject variability of Cmax, C2, and AUC. C2 is the best single-point predictor of the AUC0-4 in lung transplant recipients with and without CF.

Adult↗
PubMed2003

Everolimus in pediatric de nova renal transplant patients.

BACKGROUND: The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period. METHODS: Nineteen patients received everolimus 0.8 mg/m2 (maximum 1.5 mg) twice daily as a dispersible tablet in water in addition to cyclosporine and corticosteroids. Everolimus and cyclosporine trough concentrations were obtained on days 3, 5, 6, and 7 and at months 1, 2, 3, and 6; an everolimus pharmacokinetic profile was obtained on day 7 and month 3. RESULTS: There were 9 boys and 10 girls with a median age of 9.9 (range, 1-16) years. Steady-state pharmacokinetic parameters were as follows (median, range): C(min) (trough level), 4.7 (2.3- 9.5) ng/mL; peak concentration, 13.5 (5.9-22.2) ng/mL; area under the concentration-time curve (AUC), 77 (53-147) ng x hr/mL; and apparent oral clearance, 10.2 (5.5-15.6) L/hr/m2. Clearance (unadjusted for demographic factors) was positively correlated with age (r=0.66), body surface area (r=0.68), and weight (r=0.67). There were no trends in C(min) or AUC versus patient age when everolimus was dosed on a mg/m2 basis. Everolimus C(min) were stable over time with median values of 3.9, 3.4, and 3.1 ng/mL at months 1, 3, and 6, respectively. Intra- and interpatient variability in AUC was 29% and 35%, similar to that in adults. During the observation period, eight patients maintained stable AUCs and nine patients had increases or decreases, generally between 30% and 50% compared with the AUC at week 1. The concurrent median cyclosporine C(min) were generally at the lower end of conventional target ranges: 156, 83, and 69 ng/mL at months 1, 3, and 6, respectively. There were no graft losses and only three mild or moderate, reversible rejection episodes occurred. Everolimus was generally safe and well tolerated. CONCLUSIONS: These data support the use of body surface area-adjusted dosing for everolimus in pediatric patients. Although exposure is generally stable over time with moderate variability in AUC, therapeutic monitoring would be a helpful adjunct for individualizing everolimus exposure, assessing regimen adherence, and adjusting doses as the child matures.

Adolescent↗
PubMed2003

Everolimus in de novo cardiac transplantation: pharmacokinetics, therapeutic range, and influence on cyclosporine exposure.

We evaluated exposure, safety, and efficacy data from an international Phase 3 trial of everolimus in de novo heart transplantation to characterize the longitudinal pharmacokinetics of everolimus and cyclosporine and to identify a therapeutic concentration range for everolimus. We randomized 634 patients to receive either 0.75 mg everolimus twice daily, 1.5 mg everolimus twice daily, or azathioprine in addition to corticosteroids and cyclosporine. At 8 visits during the first 6 months after transplantation, we obtained 2,328 everolimus trough levels (Cmin) and 129 area-under-the-curve (AUC) profiles over the dosing interval in patients treated with everolimus; we collected 3,258 cyclosporine trough concentrations and 174 profiles in all 3 treatment arms. We used median-effect analysis to characterize exposure-response associations between everolimus average Cmin vs freedom from biopsy-confirmed acute rejection; maximum cholesterol, low density lipoprotein, triglyceride, and creatinine levels; and minimum leukocyte and platelet counts. Everolimus Cmins averaged 5.2 +/- 3.8 ng/ml and 9.4 +/- 6.3 ng/ml at the lower and upper dose levels. A 17% underproportionality was noted in Cmins; however, peak exposure and AUC were consistent with dose proportionality. Everolimus exposure was stable during the 6-month period. Interindividual variability was 37% for AUC and 40% for Cmin. The latter parameter was not influenced to a clinically relevant extent by sex, age, or weight. The Cmin was well correlated with AUC (r2 = 0.81). Everolimus Cmin was significantly related to freedom from rejection (p = 0.02) with 3 ng/ml being an informative lower threshold for efficacy. Thrombocytopenia, defined as <75 x 10(9)/liter, was related significantly to Cmin (p = 0.03); however, the incidence in this study was too low to establish an upper end for the therapeutic range. Lower doses of cyclosporine (by 15% to 19%) were used in patients treated with everolimus to achieve cyclosporine Cmins and AUCs similar to those in patients treated with azathioprine. Everolimus exposure was dose proportional and stable during the first 6 months after transplantation. Interindividual pharmacokinetic variability was high but not influenced by common demographic covariates. We observed a significantly increased risk of acute rejection at everolimus trough levels <3 ng/ml, which constitutes the lower therapeutic concentration limit when everolimus is used with conventionally dosed cyclosporine. Everolimus-related adverse events were manageable up to the highest troughs (22 ng/ml) observed in this population. We could not derive a precise upper therapeutic concentration limit from these data.

Adrenal Cortex Hormones↗
PubMed2003

Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation.

The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids. Pharmacokinetic data consisted of 4014 everolimus trough concentrations (Cmin) obtained in all patients and 659 area under the concentration-time curve (AUC) -profiles obtained at months 2, 3, and 6 in a subset of 261 patients. Cmins averaged 4.3 +/- 2.4 and 7.2 +/- 4.2 ng/mL at 0.75 and 1.5 mg bid, indicating a 20% under-proportionality at the upper dose level. Cmins were 19-34% lower in the first month compared with months 2 through 6-values. AUC was dose-proportional and stable over time, averaging 77 +/- 32 and 136 +/- 57 ng.h.mL-1 at the two dose levels. Within- and between-patient variability in AUC were 27% and 31%, respectively. There was no influence of sex, age (16-66 years), or weight (42-132 kg) on AUC. Everolimus exposure was significantly lower by an average 20% in blacks. Everolimus exposure was relatively stable over the first 6 months post transplant, with no major departure from dose-proportionality over the therapeutic dose range. Weight-adjusted dosing (mg/kg) does not appear warranted. Black patients may have lower bioavailability and/or higher clearance of everolimus compared with white patients.

Adult↗