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BackgroundReducing nebulisation times for tobramycin solution for inhalation in cystic fibrosis (CF) may improve compliance.MethodsIn this single-dose, open-label, two-way crossover study, 13 subjects (7 CF, 6 healthy) were randomised to receive tobramycin via eFlow rapid or LC Plus jet nebuliser. Drug deposition in the lung using gamma scintigraphic imaging, nebulisation times, pharmacokinetics, and safety were evaluated.ResultsIn CF patients, whole-lung deposition was 40% less with the eFlow rapid compared with LC Plus nebulisers was (8.9±0.8%, and 15.1±6.0%, p>0.05). Nebulisation time was shorter with eFlow rapid compared to LC Plus (7.0min versus 20.0min, p

Summary Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1–3 and once between days 5–8 post-transplant. Sotrastaurin absorption based on the area under the concentration-time curve (AUC) of total drug in blood (3544 ± 1434 ng·h/ml) was similar to that of healthy subjects in a previous study (4531 ± 1650 ng·h/ml). However, the sotrastaurin binding protein, α1-acid glycoprotein, was nominally higher in patients (1.07 ± 0.28 vs. 0.87 ± 0.16 g/l, P = 0.13) yielding a 60% lower AUC based on free drug versus that in healthy subjects (27 ± 13 vs. 62 ± 15 ng·h/ml, P

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? • Sotrastaurin is an investigational protein kinase C inhibitor. This represents a new mechanism of action for immunosuppression to prevent acute rejection after organ transplantation. In vitro experiments indicate that sotrastaurin is a substrate of CYP3A4. WHAT THIS STUDY ADDS • This study provides clinical pharmacokinetic information to quantify the effect of the strong CYP3A4 inhibitor ketoconazole on sotrastaurin. The susceptibility of sotrastaurin to CYP3A4-related drug interactions is placed in the context of similar information about calcineurin inhibitors (tacrolimus, ciclosporin) and T-cell proliferation inhibitors (everolimus, sirolimus). AIMS Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated. METHODS This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration. RESULTS Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin Cmax by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 ± 128 to 678 ± 189 ng ml−1 and increased AUC by 4.6-fold (4.1, 5.2) from 1666 ± 808 to 7378 ± 3011 ng ml−1 h. Sotrastaurin half-life was nearly doubled from 5.9 ± 1.7 to 10.6 ± 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations. CONCLUSIONS The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.

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.

Aims We sought to define the influence of verapamil, an inhibitor of CYP3A and P-glycoprotein, on the pharmacokinetics of everolimus, a substrate of this enzyme and transporter. Methods This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1 subjects received a single 2 mg oral dose of everolimus. In period 2 they received verapamil 80 mg three times daily for a total of 6 days and a single 2 mg dose of everolimus co-administered on the second day of verapamil therapy. Results During verapamil co-administration, everolimus Cmax increased 2.3-fold (90% CI, 1.9, 2.7) from 21 ± 8 to 47 ± 18 ng ml−1 and AUC increased 3.5-fold (90% CI, 3.1, 3.9) from 115 ± 45 to 392 ± 142 ng ml−1 h. Everolimus half-life was only prolonged to a minor extent (32 ± 6 vs. 37 ± 6 h). Verapamil predose concentrations doubled from 32 ± 16 to 74 ± 42 ng ml−1 after single dose administration of everolimus. Conclusions Multiple dosing with verapamil increased blood concentrations of everolimus after a single dose by an average 3.5-fold. During verapamil treatment, dose reduction for everolimus should be made guided by blood monitoring and for verapamil by blood pressure monitoring.

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.

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.

Cyclosporine absorption profiling uses either the area under the concentration curve in the first 4 h post dose, AUC(0–4), or the concentration 2 h post dose (C2) to optimize immunosuppression in adult kidney and liver transplantation. We characterized C2 versus AUC(0–4) relationships over time after transplant and across transplant indications in 56 pediatric transplant patients. There were 36 kidney transplant patients aged 9.7±3.9 years. Nineteen of these patients were studied in the de novo period on day 7 post transplant and 17 in the maintenance phase more than 1 year post transplant. In addition, 20 liver transplant patients aged 8.9±4.2 years were studied in the maintenance phase. All patients had five blood samples collected over the 12-h dose interval that were analyzed by validated assay methods at a central laboratory. Pediatric C2 values were 1,463±658 ng/ml for de novo kidney, 954±322 ng/ml for maintenance kidney, and 619±339 ng/ml for maintenance liver transplant patients. C2 was a strong predictor of AUC(0–4) in all three pediatric groups, with coefficients of determination (r 2) ranging from 0.861 to 0.936. Although data were limited from the de novo period, the C2 versus AUC(0–4) regression was consistent over time after transplant and between transplant indications, with a regression slope of 2.50 in de novo kidney, 2.54 in maintenance kidney, and 2.76 in maintenance liver transplant recipients. These slopes were also comparable to that in adult maintenance kidney transplant patients (2.60). In conclusion, C2 versus AUC(0–4) relationships demonstrated consistency over time (de novo vs. maintenance phase), between transplant indications (kidney vs. liver), and across age groups (pediatric vs. adult patients). Average C2 values achieved with current pediatric cyclosporine dosing practices cluster around the target C2 ranges recommended for adults.

Objective:To describe the time course of α4-integrin receptor desaturation and disease activity return in patients with relapsing-remitting MS who discontinued natalizumab and to investigate baseline and on-study predictors for the recurrence of disease activity.Methods:In the course of TOFINGO, a 32-week, patient- and rater-blinded multicenter, parallel-group study, we performed MRI, counted relapses, and measured α4-integrin receptor occupancy (RO) at baseline and 8, 12, 16, 20, and 24 weeks. The relationship between RO and total number of new T1 gadolinium-enhancing (Gd+) lesions was modeled using Poisson linear regression.Results:Patients (N = 142) were randomized (1:1:1) to 8-, 12-, or 16-week washout (WO) groups. At randomization, the median RO in the 8-, 12-, and 16-week WO groups was 94.5%, 92.4%, and 90.9%, which declined to 79.8%, 30.7%, and 8.7% after 8, 12, and 16 weeks of WO, respectively. The percentage of patients with new T1 Gd+ lesions increased with longer WO period before commencing fingolimod: 2.1% (8 weeks), 9.1% (12 weeks), and 50.0% (16 weeks). Overall, 71% of patients with first relapse between weeks 6 and 18 had RO values below the time-matched population median. Higher T2 lesion volume (LV) at baseline predicted a higher number of new T1 Gd+ lesions.Conclusions:A faster decline in natalizumab RO, longer WO period, and higher T2 LV at baseline were associated with an increased risk for return of inflammatory disease activity. These results provide a mechanistic rationale and, together with the main outcomes of the TOFINGO study, support initiation of fingolimod within 8 weeks of natalizumab discontinuation.ClinicalTrials.gov identifier:NCT01499667.

Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling.This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5 mg·day−1 escalated to 10 mg·day−1) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function.Following 26 weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1 s improved from baseline, with mean changes (95% confidence interval) of 10 mL (−111–132) and 114 mL (11–217), respectively; 6-min walk distance improved by 47 m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730 pg·mL−1 to 934.5 pg·mL−1, and 103 ng·mL−1 to 80.5 ng·mL−1, respectively. Adverse events were mostly grade 1−2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally.In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe.

Background: Pharmacokinetic data regarding a drug-drug interaction between everolimus and tacrolimus are sparse. Material/Methods: In a pharmacokinetic substudy of the randomized ASSET trial, 46 de novo kidney transplant patients receiving very low (1.5-3 ng/mL) or low (4-7 ng/mL) tacrolimus exposure after month 3, both with everolimus and steroids, provided area under the curve (AUC) concentration profiles at day 5 and months 1, 3, and 12. Results: At month 12, mean values for tacrolimus trough concentration (C-0), peak concentration (C-max), and AUC(0-12) in the very low tacrolimus group were approximately half that in the low tacrolimus group, but everolimus dose, C-0, C-max, and AUC(0-12) were virtually identical in both groups. In a cross-study comparison with data at months 1 and 3 from the pharmacokinetic substudy of the A2307 trial, in which patients received cyclosporine, mean values for everolimus C-0, C-max and AUC(0-12) were similar to those in the ASSET trial but the everolimus dose needed to achieve similar exposure was 1.5- to 2-fold higher with concomitant tacrolimus versus cyclosporine. Conclusions: Everolimus exposure is unaffected when tacrolimus exposure is down-titrated within the trough concentration range of 1.5-7 ng/mL. Higher doses of everolimus are needed to achieve a given exposure when combined with tacrolimus versus cyclosporine.

Potential differences in the acute effect of cyclosporin on renal function when dosed orally as the current market formulation or following a milligram-to-milligram conversion to a new microemulsion formulation were investigated in 14 stable kidney transplant patients. The study consisted of three sequential periods of 2 weeks duration each. Patients entered (period I) and completed (period III) the investigation with the market formulation and received the microemulsion formulation in period II; individualized cyclosporin doses remained unchanged throughout the study. Over one steady-state dosing interval at the end of each study period, whole blood cyclosprin pharmacokinetic profiles were assessed in parallel with endogenous creatinine clearances over sequential 1-to 2-h intervals. The rate and extent of cyclosporin absorption were significantly greater (P

Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1-3 and once between days 5-8 post-transplant. Sotrastaurin absorption based on the area under the concentration-time curve (AUC) of total drug in blood (3544 ± 1434 ng·h/ml) was similar to that of healthy subjects in a previous study (4531 ± 1650 ng·h/ml). However, the sotrastaurin binding protein, α1-acid glycoprotein, was nominally higher in patients (1.07 ± 0.28 vs. 0.87 ± 0.16 g/l, P = 0.13) yielding a 60% lower AUC based on free drug versus that in healthy subjects (27 ± 13 vs. 62 ± 15 ng·h/ml, P0.0001). There was minor excretion of sotrastaurin in drained bile (1% of dose) consistent with the fact that sotrastaurin is extensively metabolized leaving little unchanged drug to excrete. In the first week after liver transplantation, sotrastaurin is bioavailable after oral administration. However, patients with elevated α1-acid glycoprotein levels may have lower free drug concentrations. Whether a higher dose of sotrastaurin is needed to compensate for this in the short-term after surgery will be addressed in future clinical trials.

WHAT IS KNOWN ABOUT THIS SUBJECT • Clinical pharmacology and clinical therapeutic studies of fingolimod demonstrate that heart rate after the initial dose decreases by about 10–20% while normal circadian rhythm is preserved. With continued daily dosing, heart rate returns to normal over the next 2 weeks. • This negative chronotropic effect is consistent with the binding of fingolimod-phosphate to the sphingosine-1-phosphate receptor on atrial myocytes. WHAT THIS STUDY ADDS • The present clinical pharmacology study demonstrates that atropine administered at usual therapeutic doses can prevent the decrease in heart rate when given concomitantly with fingolimod and can counteract the decrease in heart rate when give at the time of the typical heart rate nadir, 4 h after the fingolimod dose. • Although therapeutic intervention is rarely needed for reduced heart rate in patients receiving fingolimod, atropine is an option, should this be desired. AIMS The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod. METHODS In this randomized, placebo-controlled, two-period, crossover study, 12 healthy subjects received 5 mg fingolimod orally concurrently with intravenous atropine (titrated to a heart rate of 110–120 beats min−1) or intravenous placebo. A second group of 12 subjects received atropine/placebo 4 h after the fingolimod dose. Continuous telemetry measurements were made for 24 h after each fingolimod dose. RESULTS Fingolimod administration alone yielded a heart rate nadir of 51 ± 5 beats min−1 at a median 4 h postdose with heart rate remaining depressed at 51–64 beats min−1 over the rest of the day. Concurrent administration of fingolimod and atropine yielded a nadir of 66 ± 6 beats min−1 resulting in an atropine : placebo ratio (90% confidence interval) of 1.30 (1.22, 1.36). When atropine was administered at the time of the nadir, it was able to reverse the negative chronotropic effect of fingolimod from a heart rate of 56 ± 9 beats min−1 (placebo) to 64 ± 8 beats min−1 (atropine) resulting in an atropine : placebo ratio of 1.15 (1.04, 1.26). Atropine had no influence on the pharmacokinetics of fingolimod. CONCLUSIONS Atropine administered concurrently with fingolimod prevented the heart rate nadir that typically occurs 4 h postdose. Atropine administered at the time of the heart rate nadir was able to reverse the negative chronotropic effect of fingolimod.

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.

The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age-group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed-dose approach for part two of the study in which infants and children received two 10-mg doses of basiliximab and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for screening for anti-idiotype antibodies and analysis of basiliximab and soluble interleukin-2 receptor (IL-2R) concentrations. Basiliximab clearance in infants and children9 yr of age (n = 30) was reduced by approximately 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9-14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25-saturating basiliximab concentrations were maintained for 27 +/- 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 +/- 11 days in part two of the study, based on the fixed-dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age-related bias observed in part one of the study. Anti-idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent-to-treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post-transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12-month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine-release syndrome or other infusion-related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients35 kg in weight should receive two 10-mg doses and thoseor = 35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.

SDZ CHI 621 is a murine-human chimeric monoclonal antibody (mAb) to the interleukin-2 (IL-2) receptor (CD25) intended for prophylactic immunosuppression against acute rejection in the first several weeks following kidney transplantation. A multicentre, prospective, dose-finding study was conducted in 37 primary, mismatched cadaver kidney transplant patients to assess its tolerability, pharmacokinetics and immunodynamics. Successive cohorts of patients were stratified to receive total doses of 20, 30, 40 or 60 mg (n = 4, 4, 14, 15, respectively) administered as 15- or 20-mg intravenous infusions with the first dose given preoperatively and subsequent doses within the first 10 days posttransplant. Daily mAb serum concentrations were analysed by a radioimmunoassay method and the percentage of peripheral T-lymphocytes expressing CD25 from serial blood samples was determined by FACScan. Intravenous administrations were well tolerated. mAb concentration profiles exhibited a biphasic decline with an initial t1/2 of 14.4 ± 14.2 h, terminal t1/2 of 13.4 ± 6.0 days, distribution volume (Vss) of 6.9 ± 3.31 and clearance of 17.4 ± 7.8 ml/h. The concentration-effect (mAb-CD25) relationship indicated that mAb concentrations exceeding a threshold of about 0.7.µg/ml corresponded to complete suppression of CD25 (≤ 3% CD25+ T-cells). The threshold mAb concentration was exceeded at all dose levels, whereas the duration above the threshold (and thus of CD25 suppression) rose with increasing dose: 20 mg, 20 ± 7 days; 30 mg, 32 ± 6 days; 40 mg, 37 ± 10 days; and 60 mg, 53 ± 17 days. As mAb concentrations declined below the threshold following the last dose, CD25 expression returned to baseline (18–44% CD25+ T-cells) within a few days.