Pharmacokinetics of vandetanib in subjects with renal or hepatic impairment.

BACKGROUND AND OBJECTIVE: Vandetanib, an oncology drug being evaluated in phase III clinical trials, undergoes significant renal and hepatic excretion. The objective of these two studies was to investigate the single-dose pharmacokinetics of vandetanib in subjects with renal or hepatic impairment in comparison with healthy subjects. SUBJECTS AND METHODS: Two open-label, parallel-group studies were conducted at a single centre in Germany. Subjects aged 18-75 years with a body mass index of 18-32 kg/m2 were eligible. The renal impairment study recruited subjects with normal renal function and mild, moderate and severe renal impairment according to creatinine clearance calculated from a 24-hour urine collection pre-dose. The hepatic impairment study recruited subjects with normal hepatic function and mild, moderate and severe hepatic impairment according to the Child-Pugh classification. All subjects received a single 800 mg oral vandetanib dose. Blood samples for measurement of vandetanib, N-desmethylvandetanib and vandetanib N-oxide were collected before and at various timepoints after vandetanib administration for up to 63 days. Pharmacokinetic parameters were determined using noncompartmental methods. RESULTS: Thirty-two subjects were recruited for the renal impairment study (ten with normal renal function and six, ten and six with mild, moderate and severe impairment, respectively). Thirty subjects were recruited for the hepatic impairment study (eight with normal hepatic function and eight, eight and six with mild, moderate and severe impairment, respectively). The area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) values of free vandetanib increased by approximately 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. These increases were statistically significant, with the increase in the severe renal impairment group having the possibility of being double the value observed in subjects with normal renal function (geometric least squares [GLS] mean ratio [renal impairment : normal renal function] of 1.79; 90% CI 1.39, 2.31). Peak plasma concentrations of free vandetanib increased slightly by approximately 7%, 9% and 11% in subjects with mild, moderate and severe renal impairment, respectively. Total plasma clearance of free vandetanib decreased with all degrees of renal dysfunction. Hepatic impairment did not have a statistically significant effect on the AUC(infinity) of total vandetanib. Peak plasma concentrations of total vandetanib were reduced in subjects with all classifications of hepatic impairment compared with normal hepatic function, with a statistically significant effect in the severe hepatic impairment group (GLS mean ratio 0.71; 90% CI 0.53, 0.96). Increased exposure to both metabolites was seen in subjects with renal impairment. Exposure to N-desmethylvandetanib was reduced in subjects with hepatic impairment, while exposure to vandetanib N-oxide was increased in subjects with severe hepatic impairment. Vandetanib was well tolerated and had a similar tolerability profile in subjects with renal or hepatic impairment compared with healthy subjects. CONCLUSION: Exposure to vandetanib was increased by about 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. A doubling in exposure could be ruled out in subjects with mild or moderate renal impairment but not for those with severe renal impairment. The possibility of dose reductions in patients with severe renal impairment will need to be assessed when the safety and tolerability profile is fully defined. Exposure to vandetanib was not altered in subjects with hepatic impairment, and no dose adjustment would be expected in patients with hepatic impairment.

Pharmacokinetics and pharmacodynamics of growth hormone in patients on chronic haemodialysis compared with matched healthy subjects: an open, nonrandomized, parallel-group trial.

BACKGROUND: GH may be beneficial in treating patients with end-stage renal disease (ESRD). However, the efficacy and safety of GH could be compromised by the potential for accumulation in the circulation. OBJECTIVE: The objective was to investigate the pharmacokinetics and safety of GH treatment in ESRD patients. DESIGN: This was an open, nonrandomized, single-centre parallel-group study lasting 8-9 days. SUBJECTS: Eleven adult ESRD patients and 10 matched healthy individuals received recombinant human GH (50 microg/kg/day for 7 days) by subcutaneous injection; there were two dose reductions (25%) from Day 5/7. ESRD patients underwent dialysis four times. MEASUREMENTS: Serum concentrations of GH, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-I (IGFBP-I), IGFBP-III and GHBP were measured. The primary end-point was GH exposure [area-under-the-curve (AUC) calculated from the 24-h profile] on Days 7-8. RESULTS: GH AUC(0-24 h) was greater for patients (387.91 +/- 134.13 microg h/l) than healthy subjects (225.35 +/- 59.63 microg h/l) and the 90% confidence interval (CI) for the estimated patient : healthy subject ratio (1.40-2.07) was not within the acceptance interval (0.67-1.50). GH AUC(18-24 h) for patients and healthy subjects (3.03 +/- 2.71 microg h/l and 6.37 +/- 4.21 microg h/l) returned approximately to baseline (2.86 +/- 3.91 microg h/l and 1.09 +/- 1.43 microg h/l); terminal half-life (t(1/2,z)) was shorter for patients (2.28 +/- 00.43 h vs. 3.23 +/- 00.75 h). No major safety issues were identified. CONCLUSIONS: Results demonstrate a difference between patients and healthy subjects regarding GH AUC(0-24 h). However, GH concentrations for both groups were comparable to baseline by 20-22 h, thus GH was not retained in the circulation of ESRD patients.

The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole.

AIMS: Fosfluconazole is a phosphate prodrug of fluconazole (FLCZ). This study was conducted to investigate the effect of renal impairment on the pharmacokinetics of fosfluconazole and FLCZ, and to assess the safety and toleration of fosfluconazole following a single intravenous bolus injection of fosfluconazole in subjects with normal and impaired renal function. METHODS: In an open, parallel-group, two-centre study, subjects with normal and impaired renal function received a single 1000-mg bolus intravenous injection of fosfluconazole. Subjects were categorized as Normal (> 80 ml min(-1)), Mild (51-80 ml min(-1)), Moderate (30-50 ml min(-1)) or Severe (< 30 ml min(-1)) impairment group according to their Cockcroft and Gault creatinine clearance (CLcr) values. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 240 h and 48 h postdose, respectively. RESULTS: Fosfluconazole plasma concentrations were very similar across the four groups, and there was no apparent relationship between any of the fosfluconazole pharmacokinetic parameters with increasing renal impairment. The conversion of fosfluconazole to FLCZ was unaffected by the degree of renal impairment. Only small amounts of fosfluconazole were excreted in the urine suggesting almost complete conversion to FLCZ. FLCZ concentrations were still detected in plasma after 240 h postdose and remained higher at the later sampling times in subjects in the Moderate and Severe groups. The area under the plasma concentration vs. time curve between time zero and infinity (AUC), the terminal elimination phase half-life (t(1/2)) and the mean residence time (MRT) of FLCZ all increased with the degree of renal impairment. The ratios (95% confidence interval) for AUC (Renal impairment group/Normal group) were 112.8% (89.5, 142.1), 240.6% (128.2, 451.4) and 355.1% (259.3, 486.3) for the Mild, Moderate and Severe impairment groups, respectively. There was a linear relationship between CLcr with AUC, t(1/2), MRT and the total plasma clearance of FLCZ (CL/F). Both the amount excreted over 48 h in the urine and the renal clearance of FLCZ decreased with an increase in renal impairment. The adverse events reported were mild to moderate in intensity, and there was no observed relationship with impairment group. There were no severe or serious adverse events, and in general fosfluconazole was well tolerated. CONCLUSIONS: The pharmacokinetics of fosfluconazole, including its efficient conversion into FLCZ, were unaffected by renal impairment. For FLCZ, there was a significant linear relationship between CLcr and AUC, t(1/2), MRT and CL/F, with AUC, t(1/2) and MRT increasing and CL/F decreasing as renal impairment increased. The dose adjustment used for FLCZ (half normal dose for patients with CLcr at

Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole.

OBJECTIVE: Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects. METHODS: Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of clomethiazole and its active alpha-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6. RESULTS: The fraction excreted unchanged in urine was less than 0.2% for clomethiazole and less than 0.4% for NLA-715. Urine concentrations of clomethiazole were strongly correlated (r(2)=0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of clomethiazole in all groups. Plasma clearance of clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation. CONCLUSION: The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.

Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based, free-radical trapping agent developed for the treatment of acute stroke.

OBJECTIVE: NXY-059 is a nitrone-based, free-radical trapping agent being developed for the treatment of acute ischaemic stroke. Elimination of NXY-059 is primarily renal. The objective of the study was to investigate the pharmacokinetics of NXY-059 in subjects with renal impairment. METHODS: Twenty-four subjects with a glomerular filtration rate (GFR) ranging from 19 ml/min to 100 ml/min received NXY-059 intravenously over a 24-h period. Drug in plasma and urine was measured for 72 h. One-hour loading infusion rates were proportional to body weight, while maintenance infusion rates were proportional to GFR. Target plasma levels were 60 micro mol/l for subjects with mild (GFR 50-100 ml/min) and moderate (GFR 30-49 ml/min) renal impairment, and 30 micro mol/l for subjects with severe renal impairment (GFR <30 ml/min). GFR was measured as sinistrin clearance. RESULTS: The data indicated no tolerability or safety concerns with NXY-059. The half-life, which normally is approximately 2-4 h, was in the order of 10-12 h in subjects with moderate and severe renal impairment. The distribution parameters steady-state volume of distribution (V(ss)) and unbound fraction in plasma at 13-15 l and 0.53-0.58, respectively, were virtually the same as previously observed in healthy subjects. Plasma clearance of NXY-059, which ranged from 9 ml/min to 76 ml/min, was directly proportional to kidney function (GFR) with no discernible contribution by non-renal clearance. The correlation coefficient squared (r(2)) was 0.93, both when the renal function parameter was GFR and when it was creatinine clearance estimated from serum creatinine, age, weight and sex. CONCLUSION: Non-renal elimination of NXY-059 appeared to be insignificant even in subjects with low renal capacity. Patients with renal impairment should have their dose of NXY-059 adjusted for renal function, conveniently assessed from serum creatinine.