Effect of hepatic or renal impairment on the pharmacokinetics of casopitant, a NK-1 receptor antagonist

Two studies were conducted in subjects with mild or moderate hepatic or renal impairment and subjects with normal organ function to evaluate the pharmacokinetics of casopitant and to assess its safety in these populations. A total of 26 subjects were enrolled in the hepatic impairment study and 18 subjects in the renal impairment study. All subjects received oral casopitant 100 mg once-daily for 5 days. Casopitant area under the concentration-time curve (AUC) increased 11% and 24% in subjects with mild or moderate hepatic impairment, respectively, on Day 1, compared with subjects with normal hepatic function; a similar increase was observed on Day 5. The AUC of the active major metabolite, GSK525060, was reduced 29% and 19% on Days 1 and 5, respectively, in subjects with moderate hepatic impairment, but not altered by mild hepatic impairment. Casopitant AUC increased 34% and 22% on Day 1 in subjects with mild or moderate renal impairment, respectively, and 28% and 11% on Day 5, respectively, compared with subjects with normal renal function. GSK525060 AUC was increased 17% and 24% on Days 1 and 5, respectively, in subjects with mild renal impairment; but did not significantly change in subjects with moderate renal impairment. Further age-adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Plasma protein binding of casopitant and GSK525060 was similar in all subjects. The pharmacokinetics of casopitant is not altered to a clinically significant extent in subjects with mild or moderate, hepatic or renal impairment. The impact of severe hepatic or renal impairment was not evaluated.     

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 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 and pharmacodynamics of cinacalcet in hepatic impairment : phase I, open-label, parallel-group, single-dose, single-centre study

BACKGROUND and objective: The calcimimetic cinacalcet lowers blood para-thyroid hormone (PTH), calcium and phosphorus levels and calcium-phosphorus product in patients with chronic kidney disease receiving dialysis. Cinacalcet is metabolized primarily through oxidative and conjugative pathways. Hepatic disease has the potential to alter cinacalcet metabolism. Thus, it is important to establish the potential for altered cinacalcet metabolism according to the level of hepatic function. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of cinacalcet in subjects with different degrees of hepatic function. METHODS: This was a phase I, open-label, single-dose, parallel-group, single-centre study that included 24 subjects (six with normal hepatic function and six each with mild, moderate and severe hepatic impairment according to Child-Pugh criteria). Subjects were given a single 50 mg oral dose of cinacalcet. Blood samples were taken for pharmacokinetic (pre-dose and up to 120 hours post-dose) and pharmacodynamic (pre-dose and up to 72 hours post-dose) evaluations. Plasma concentrations of cinacalcet were determined using a validated normal phase turbo ion spray liquid chromatography-mass spectrometry/mass spectrometry assay. Serum ionized calcium levels were determined by standard biochemical measures, and PTH levels were determined using an immunometric intact PTH (iPTH) assay. The primary endpoints of the study were area under the concentration-time curve from 0 to time t (AUC(t)), AUC from 0 to infinity (AUC(infinity)) and maximum plasma concentration (C(max)). Other pharmacokinetic parameters (time to C(max) [t(max)], terminal half-life [t((1/2))(beta)], total body clearance [CL/F] and protein binding) and the effect of cinacalcet on plasma PTH and serum calcium were secondary endpoints. RESULTS: Total cinacalcet exposure (AUC(infinity)) was comparable in subjects with normal hepatic function and mild hepatic impairment. In subjects with moderate and severe hepatic impairment, mean AUC(infinity) was 2.4- and 4.2-fold higher, respectively, than in healthy subjects. Cinacalcet t((1/2))(beta) was 1.3- and 1.7-fold longer in subjects with moderate and severe hepatic impairment, respectively, compared with subjects with normal hepatic function. Mean C(max) and t(max), as well as protein binding, were similar in all groups. Consistent with the increase in cinacalcet exposure, decreases in iPTH tended to be greater and prolonged in subjects with moderate and severe hepatic impairment. In this study, cinacalcet was well tolerated. CONCLUSION: These data demonstrate that cinacalcet can be used without dose adjustment in patients with mild hepatic impairment. However, increased drug exposure observed in subjects with moderate to severe hepatic impairment indicates that iPTH and serum calcium levels should be monitored closely and physicians should be more cautious about dose titration in patients with moderate or severe hepatic 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.     

Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban,an oral,direct Factor Xa inhibitor

Aim

This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor.

Method

This single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child–Pugh classification, and gender-matched healthy subjects (n = 16).

Results

Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration–time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect–time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment.

Conclusion

Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects.     

Effect of hepatic impairment on the pharmacokinetics of pasireotide (SOM230): results from a multicenter phase I study

Pasireotide is a novel, multireceptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5) under clinical evaluation in tumors of neuroendocrine origin, including Cushing's disease, acromegaly, and neuroendocrine tumors. In this phase I, open-label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 μg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 μg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC(∞) by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 μg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.     

Pharmacokinetics and safety of galantamine in subjects with hepatic impairment and healthy volunteers

The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open-label study in which a single oral 4-mg dose of galantamine was administered to volunteers with mild (Child-Pugh score of 5-6, n = 8), moderate (Child-Pugh score of 7-9, n = 8), or severe hepatic impairment (Child-Pugh score of 10-15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma-concentration curve from zero to infinity (AUC0-infinity) (+33%) and terminal half-life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similarto those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild ormoderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.     

Pharmacokinetics of linagliptin in subjects with hepatic impairment

AIM

To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability.

METHOD

This open label, parallel group, single centre study enrolled patients with mild (n = 8), moderate (n = 9) or severe (n = 8) hepatic impairment and healthy subjects (n = 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects.

RESULTS

In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects [AUC_τ,ss geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and C_max,ss GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUC_τ,ss GMR 85.5%, 90% CI 70.2%, 104.2% and C_max,ss GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and C_max was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or C_max and renal excretion of unchanged linagliptin (≤7%) were comparable across groups. Median plasma DPP-4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady-state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated.

CONCLUSION

Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment.     

FTY720 pharmacokinetics in mild to moderate hepatic impairment

The influence of mild and moderate hepatic impairment on FTY720 pharmacokinetics was assessed. The authors enrolled 32 subjects consisting of 8 with mild and 8 with moderate hepatic impairment based on Child-Pugh criteria and 16 demographically matched control subjects. A single 1-mg oral dose of FTY720 was administered under fasting conditions. Blood, plasma, and urine samples were obtained over a 14-day period for measurement of FTY720 and metabolite concentrations and protein binding. Total blood lymphocyte counts and heart rate were serially monitored to assess pharmacologic responses to FTY720. Peak FTY720 blood concentrations were similar across groups. Oral clearance (CL/F) was reduced 10% in mild hepatic impairment (P = .493) and 31% in moderate hepatic impairment (P = .034). There were no significant differences in blood exposure to the hexanoic or butanoic acid metabolites among groups. The effect of FTY720 on blood lymphocytes was similar across groups, with a mean decrease of 44% from the predose value. Like-wise, the effect of FTY720 on supine heart rate was similar across groups, with a mean 13% decrease from the predose rate occurring 2 to 4 hours postdose and recovering within 1 to 2 days. Although hepatic impairment elicited changes in the disposition of FTY720, the magnitude of these changes suggests that the FTY720 dose does not need to be adjusted in mild or moderate hepatic-impaired patients.     

The effect of hepatic or renal impairment on the pharmacokinetics of edivoxetine, a selective norepinephrine transporter reuptake inhibitor

Purpose

To assess the impact of hepatic or renal impairment on the pharmacokinetics (PK) of edivoxetine.

Methods

Two separate multi-center, open-label studies with males and females were conducted. Subjects were categorized according to their hepatic function, determined by the Child–Pugh classification, or renal function, determined by creatinine clearance using the Cockcroft–Gault equation. Subjects received a single dose of 18 mg in the hepatic impairment study or 6 mg in the renal impairment study. Noncompartmental PK parameters were computed from the edivoxetine plasma concentration–time data.

Results

In the hepatic study, the geometric least squares mean (GLSM) and 90 % confidence interval (CI) of the ratio [impaired : normal] of area under the concentration versus time curve from time zero to infinity (AUC0-∞; h?×?ng/mL) was 1.24 (0.93, 1.64) in the mild, 1.60 (1.21, 2.12) in the moderate, and 1.70 (1.28, 2.24) in the severe group. In the renal impairment study, the GLSM (90 % CI) of the ratio [impaired : normal] of AUC0-∞ was 1.13 (0.73, 1.73) in mild, 1.90 (1.28, 2.82) in moderate, 1.55 (0.94, 2.55) in severe, and 1.03 (0.66, 1.59) in ESRD groups. Overall, the GLSM of the ratio [impaired : normal] of C_max was slightly less than or approximately 1 across the hepatic and renal impairment groups. Across both studies, there were no clinically significant changes in vital signs and laboratory values, the adverse events were mild in severity and mostly related to nervous system and gastrointestinal disorder-related events.

Conclusions

PK changes in subjects with hepatic or renal impairment were of small magnitude and did not appear to impact overall subject tolerability. Daily dosing of edivoxetine in a larger population of impaired subjects, including those with dual impairment, would aid in establishing edivoxetine tolerability and PK in a clinical practice scenario.     

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

AIMS: Fosfluconazole is a phosphate pro-drug of fluconazole (FLCZ). This study was conducted to determine the pharmacokinetics of fosfluconazole and FLCZ following a single intravenous injection of fosfluconazole in subjects with hepatic impairment and to compare them with healthy subjects. METHODS: Twenty-four subjects (12 with normal hepatic function and 12 with chronic stable mild to moderate impaired hepatic function) received a single 1000-mg bolus intravenous injection of fosfluconazole. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 192 h and 48 h postdose, respectively. RESULTS: The total clearance of fosfluconazole was higher and the t(1/2,Z) and mean residence time were shorter in hepatically impaired subjects than in normal subjects. This may reflect more rapid conversion to FLCZ. The degree of protein binding of fosfluconazole (> 90%) and the amount of fosfluconazole excreted in the urine were similar in both groups. Slightly higher mean plasma concentrations of FLCZ were observed in the impaired group than in the normal group; however, hepatic impairment had no statistically significant effect on the FLCZ pharmacokinetic parameters apart from t(max). The t(max) values were 4.8 h and 3.1 h in the normal and impaired subjects, respectively. The shorter t(max) for FLCZ is also consistent with the more rapid conversion in the impaired subjects. The ratios (95% confidence intervals) for C(max) and AUC of FLCZ (impaired/normal) were 106.0% (92.8, 121.2) and 115.6% (86.4, 154.7), respectively. There were no serious adverse events, and no discontinuations due to adverse events or laboratory test abnormalities. The adverse events reported were mostly mild in severity and no trend could be discerned between the groups. CONCLUSIONS: Fosfluconazole was more rapidly converted to FLCZ in the hepatically impaired subjects but the FLCZ pharmacokinetic parameters (except t(max)) were not statistically significantly affected by hepatic impairment. Fosfluconazole was well tolerated by both groups. These results suggest that there is no requirement to adjust the dose of fosfluconazole when administered to subjects with mild to moderate hepatic impairment.     

The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase

Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once-daily oral febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and >or=65 years. Although unbound peak concentration (C(max,u)) and area under the concentration-time curve (AUC(24,u)) for febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P 相似文献   

Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment

Aims

To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT®) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function.

Methods

Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein).

Results

Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUC_inf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6–132%) and 119% (90% confidence interval, 94.1–151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg).

Conclusions

These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.     

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.     

The effect of mild and moderate hepatic impairment on the pharmacokinetics of valdecoxib, a selective COX-2 inhibitor

Purpose This study evaluated the effects of varying degrees of hepatic impairment on the pharmacokinetics and safety of valdecoxib following single and multiple dosing.Methods This was an open-label, randomised, parallel group study in 12 subjects with mild hepatic impairment (Child-Pugh Class A) and in 13 with moderate hepatic impairment (Child-Pugh Class B) matched for age, weight, sex, and smoking status; there were two control groups of 12 healthy volunteers, one for each study group. All subjects received a single dose of valdecoxib 20 mg on day 1 and valdecoxib 20 mg twice daily on days 4–7, followed by a single morning dose on day 8. Plasma concentrations of free (unbound) and total valdecoxib and its active hydroxylated metabolite (SC-66905) were measured following single and multiple dosing (day 1 and day 8). Additionally, all subjects received a single intravenous dose of lidocaine 60 mg during the pretreatment period to determine plasma concentrations of monoethylglycinexylidide (MEGX) as a marker of hepatic CYP3A4 activity.Results The mean apparent oral clearance of free valdecoxib in plasma at steady state decreased by 22–25% in those with mild to moderate impairment (corresponding to a 28–33% increase in the AUC of free valdecoxib and a 19–23% decrease in the AUC of total SC-66905). The mean free fraction of valdecoxib in plasma increased by 9–38%, resulting in a mean decrease in apparent oral clearance of total valdecoxib in plasma of 0–15% (corresponding to a 0–17% increase in the AUC of total valdecoxib). Individual AUCs for free valdecoxib and total SC-66905 did not correlate well with AUCs for MEGX, indicating that decreases in intrinsic clearance of valdecoxib in those with hepatic impairment could not solely be explained by decreased CYP3A4 expression in hepatic impairment.Conclusions In our small study sample, mild and moderate hepatic impairment appeared to have only a modest effect on valdecoxib and SC-66905 pharmacokinetics. The adjustment of valdecoxib dose or dosing regimen does not appear mandatory in subjects with mild or moderate hepatic impairment, although caution is necessary during treatment of these patients with valdecoxib.     

Effect of mild and moderate hepatic impairment on the pharmacokinetics and safety of carisbamate

This open-label, parallel-group study was designed to characterize the pharmacokinetics (PK) of carisbamate in participants with mild or moderate hepatic impairment versus those with normal hepatic function. Healthy (n = 10) and hepatic-impaired (n = 20) participants received a single 200-mg oral dose of carisbamate. Serial PK blood samples were collected up to 120 hours postdose. A modest increase in mean area under the plasma concentration-time curve from 0 to infinity (AUC(∞)) was observed for the mild impairment group compared with the normal group (ratio of geometric means ~116%), while mean maximum plasma concentration (C(max)) values were similar (ratio of geometric means ~94%). The AUC(∞) value for the moderate hepatic-impaired group was approximately 207% that of the normal group, while there was a smaller increase in C(max) (~118%) compared with the normal group. Mean half-life (t(1/2)) values were prolonged in the moderate impairment group (21 hours) relative to the normal group (11 hours). There was a decrease in apparent clearance (CL/F) and an increase in AUC(∞u) (AUC(∞) × % drug unbound). The percentage of carisbamate unbound to proteins did not change across the groups, suggesting the increases in AUC(∞) were due to decreased intrinsic hepatic clearance. Carisbamate 200 mg was well tolerated.     

Effect of mild and moderate hepatic impairment on azimilide pharmacokinetics following single dose oral administration

Azimilide dihydrochloride (75-125 mg/day) is currently being developed for use in prolonging the time to recurrence of atrial fibrillation/flutter and for reducing the frequency of shocks in patients with an implantable cardioverting defibrillator. This study investigated the influence of mild and moderate hepatic impairment on azimilide pharmacokinetics. Six subjects each with mild and moderate hepatic impairment (Child-Pugh grades A and B, respectively) were age, weight, smoking status, and gender-matched to a healthy subject (total N = 24). Each subject was administered a single, oral dose of 100 mg azimilide dihydrochloride following an overnight fast. Blood/plasma and urine samples were collected up to 28 days and over 9 days, respectively, and analyzed using HPLC with MS/MS or UV detection. For azimilide, most parameters in subjects with mild to moderate hepatic impairment were within 25% of those observed in matched healthy subjects, with no statistically significant differences observed. For F-1292 (major metabolite in plasma), a significant decrease in AUC was observed in subjects with moderate hepatic impairment, secondary to an increase in renal clearance (CL(r)). Based on these results, no a priori dosage adjustment is required in subjects with mild to moderate hepatic impairment.     

Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment

Desloratadine, a nonsedating histamine H(1)-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6- to 6.5-fold greater than in other subjects with normal liver function. Eleven treatment-related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.     

Effects of gender, age, diabetes mellitus and renal and hepatic impairment on tadalafil pharmacokinetics

AIMS: To evaluate the effects of gender, age, diabetes mellitus, renal and hepatic impairment on tadalafil pharmacokinetics and tolerability. METHODS: Six single-dose (5, 10 or 20 mg orally) clinical pharmacology studies were conducted in the UK, Belgium, Poland and Germany in healthy male and female subjects, elderly subjects and subjects with diabetes mellitus, renal impairment, end-stage renal failure (ESRF) or hepatic impairment. The gender study also incorporated administration of 10 mg tadalafil daily for 10 days. RESULTS: Systemic exposure in the elderly was 25% greater than in young subjects (mean AUC ratio 1.25; 90% confidence interval 0.972, 1.61). The AUC was 19% lower in subjects with diabetes mellitus than in healthy age/gender-matched controls. Pharmacokinetics in female subjects were essentially similar to those in males. Exposure in subjects with mild or moderate renal insufficiency was approximately twice that in healthy subjects. The mean AUC for the major metabolite (total methylcatechol glucuronide) in the presence of ESRF was three times the mean for healthy subjects. Haemodialysis contributed negligibly to elimination of tadalafil or the metabolite. Hepatic impairment had negligible effects on exposure. The most common adverse events in these six studies were headache, back pain and myalgia. A 10-mg dose was not well tolerated by subjects with moderate renal dysfunction in this study. CONCLUSIONS: No clinically significant effect of gender, age, diabetes mellitus or hepatic impairment on tadalafil pharmacokinetics was observed. Renal insufficiency resulted in increased systemic exposure. Tadalafil was not associated with any serious clinically significant adverse events or study discontinuations due to adverse events.