The pharmacokinetics of peginterferon lambda-1a following single dose administration to subjects with impaired renal function.

AIMS: This open label study was conducted to assess the effect of renal impairment (RI) on the pharmacokinetics (PK) of peginterferon lambda-1a (Lambda). METHODS: Subjects (age 18-75 years, BMI 18-35 kg m(-2) ) were enrolled into one of five renal function groups: normal (n = 12), mild RI (n = 8), moderate RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8) based on estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation. Subjects received a single dose of Lambda (180 µg) subcutaneously on day 1 followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity data were collected through day 43. PK parameters were estimated and summarized by group. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between normal and RI groups. RESULTS: With decreasing eGFR, Lambda exposure (Cmax , AUC) increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. Relative to subjects with normal renal function (geometric mean AUC = 99.5 ng ml(-1) h), Lambda exposure estimates (AUC) were slightly increased in the mild RI group (geometric mean [90% CI]: 1.20 [0.82, 1.77]) and greater in the moderate (1.95 [1.35, 2.83]), severe RI (1.95 [1.30, 2.93]) and ESRD (1.88 [1.30, 2.73]) groups. Lambda was generally well tolerated. CONCLUSIONS: The results demonstrated that RI reduces the clearance of Lambda and suggests that dose modifications may not be required in patients with mild RI but may be required in patients with moderate to severe RI or ESRD.

Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations.

This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single-dose study, 8 patients each with mild and moderate hepatic insufficiency received 70 mg of caspofungin. In the multiple-dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration-time profile over the interval of last quantifiable point to infinity (AUC(0-infinity)) geometric mean ratio (GMR) (90% confidence interval [CI]) for mild hepatic insufficiency/historical controls was 1.55 (1.32-1.86) in the single-dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04-1.39) for day 14 area under the concentration-time profile calculated over the interval 0 to 24 hours (AUC(0-24h)) following multidose. The AUC(0-infinity) GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51-2.06) following 70 mg; AUC(0-24h) GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90-1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70-mg loading dose is recommended for patients with moderate hepatic insufficiency.

Pharmacokinetics of ertapenem in patients with varying degrees of renal insufficiency and in patients on hemodialysis.

Ertapenem is a parenteral beta-lactam carbapenem antibiotic. This open-label study examined the pharmacokinetics of single 1-g intravenous doses of ertapenem, administered over 30 minutes, in patients with mild, moderate, and advanced renal insufficiency (RI) and in patients with end-stage renal disease (ESRD) requiring hemodialysis. Pharmacokinetics were compared with historical controls pooled across healthy young and elderly subjects. Area under the concentration-time curve from time zero to infinity increased 7% in mild, 53% in moderate, 158% in advanced RI, and 192% in ESRD; end of infusion concentration changed minimally; half-life was 4.5 hours in the historical control group and 4.4, 6.1, 10.6, and 14.1 hours in mild RI, moderate RI, advanced RI, and ESRD, respectively. Hemodialysis cleared approximately 30% of the dose. The recommended dose in mild to moderate RI and after hemodialysis is unchanged at 1 g daily; and in advanced RI and ESRD is reduced to 0.5 g daily. If the daily dose is given 6 hours prior to hemodialysis, a supplementary 150-mg dose (30% of the daily dose) is recommended postdialysis.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that enhances prevention of chemotherapy-induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5-hydroxytryptamine(3) (5-HT(3)) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study. METHODS: In this open-label, randomized, single-period study, 16 healthy male subjects were enrolled. Subjects received one of two oral aprepitant regimens for 5 days (8 subjects per regimen): (1) 125 mg aprepitant on day 1 and then 80 mg/d on days 2 to 5 or (2) 40 mg aprepitant on day 1 and then 25 mg/d on days 2 to 5. All subjects also received a single oral dose of midazolam, 2 mg, at prestudy (3 to 7 days before aprepitant treatment) and on days 1 and 5 (1 hour after aprepitant administration). RESULTS: Coadministration of midazolam and 125/80 mg aprepitant increased the midazolam area under the plasma concentration-time curve by 2.3-fold on day 1 (P <.01) and by 3.3-fold on day 5 (P <.01), as compared with midazolam alone (prestudy). The 125/80-mg regimen of aprepitant also increased the midazolam maximum observed concentration by 1.5-fold on day 1 (P <.05) and by 1.9-fold on day 5 (P <.01). The midazolam half-life values increased from 1.7 hours (prestudy) to 3.3 hours on both day 1 and day 5. Coadministration of 40/25 mg aprepitant and midazolam did not result in significant changes in the midazolam area under the plasma concentration-time curve, maximum observed concentration, and half-life at either day 1 or day 5. CONCLUSIONS: The 5-day 125/80-mg regimen of aprepitant produced moderate inhibition of CYP3A4 activity in humans, as measured with the use of midazolam as a probe drug.

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated. METHODS: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen. RESULTS: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P <.010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P <.010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P <.010). CONCLUSIONS: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.

Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects.

Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0-24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5-day regimen, did not interact with a known substrate of the P-glycoprotein transporter.

Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects.

BACKGROUND: The neurokinin-1-receptor antagonist aprepitant, when given in combination with a corticosteroid and a 5-hydroxytryptamine type 3 (5-HT(3))-receptor antagonist, has been shown to be effective for the prevention of acute and delated chemotherapy-induced nausea and vomiting (CINV). OBJECTIVE: Two studies were conducted to determine whether concomitant administration of aprepitant altered the pharmacokinetic profiles of ondansetron and granisetron, two 5-HT(3)-receptor antagonists commonly used as antiemetic therapy for CINV. METHODS: The 2 studies were randomized, open-label, crossover trials conducted in healthy subjects aged between 18 and 46 years. Study 1 involved the following 2 treatment regimens: aprepitant 375 mg PO, dexamethasone 20 mg PO, and ondansetron 32 mg IV on day 1, followed by aprepitant 250 mg PO and dexamethasone 8 mg PO on days 2 through 5; and dexamethasone 20 mg PO and ondansetron 32 mg IV on day 1, followed by dexamethasone 8 mg PO on days 2 through 5. Study 2 involved the following 2 treatment regimens: aprepitant 125 mg PO with granisetron 2 mg PO on day 1, followed by aprepitant 80 mg PO on days 2 and 3; and granisetron 2 mg PO on day 1 only. Individual plasma samples were used to estimate area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )), peak plasma concentration, and apparent terminal elimination half-life (t(12)) of both ondansetron and granisetron. RESULTS: Study 1 included 19 subjects (10 women, 9 men), and study 2 included 18 subjects (11 men, 7 women). Coadministration of aprepitant 375 mg produced a small but statistically significant increase in the AUC(0- infinity ) for intravenous ondansetron (from 1268.3 to 1456.5 ng.h/mL; P = 0.019), with no significant effect on peak concentration at the end of the infusion (360.8 ng/mL with aprepitant vs 408.4 ng/mL without) or t(12) (5.0 vs 4.5 hours, respectively). Coadministration of aprepitant 125 mg/80 mg did not alter the mean pharmacokinetic characteristics of oral granisetron (AUC(0- infinity ), 101.4 ng.h/mL with aprepitant vs 92.2 ng.h/mL without; maximum plasma concentration, 9.0 ng/mL with and without aprepitant; time to maximum plasma concentration, both 3.0 hours; t(12), 6.5 vs 6.9 hours, respectively). CONCLUSION: Concomitant administration of aprepitant had no clinically significant effect on the mean pharmacokinetic characteristics of either ondansetron or granisetron in these healthy subjects.

Single- and multiple-dose pharmacokinetics of caspofungin in healthy men.

Caspofungin, a glucan synthesis inhibitor, is being developed as a parenteral antifungal agent. The pharmacokinetics of caspofungin following 1-h intravenous infusions in healthy men was investigated in four phase I studies. In an alternating two-panel (six men each), rising-single-dose study, plasma drug concentrations increased proportionally with the dose following infusions of 5 to 100 mg. The beta-phase half-life was 9 to 10 h. The plasma drug clearance rate averaged 10 to 12 ml/min. Renal clearance of unchanged drug was a minor pathway of elimination (approximately 2% of the dose). Multiple-dose pharmacokinetics were investigated in a 2-week, serial-panel (5 or 6 men per panel) study of doses of 15, 35, and 70 mg administered daily; a 3-week, single-panel (10 men) study of a dose of 70 mg administered daily; and a parallel panel study (8 men) of a dose of 50 mg administered daily with or without a 70-mg loading dose on day 1. Moderate accumulation was observed with daily dosing. The degree of drug accumulation and the time to steady state were somewhat dose dependent. Accumulation averaged 24% at 15 mg daily and approximately 50% at 50 and 70 mg daily. Mean plasma drug concentrations were maintained above 1.0 microg/ml, a target selected to exceed the MIC at which 90% of the isolates of the most clinically relevant species of Candida were inhibited, throughout therapy with daily treatments of 70 or 50 mg plus the loading dose, while they fell below the target for the first 2 days of a daily treatment of 50 mg without the loading dose. Caspofungin infused intravenously as a single dose or as multiple doses was generally well tolerated. In conclusion, the pharmacokinetics of caspofungin supports the clinical evaluation of once-daily dosing regimens for efficacy against fungal infections.