Effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole

BACKGROUND AND OBJECTIVES: Two studies were conducted to investigate whether the pharmacokinetics of the atypical antipsychotic aripiprazole were altered in individuals with hepatic or renal impairment compared with those with normal hepatic or renal function. STUDY DESIGN: Two open-label, single-dose studies. STUDY SETTING: Clinical research unit. PATIENTS: Study 1: Subjects with normal hepatic function (n = 6) and subjects with hepatic impairment (Child-Pugh class A [mild, n = 8], B [moderate, n = 8] or C [severe, n = 3]). Study 2: Subjects with normal renal function (creatinine clearance >80 mL/min; n = 7) and subjects with severe renal impairment (creatinine clearance <30 mL/min; n = 6). TREATMENT: Single oral dose of aripiprazole 15 mg. PHARMACOKINETIC ANALYSES: Noncompartmental pharmacokinetic analysis was performed using plasma aripiprazole and dehydro-aripiprazole concentration-time data. MAIN OUTCOME MEASURES: Study 1 (hepatic impairment study): apparent oral clearance of unbound drug (CL/Fu) and the maximum plasma concentration (Cmax) of aripiprazole; Study 2 (renal impairment study): CL/Fu, Cmax and renal clearance (CL(R)). Safety assessments included 12-lead ECGs, vital sign monitoring, clinical laboratory measurements and assessment of adverse events.f RESULTS: In the hepatic impairment study, the mean total Cmax of aripiprazole was significantly lower in subjects with severe hepatic impairment compared with those with normal hepatic function (p = 0.04). The fraction of aripiprazole unbound (fu) was significantly greater for subjects with mild (p = 0.02) or severe hepatic impairment (p < 0.01) but not for those with moderate hepatic impairment (p = 0.09) compared with healthy controls. There were no meaningful differences in either the Cmax of unbound aripiprazole or CL/Fu between groups. The mean CL(R) of aripiprazole was negligible (0.04 mL/h/kg in controls and 0.19 mL/h/kg in patients with severe hepatic impairment). In the renal impairment study, the mean total Cmax values were numerically higher (approximately 40%) and the area under the plasma aripiprazole concentration-time curve from time zero to infinity was lower (approximately 19%) in renally impaired subjects versus those with normal renal function; the fu was comparable between groups. Aripiprazole CL(R) was approximately 3-fold higher in renally impaired subjects, but this difference was not statistically significant. No deaths or serious adverse events were reported during either study. CONCLUSION: A single aripiprazole 15-mg dose was well tolerated. There were no meaningful differences in aripiprazole pharmacokinetics between groups of subjects with normal hepatic or renal function and those with either hepatic or renal impairment. Adjustment of the aripiprazole dose does not appear to be required in populations with hepatic or renal impairment.     

Pharmacokinetics of maribavir, a novel oral anticytomegalovirus agent, in subjects with varying degrees of renal impairment

The effect of renal function on the pharmacokinetics of maribavir, a novel anticytomegalovirus agent, was evaluated in 12 adults with normal renal function (creatinine clearance [CrCl] >80 mL/min) and 19 adults with renal impairment classified as mild (n = 5), moderate (n = 5), or severe (n = 9), as measured by CrCl 50-80, 30-49, and <30 mL/min, respectively. After a single oral dose of maribavir 400 mg, the pharmacokinetics of maribavir, based on total and unbound plasma concentrations, showed no statistically significant difference between subjects with normal renal function and subjects with mild/moderate or severe renal impairment. Renal impairment was associated with an increase in area under the plasma concentration-time curve (AUC) values for an inactive metabolite of maribavir, VP 44469. Results were consistent with those of previous studies, which showed that very little maribavir was excreted unchanged in urine, whereas about 22% of an oral dose of maribavir is recovered in urine as VP 44469.     

Famotidine disposition in children and adolescents with chronic renal insufficiency

The pharmacokinetics of intravenous famotidine (0.5 mg/kg, maximum 20 mg) were evaluated in 18 pediatric patients (ages 1-18 years) with stable, chronic renal insufficiency. Subjects were stratified by calculated creatinine clearance (Clcr) into mild (Clcr > or = 50 to < 90 mL/min/1.73 m2), moderate (Clcr > or = 25 to < 50 mL/min/1.73 m2), and severe (Clcr < or = 10 mL/min/1.73 m2) renal insufficiency groups. Significant differences between the mild, moderate, and severe groups were found for elimination rate (Kel), apparent elimination half-life (t1/2), area under the curve (AUC), and total plasma clearance (Clp) (p < 0.01). Famotidine renal clearance (Clr) was found to be significantly different between the mild and severe groups (p < 0.05). A linear relationship was observed between Clcr and Clp (p < 0.0001; R2 = 0.70). No significant differences in nonrenal clearance (Clnr) were found between groups; however, Clnr as a percentage of Clp was significantly different in the severe group (92.9% +/- 7.3% Clnr) compared to the combined mild and moderate groups (21.9% +/- 45.6% Clnr) (p < 0.05). It was concluded that the pharmacokinetics of famotidine are significantly altered in children with chronic renal insufficiency; accordingly, dosing should be based on glomerular filtration rate (i.e., Clcr).     

Pharmacokinetics of intravenous, single-dose tiotropium in subjects with different degrees of renal impairment

Tiotropium, a new potent anticholinergic bronchodilator, is excreted mainly by the kidney. To investigate the pharmacokinetics of tiotropium in renal impairment, the authors evaluated the pharmacokinetics and safety after administration of a single dose of intravenous tiotropium 4.8 microg, given as an infusion over 15 minutes in subjects with normal renal function and a wide range of renal impairment based on measured creatinine clearance (normal: > 80 mL/min, n = 6; mild impairment: > 50-80 mL/min, n = 5; moderate impairment: 30-50 mL/min, n = 7; severe impairment: < 30 mL/min, n =6). As expected for a drug excreted predominantly in unchanged form by the kidneys, tiotropium plasma concentrations increased as renal impairment worsened, with mean values of 55.5 (16.2 percent geometric coefficient of variation [%gCV]), 77.1 (20.1 %gCV), 101 (29.8 %gCV), and 108 (27.3 %gCV) pgh/mL for AUC(0-4h) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. The percentage of tiotropium dose excreted unchanged in the urine decreased from 60.1% of dose (17.7 %gCV) to 59.3% (14.4 %gCV), 39.9% (34.5 %gCV), and 37.4% (10.2 %gCV) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. Plasma protein binding of tiotropium did not significantly change in the renal-impaired subjects. Two subjects with normal renal function experienced headache 10 hours after the infusion, which was mild and transient. No adverse events occurred in subjects with renal impairment. There were no clinically relevant changes in blood pressure, pulse rate, 12-lead ECG, physical examination, hematology, or clinical chemistry, compared with baseline values, in any subject after intravenous administration of tiotropium. Tiotropium should only be used in patients with moderate to severe renal insufficiency if the potential benefit outweighs the potential risks.     

Pharmacokinetics of rizatriptan in healthy elderly subjects.

OBJECTIVE: Rizatriptan is a serotonin 5-HT1B/1D receptor agonist for acute treatment of migraine. Its pharmacokinetics were assessed in healthy elderly males and females receiving a single 10 mg tablet oral dose. The pharmacokinetic data (AUC(0-infinity) and Cmax) for the elderly in this study were compared with historical data from previous studies for healthy young adults (n = 65). METHODS: In a double-blind, parallel, placebo-controlled study, healthy elderly female and male subjects aged 65 or older (n = 8 each) received a single oral dose of 10 mg rizatriptan. Plasma and urine concentrations of drug were determined by HPLC with tandem mass spectrometry detection at several collection time points or intervals starting at predose and postdose over 24 h. RESULTS: In elderly subjects, the geometric mean values for AUC(0-infinity) and Cmax were 77.7 ng/h/ml and 21.9 ng/ml; the average values for tmax, half-life (t 1/2), renal clearance (Clr), and percent urinary excretion of dose (Ue) were 1.2 h, 1.8 h, 197 ml/min and 9.3%, respectively. The AUC(0-infinity) and Cmax of rizatriptan were similar in elderly and young subjects. The geometric mean AUC ratio of elderly to young was 0.96 with 90% confidence interval (0.83, 1.11), p > 0.25. The geometric mean Cmax ratio was 0.89 with 90% confidence interval (0.72, 109), p > 0.25. No significant pharmacokinetic differences were observed between elderly males and females. CONCLUSIONS: The plasma pharmacokinetics of rizatriptan appear to be similar in the elderly and young. In the elderly, the pharmacokinetics of rizatriptan do not appear to differ between male and female to a clinically significant extent.     

Pharmacokinetics of single-dose reboxetine in volunteers with renal insufficiency

Reboxetine is a new selective norepinephrine reuptake inhibitor (selective NRI) for the short- and long-term treatment of depression that is effective and well tolerated at a dose of 8 to 10 mg/day. This study assessed the pharmacokinetics of reboxetine in volunteers with renal impairment. A single 4 mg dose of reboxetine was administered to a total of 18 volunteers with mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment (creatinine clearance: 56-64, 26-51, and 9-19 ml/min, respectively), and reboxetine concentrations were measured in plasma by HPLC. Mean AUC infinity increased by 43% (mild vs. severe; p < 0.01) as renal function declined, while renal clearance and total urinary excretion of unchanged reboxetine decreased by 67% and 62%, respectively (mild vs. severe; p < 0.01 for both parameters). tmax and t1/2 were not significantly different between groups. In comparison with historical data from young healthy volunteers, AUC infinity and t1/2 are at least doubled in volunteers with renal impairment, while CLr is halved. This pharmacokinetic study has shown that increasing renal dysfunction leads to increasing systemic exposure to reboxetine, particularly in severe renal insufficiency, although reboxetine was well tolerated by all volunteers. Thus, a reduction of the starting dose of reboxetine to 2 mg twice daily would be prudent in patients with renal dysfunction.     

Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate

OBJECTIVE: Antiepileptic drugs are often used in patients with some degree of renal impairment. The objective of this study was to evaluate the effect of renal function on the pharmacokinetics of eslicarbazepine acetate (ESL, formerly known as BIA 2-093), a new antiepileptic drug under clinical development. METHODS: ESL pharmacokinetics following 800 mg single dose was characterized in subjects with normal renal function (n=8, control group), and in patients with mild renal impairment (n=8), moderate renal impairment (n=8), severe renal impairment (n=8), and end-stage renal disease requiring hemodialysis (n=8). RESULTS: ESL suffered extensive first-pass hydrolysis to eslicarbazepine (S-licarbazepine), the main active metabolite. While eslicarbazepine Cmax did not significantly differ between the different groups, the extent of systemic exposure, assessed by AUC, increased when renal function decreased. Eslicarbazepine CL/F and CLR were, respectively, 3.40 l/h and 1.04 l/h (17.3 ml/min) in the control group, and 2.10 l/h (35.0 ml/min) and 0.61 l/h (10.2 ml/min) in the mild, 1.60 l/h (26.7 ml/min) and 0.22 l/h (3.7 ml/min) in the moderate, and 1.33 l/h (21.2 ml/min) and 0.09 l/h (1.5 ml/min) in the severe renal impairment groups. Although the total amount of eslicarbazepine recovered in urine until 72 h post-dose was similar in the control and mild renal impairment groups, a decrease was found in the moderate and severe renal impairment groups. Major metabolites recovered in urine were eslicarbazepine and its glucuronide form. Clearance of minor metabolites (R-licarbazepine, oxcarbazepine and their glucuronides) was also dependent on renal function. In patients with end-stage renal disease, dialysis was effective in removing the ESL metabolites from the circulation. CONCLUSIONS: ESL metabolites are excreted primarily by renal route and their clearance is dependent on renal function. ESL dosage adjustment may be necessary in patients with a creatinine clearance <60 ml/min.     

Pharmacokinetics and safety of a single oral dose of once-daily alfuzosin, 10 mg,in male subjects with mild to severe renal impairment

The effect of renal impairment on the safety and pharmacokinetics of a once-daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single-dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.20, 1.52, and 1.20 in subjects with mild, moderate, or severe renal impairment, respectively, compared with controls. Values for AUC(0-infinity) were 1.46, 1.47, and 1.44, respectively. The t(1/2z) was increased only in the group with severe renal impairment. Emergent vasodilatory adverse events were reported by 4 of 26 subjects. No discontinuations due to adverse events occurred. Laboratory parameters were satisfactory in all groups. In conclusion, once-daily alfuzosin, 10 mg, could be safely administered to patients with impaired renal function, and dosage adjustment does not seem necessary.     

The effect of acarbose on the pharmacokinetics of rosiglitazone

OBJECTIVES: To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. METHODS: Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. RESULTS: Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-h (23%) reduction in terminal elimination half-life t1/2 (4.9 h versus 3.8 h). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and t1/2 are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. CONCLUSION: Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.     

Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C(max), CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.     

Pharmacokinetics of cerivastatin in renal impairment are predicted by low serum albumin concentration rather than by low creatinine clearance

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.     

Pharmacokinetics of lopinavir/ritonavir in HIV/hepatitis C virus-coinfected subjects with hepatic impairment

The effect of hepatic impairment on lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.     

Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis

The present study investigated the effect of renal impairment and hemodialysis on the pharmacokinetics of lenalidomide following a single 25-mg oral dose in 30 subjects aged 39 to 76 years. A single 25-mg dose was well tolerated by renally impaired subjects. Renal impairment did not alter the oral absorption, protein binding, or nonrenal elimination of lenalidomide. Mean urinary recovery of unchanged lenalidomide was 84% of the dose in subjects with normal renal function (creatinine clearance [CL(Cr)] > 80 mL/min), and it declined to 69%, 38%, and 43% in subjects with mild (50 < or = CL(Cr) < or = 80 mL/min), moderate (30 < or = CL(Cr) < 50 mL/min), and severe (CL(Cr) < 30 mL/min) renal impairment, respectively. The differences in pharmacokinetic parameters between normal renal function and mild renal impairment were minor to modest (11%-32%). As renal impairment progressed to moderate, severe, or end-stage renal disease, total and renal lenalidomide clearance decreased drastically, area under the concentration-time curve increased by approximately 185% to 420%, and t((1/2)) was prolonged by approximately 6 to 12 hours. A 4-hour hemodialysis removed 31% of lenalidomide in the body. Therefore, lenalidomide dose adjustments should be considered for patients with CL(Cr) < 50 mL/min, and the recommendations are given for the starting doses.     

The influence of renal function on hydroxyurea pharmacokinetics in adults with sickle cell disease

This was an open-label, nonrandomized, 2-center study conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea in adults with sickle cell disease (SCD). Seventeen patients were divided into 5 groups: normal renal function (n = 7), mild renal impairment (n = 2), moderate renal impairment (n = 3), severe renal impairment (n = 2), and end-stage renal disease (ESRD, n = 3). Except for patients with ESRD, all the patients received a 15-mg/kg single oral dose of hydroxyurea. Patients with ESRD received a 15-mg/kg oral dose of hydroxyurea on 2 occasions. Blood and urine samples were collected for the assessment of hydroxyurea pharmacokinetics. The results indicate that the systemic exposure increases and the urinary recovery decreases as the degree of renal insufficiency worsens. On the basis of the exposure and the apparent clearance from the current and 2 historical studies, the authors have proposed an initial dosing regimen of hydroxyurea (7.5 mg/kg/day) for SCD patients with CL(cr) <60 mL/min. This dosing strategy is anticipated to provide a safe dose for SCD patients with renal impairment.     

Influence of severe renal dysfunction on the pharmacokinetics and metabolism of bosentan,a dual endothelin receptor antagonist

BACKGROUND: One of the potential indications of bosentan, a dual endothelin receptor antagonist, is chronic heart failure. Patients with chronic heart failure frequently also suffer from impaired renal function. OBJECTIVE: To explore the influence of severe renal dysfunction on the pharmacokinetics and metabolism of bosentan in a monocenter, open label, parallel group study. METHODS: Eight renal patients with creatinine clearance 17 - 27 ml/min and 8 healthy subjects (creatinine clearance 99 - 135 ml/min) received a single oral dose of 125 mg bosentan and plasma samples drawn for up to 36 hours after administration were analyzed for bosentan and 3 metabolites. RESULTS: The pharmacokinetic parameters of bosentan did not differ significantly between the study groups: geometric means (95% confidence interval) for Cmax were 1.8 (1.2 - 2.8) and 1.1 microg/ml (0.74 - 1.7), and for AUC0-infinity 7.2 (5.1 - 10.4) and 6.4 (3.4 - 11.2) microg x h/ml in healthy subjects and renal patients, respectively. Levels of the 3 CYP2C9- and CYP3A4-derived metabolites increased approximately 2-fold in renal patients, both in absolute terms and in relation to the parent compound. In renal patients, the exposure to Ro 48-5033, the only pharmacologically active metabolite, was 13% of that to bosentan. CONCLUSION: Severe renal dysfunction did not affect the pharmacokinetics of bosentan to a clinically relevant extent and, therefore, no dose adjustments are deemed necessary in patients with any grade of renal insufficiency.     

Effect of renal impairment on the pharmacokinetics of memantine

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.     

Clinical pharmacokinetics of trospium chloride

Trospium chloride, a quaternary amine with anticholinergic properties, is used for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. The pharmacokinetics of trospium chloride have been investigated in healthy volunteers, in patients with renal and hepatic impairment, and in those with symptoms of overactive bladder, after oral, intravenous and intravesical administration.After oral administration, absorption of the hydrophilic trospium chloride is slow and incomplete. Peak plasma concentrations (Cmax) of approximately 4 ng/mL are reached 4-5 hours after administration of a 20 mg immediate-release preparation. The mean bioavailability is approximately 10% and decreases by concomitant food intake (to a mean of 26% of the fasting area under the plasma concentration-time curve [AUC]). Trospium chloride displays dose proportional increases in AUC and Cmax after a single dose within the clinically relevant dose range (20-60 mg). The mean volume of distribution is approximately 350-800 L. The drug is minimally (mean approximately 10%) metabolised to spiroalcohol by hydrolysis, is 50% plasma protein bound and does not cross the blood-brain barrier. Urinary excretion of the parent compound plays a major role in the disposition of the drug, with a mean renal clearance of 29 L/h (accounting for approximately 70% of total clearance) and a mean elimination half-life ranging from 10 to 20 hours. Elimination of the drug is slowed in patients with renal insufficiency, and population pharmacokinetic modelling has demonstrated that drug clearance is correlated with serum creatinine concentration. Thus, dose reduction is needed in patients with severe renal impairment (i.e. creatinine clearance < 30 mL/min).To date, no clinically relevant pharmacokinetic drug-drug interactions have been identified; the drug does not bind to any of the drug metabolising cytochrome P450 enzymes.The pharmacokinetics of the drug are compatible with twice-daily administration. A once-daily schedule may also be appropriate, but this regimen needs formal clinical evaluation.     

Population pharmacokinetics of unbound mycophenolic Acid in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation

Mycophenolate mofetil (MMF) is an immunosuppressant routinely used in allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment and prevent acute graft vs host disease. Administered as a prodrug, MMF is converted by esterases to the active moiety, mycophenolic acid (MPA). The impact of clinical covariates on unbound MPA exposure was investigated with a population pharmacokinetic approach. Pharmacokinetic data were obtained from routine area under the curve (AUC) monitoring of unbound MPA drug levels in 36 pediatric (n = 31) and young adult (n = 5) patients undergoing alloHCT for a variety of malignant and nonmalignant disorders. Unbound MPA pharmacokinetics were well described by a 2-compartment model with linear elimination and first-order absorption. The important clinical covariates affecting unbound MPA pharmacokinetics were weight, estimated creatinine clearance, and total bilirubin. Unbound MPA clearance was reduced, and exposure (AUC(0-8)) increased in individuals with decreased renal function. In individuals with severe hepatic dysfunction (total bilirubin >10 mg/dL) unbound MPA clearance was approximately 3-fold lower compared with patients with normal to mild hepatic impairment. In alloHCT recipients with renal dysfunction or severe hepatic injury, dose reductions may be necessary to prevent toxicity and ensure optimal immunosuppression.     

Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function

In this open-label study, the authors assessed the pharmacokinetics and safety of ibandronate in patients with multiple myeloma and varying renal function. Renal deterioration was graded at baseline depending on creatinine clearance in 4 stages (0: >80; 1: 50-79; 2: 30-49, and 3: <30 mL/min). Patients (n = 40) received intravenous ibandronate 6 mg (30-minute infusion). Ibandronate excretion and serum levels were measured over 24 hours. Serum creatinine, creatinine clearance, and markers of tubular damage were monitored before ibandronate infusion and at 24 and 72 hours following ibandronate infusion. Ibandronate clearance, AUC(0-24), AUC(0-infinity), serum t((1/2)), and C(max) were calculated. There was a significant positive correlation between ibandronate clearance and creatinine clearance (r = 0.858; P < .00001). The AUC for grade 3 renal insufficiency increased by approximately 60% versus grade 0 (P < .01) but was not significantly different between other grades of renal function. The t((1/2)) did not increase significantly, and peak serum levels of ibandronate were similar for the 4 grades of renal function. Serum creatinine, creatinine clearance, and markers of tubular damage did not change significantly within 72 hours of ibandronate infusion. Despite renal function already being compromised in this patient group, there was no evidence of acute nephrotoxicity with ibandronate.     

Pharmacokinetics of flutamide in patients with renal insufficiency

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.