This phase I, open-label, single-dose study evaluates the effects of severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics, safety, and tolerability of sunitinib and its primary active metabolite, SU12662. Subjects with normal renal function (creatinine clearance > 80 mL/min), severe renal impairment (creatinine clearance < 30 mL/min), and ESRD requiring hemodialysis receive a single dose of sunitinib 50 mg. Serial blood samples are collected for quantification of plasma concentrations using a validated liquid chromatography with tandem mass spectrometry assay. Safety is monitored. Twenty-four subjects complete the study. Pharmacokinetics in subjects with severe renal impairment appear similar to those with normal renal function. Plasma exposure to sunitinib and SU12662 appears lower in subjects with ESRD compared with subjects with normal renal function or severe renal impairment. Single-dose sunitinib 50 mg is well tolerated regardless of renal function. The currently approved starting dose of sunitinib 50 mg on Schedule 4/2 is expected to be appropriate for patients with renal impairment; any subsequent dose modifications should be based on patients' ability to tolerate treatment.

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor with potent activity in vitro and in vivo. Raltegravir is primarily cleared by hepatic metabolism via glucuronidation (via UDP glucuronosyltransferase 1A1), with a minor component of elimination occurring via the renal pathway. Since the potential exists for raltegravir to be administered to patients with hepatic or renal insufficiency, two studies were conducted to evaluate the influence of moderate hepatic insufficiency (assessed by using the Child-Pugh criteria) and severe renal insufficiency (creatinine clearance, <30 ml/min/1.73 m 2 ) on the pharmacokinetics of raltegravir. Study I evaluated the pharmacokinetics of 400 mg raltegravir in eight patients with moderate hepatic insufficiency and eight healthy, matched control subjects. Study II evaluated the pharmacokinetics of 400 mg raltegravir in 10 patients with severe renal insufficiency and 10 healthy, matched control subjects. All participants received a single 400-mg dose of raltegravir in the fasted state. In study I, the geometric mean ratios (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% confidence intervals ( Raltegravir (Isentress, MK-0518), a human immunodeficiency virus (HIV) type 1 (HIV-1) integrase strand transfer inhibitor, is a member of a promising new class of drugs for the treatment of patients infected with HIV-1. Raltegravir has been demonstrated to have potent activity in vitro and in the clinic (10) and may become a useful tool in antiretroviral treatment regimens. The pharmacokinetic properties of raltegravir have been characterized (7,8,9). Raltegravir demonstrates dose-proportional pharmacokinetics over 100 to 800 mg. At the clinical dose of 400 mg, the apparent terminal elimination half-life (t 1/2␤ ) is approximately 9 h and the distribution-phase half-life (t 1/2␣ ) is shorter (approximately 1 h) and accounts for much of the area under the concentration-time curve (AUC). Raltegravir is relatively rapidly absorbed, with the median time to the maximum plasma concentration (T max ) being ϳ3 h in the fasted state. Raltegravir is cleared primarily by metabolism, with a minor component of elimination occurring via renal excretion (ϳ9%) (8). Metabolism is primarily hepatic, and the major metabolite is derived through the UDP glucuronosyltransferase 1A1 (UGT1A1) isozyme (8). As the elimination of raltegravir is dependent upon both hepatic and renal processes, there is the potential for the pharmacokinetics of raltegravir to be altered in patients with hepatic or renal organ dysfunction. However, the likelihood of an interaction is projected to be low on the basis of the modest renal clearance (CL R ) of raltegravir and the fact that UGT1A1 metabolism is not as likely to be affected by moderate hepatic insufficiency (3, 4). The intended patient population for raltegravir includes patients with hepatic insufficiency and renal insufficiency, and an investigation of the effects of hepatic an...

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Background: Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing. Methods: Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects. Results: Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive ≧30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca × P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens. Conclusions: QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive ≧30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca × P product as compared with placebo or intermittent dosing.