Effect Of Severe Renal Impairment Research Articles

Effect of Severe Renal Impairment on Pharmacokinetics, Safety, and Tolerability of ACT-1014-6470, a Novel Oral Complement Factor 5a Receptor 1 Antagonist.

The aim of this study was to examine the safety and the effect of severe renal impairment (RI) on the pharmacokinetics of ACT-1014-6470, a novel oral complement factor 5a receptor 1 antagonist. A phase 1 single-center, open-label, single-dose, parallel-group study was conducted in subjects with severe RI (n=8) compared to demographically pairwise matched subjects with normal renal function (n=8). Plasma levels of ACT-1014-6470 were measured up to 120hours following an oral 40-mg dose. Safety evaluations included adverse events (AEs), vital signs, hematology, coagulation, clinical chemistry tests, and electrocardiograms. All 16 subjects completed the study. Relative to subjects with normal renal function, ACT-1014-6470 time to maximum plasma concentration was delayed with a median of differences of 3hours. The maximum plasma concentration and the area under the plasma concentration-time profile from time zero to infinity were comparable indicated by geometric mean ratios (90%CI) of 0.85 (0.53-1.37) and 1.17 (0.73-1.85), respectively. Four transient and mild AEs in three subjects with severe RI were reported; three AEs were considered not related to ACT-1014-6470. These results support the use of ACT-1014-6470 in subjects with mild to severe RI without the need of dose adjustment.

Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986.

IntroductionAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure (HF). The safety and pharmacokinetics (PK) of AMG 986 in participants with renal impairment (RI) remains unknown.MethodsThis phase 1 study compared the safety and PK of AMG 986 200 mg in six participants with severe RI (estimated glomerular filtration rate [eGFR] 15–29 mL/min/1.73 m2) versus six participants with normal renal function (eGFR ≥ 90 mL/min/1.73 m2).ResultsFollowing a single oral dose of AMG 986 200 mg on day 1, the maximum observed concentration increased 1.41-fold (90% confidence interval [CI] 0.88–2.27) and the area under the curve from time zero to infinity increased 1.23-fold (90% CI 0.73–2.06) in participants with severe RI versus normal renal function. AMG 986 had an acceptable safety profile; all adverse events were mild in severity.ConclusionsThe results of this study support the enrollment of HF patients with RI to clinical trials of AMG 986 without the need for dose adjustments.Trial Registration NumberNCT03318809 (registered: October 24, 2017).

CPX-351 Population Pharmacokinetics in Patients with Hematologic Malignancies

CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, demonstrated significant survival benefit versus the conventional 7+3 regimen of cytarabine/daunorubicin in patients with secondary acute myeloid leukemia. A population pharmacokinetic (PK) analysis of total (ie, encapsulated + unencapsulated drug) plasma concentrations of cytarabine and daunorubicin following IV administration of CPX-351 assessed sources of variability in PK and determined if covariate-based dose adjustments may be warranted, particularly in patients with renal or hepatic impairment.The PK population consisted of 195 patients with advanced hematologic malignancies. The median age was 67 years (range: 24-81) and body weight was 79.8 kg (range: 38.9-156.5). There were 119 (61.0%) male and 76 (39.0%) female patients, mainly of white race (84.6%). A total of 83 (42.6%) patients had normal renal function (creatinine clearance [CrCL] ≥90 mL/min), 83 (42.6%) had mild renal impairment (CrCL 60-89 mL/min), 28 (14.4%) had moderate renal impairment (CrCL 30-59 mL/min), and 1 (0.5%) had severe renal impairment (CrCL 15-29 mL/min). The majority (n = 179 [91.8%]) of patients had bilirubin <1.2 mg/dL; the rest (n = 16 [8.2%]) had bilirubin between 1.2-3 mg/dL. No patient had end-stage renal disease or bilirubin >3 mg/dL, as expected since these patients are not usually considered fit for intensive chemotherapy.Nonlinear mixed-effect modeling was performed using NONMEM. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and pertinent graphical representations of goodness-of-fit. Model validation/qualification was performed according to FDA and EMA guidelines for industry. Separate PK models were developed for cytarabine and daunorubicin, and intrinsic and extrinsic factors were evaluated as covariates. Intrinsic factors included body weight, body mass index, age, sex, race, white blood cell count, and markers of renal function (CrCL and serum creatinine) and hepatic function (bilirubin, aspartate and alanine aminotransferases, and alkaline phosphatase). The extrinsic factors were first dose amount, clinical study, and formulation.The base PK models for cytarabine and daunorubicin used 2-compartment structural models, with drug input into the central compartment, first-order distribution between the central and peripheral compartments, and first-order elimination from the central compartment. Two-compartment structural models with body surface area (BSA) as an allometric scalar provided minimum bias in estimates of systemic clearance (CL) and volume of distribution for the central compartment (Vc).Based on the final population PK model for cytarabine, a typical patient with BSA of 1.95 m2 receiving 100 units/m2 CPX-351 (100 mg/m2 cytarabine + 44 mg/m2 daunorubicin) is expected to have CL of 0.106 L/h with between-subject variability (BSV) of 70.5%, a Vc value of 5.12 L with BSV of 29.7%, and a peripheral volume of distribution (Vp) value of 0.214 L with BSV of 80.5%. Total volume of distribution (Vd = Vc + Vp) is predicted to be 5.33 L. The predicted half-lives associated with the distribution and elimination phases are 20.7 and 37.1 hours, respectively. The final population PK model for daunorubicin predicted a typical patient receiving the lyophilized formulation will have a CL value of 0.145 L/h with BSV of 49.4%, a Vc value of 4.34 L with BSV of 24.1%, and a Vp value of 0.523 L with BSV of 80.5%. Vd is predicted to be 4.86 L. The half-lives associated with the distribution and elimination phases are predicted to 11.1 and 26.2 hours, respectively.All covariates were eventually excluded from the population PK models, except dose and formulation, which had a small effect on PK and are not expected to result in detectable changes in clinical safety or efficacy. The PK of total cytarabine and daunorubicin were unaltered in patients with mild or moderate renal impairment (30 mL/min ≤ CrCL ≤ 89 mL/min). The potential effects of severe renal impairment could not be determined. Furthermore, the PK of total cytarabine and daunorubicin were unaltered in patients with serum bilirubin ≤3 mg/dL. In conclusion, the results of the population PK analysis indicated that dose adjustments of CPX-351 are not warranted for mild or moderate renal impairment or serum bilirubin up to 3 mg/dL. DisclosuresWang:Celator/Jazz: Employment, Equity Ownership. Banerjee:Celator/Jazz: Employment, Equity Ownership. Vasilinin:Celator/Jazz: Consultancy. Marier:Celator/Jazz: Consultancy. Gibbons:Celator/Jazz: Employment, Equity Ownership.

Effect of severe renal impairment on the pharmacokinetics of brigatinib

SummaryBackground Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non–small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.

Application of Physiologically Based Pharmacokinetic Modeling to Predict the Effect of Renal Impairment on the Pharmacokinetics of Olanzapine and Samidorphan Given in Combination.

BackgroundA combination of the antipsychotic olanzapine and opioid receptor antagonist samidorphan (OLZ/SAM) is in development for the treatment of patients with schizophrenia or bipolar I disorder. The effect of severe renal impairment on the pharmacokinetics of olanzapine and samidorphan after a single oral dose of OLZ/SAM was evaluated in a clinical study. Complementary to the clinical findings, physiologically based pharmacokinetic modeling was used to assess the effects of varying degrees of renal impairment on the pharmacokinetics of olanzapine and samidorphan.MethodsA physiologically based pharmacokinetic model for OLZ/SAM was developed and validated by comparing model-simulated data with observed clinical data. The model was applied to predict changes in olanzapine and samidorphan pharmacokinetics after administration of OLZ/SAM in subjects with mild, moderate, and severe renal impairment relative to age-matched controls with normal renal function.ResultsThe model predicted 1.5- and 2.2-fold increases in olanzapine and samidorphan area under the plasma concentration–time curve (AUC), respectively, after a single dose of OLZ/SAM in subjects with severe renal impairment vs controls, which was consistent with results from the clinical study. Application of the model prediction indicated increases in steady-state olanzapine AUC of 1.2-, 1.5-, and 1.6-fold, and samidorphan AUC of 1.4-, 1.8-, and 2.2-fold, in subjects with mild, moderate, and severe renal impairment, respectively, relative to healthy controls.ConclusionsPhysiologically based pharmacokinetic modeling extended the findings from a clinical study in severe renal impairment to other untested clinical scenarios; these data could be of interest to clinicians treating patients with renal impairment.

Integrative assessment of the effect of renal function on ribociclib treatment and dose recommendation in advanced breast cancer patients.

e13037 Background: Ribociclib is an orally administered CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative advanced breast cancer (ABC). An integrative assessment was conducted to evaluate the effect of renal function on the pharmacokinetics (PK), efficacy and safety of ribociclib. Methods: To assess the effect of mild and moderate renal impairment, a subgroup analysis was performed to evaluate PK parameters of ribociclib following oral administration of 600 mg QD 3 weeks on/1 week off in two Phase 1/2 and one Phase 3 clinical trials. Steady-state PK exposures in ABC patients at the 600 mg dose was estimated by a population PK model developed based on a pooled dataset from five Phase 1 to 3 trials and were compared by renal function. Efficacy and safety were also analyzed by renal function in a Phase 2 and three Phase 3 trials in ABC patients. The effect of severe renal impairment on ribociclib PK was assessed in a Phase I study in non-cancer subjects following a single oral 400 mg dose. Results: PK analyses in cancer patients showed that both single-dose and steady-state exposure of ribociclib at the 600 mg dose in patients with mild or moderate renal impairment were comparable to patients with normal renal function. Estimated steady-state PK exposure in patients with mild or moderate renal impairment is also comparable to patients with normal renal function. The primary efficacy results of progression free survival (PFS) and the safety profiles were comparable across renal-function cohorts in ABC patients. In non-cancer subjects administered a single oral dose of 400 mg, ribociclib AUCinf and Cmax increased 2.67- and 2.30-fold in subjects with severe renal impairment, respectively, compared to subjects with normal renal function. Conclusions: PK, efficacy and safety of ribociclib are consistent across patients with normal renal function, mild or moderate renal impairment. Hence, no dose adjustment is required in mild or moderate renal impaired patients. Severe renal impaired patients are recommended to have a reduced dose based on PK data in non-cancer subjects.

Effects of Renal Function on Crizotinib Pharmacokinetics: Dose Recommendations for Patients with ALK-Positive Non-Small Cell Lung Cancer.

Crizotinib (250mg twice daily) is the first anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small-cell lung cancer (NSCLC). The objectives of the current study were to evaluate the effects of mild, moderate, and severe renal impairment on crizotinib pharmacokinetics and to make crizotinib dosing recommendations for ALK-positive NSCLC patients with renal impairment on the basis of the findings. The effects of varying degrees of renal impairment on crizotinib pharmacokinetics were evaluated by: (1) analysis of mild and moderate renal impairment on multiple-dose pharmacokinetics of crizotinib in ALK-positive NSCLC patients from the PROFILE 1001 and PROFILE 1005 trials; (2) analysis of severe renal impairment on single-dose pharmacokinetics of crizotinib in volunteers (Study 1020); and (3) prediction of the effect of severe renal impairment on multiple-dose crizotinib pharmacokinetics using a physiologically-based pharmacokinetic model of crizotinib. No clinically relevant changes in plasma crizotinib exposure were observed in NSCLC patients with mild or moderate renal impairment. After a single 250-mg dose, the area under the plasma concentration-time curve (AUC) for crizotinib was 1.8-fold greater in subjects with severe renal impairment than in those with normal renal function. Physiologically-based pharmacokinetic modeling indicated a similar increase in steady-state AUC after multiple dosing. These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250mg once daily.

Comment on: “Enzalutamide: A Step Towards Pharmacokinetic-Based Dosing in Men with Metastatic Castration-Resistant Prostate Cancer”

Dear Editors, We thank Dr. Paul Hutson for his thorough commentary [1] on our recent article entitled ‘Enzalutamide: a step towards pharmacokinetic-based dosing in men with metastatic castration-resistant prostate cancer’ [2]. We would like to provide an important correction to Dr. Hutson’s commentary, regarding the following statements: Gibbons et al. do not report the renal clearance or the effect of renal failure on the clearance of enzalutamide or its active N-desmethyl metabolite, and to date no other reports of enzalutamide renal clearance are available to guide dosing. The mass-balance studies in the present study demonstrate that approximately 60 % of the dose was recovered in the urine, suggesting that dosing of the drug may need to be reduced in patients with kidney dysfunction. While not emphasized, the article does describe renal clearance on page 1050 (paragraph 2): The major route of excretion of 14C-radioactivity was urine (71.0 % of dose), primarily as metabolites. The remainder of the radioactivity was excreted in feces (13.6 % of dose). Based on LC–MS/MS analysis, the main component in urine was the carboxylic acid metabolite, which accounted for 62.7 % of the dose. A trace amount of unchanged parent enzalutamide was excreted in urine. N-Desmethyl enzalutamide was too low to quantitate in urine by LC–MS/MS. Based on this information, renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. As indicated in this excerpt, 62.7 % of the dose was recovered in urine as the inactive carboxylic acid metabolite, and the remainder was additional minor metabolites; enzalutamide and N-desmethyl enzalutamide (active metabolite) were present in urine at only trace amounts. These data indicate that renal excretion is a minor elimination pathway for unchanged parent enzalutamide and N-desmethyl enzalutamide. Further details are captured in the US prescribing information for XTANDI® (enzalutamide) capsules (product label), which states the following: A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment [30 mL/min ≤ creatinine clearance (CrCL) ≤ 89 mL/min] compared to patients and volunteers with baseline normal renal function (CrCL ≥90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL <30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. In summary, data presented in our original research article [2], as well as results in the XTANDI® product label, indicate that starting dose reductions are not required in patients with mild to moderate renal impairment. There are no data to assess the effects of severe renal impairment (CrCL <30 mL/min). As Dr. Hutson’s commentary misstates dosing recommendations for XTANDI®, we request that you kindly publish a supplementary response to Dr. Hutson’s commentary in Clinical Pharmacokinetics.

Influence of Renal and Hepatic Impairment on the Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Fluticasone Furoate and Vilanterol in Combination

BackgroundRenal and hepatic disease may lead to alterations in drug absorption, distribution, and elimination, and, therefore, the potential effect of renal and hepatic impairment should be investigated in drugs under development. ObjectiveTo assess the effects of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate/vilanterol (FF/VI) administered in combination. MethodsTwo open-label, parallel-group studies were conducted. Eligible study participants included adults with severe renal impairment (CrCl <30 mL/min) and those with mild, moderate, or severe hepatic impairment (by Child-Pugh classification). Patients were matched with healthy subjects. Participants received 7 days of inhaled FF/VI 200/25 or 100/12.5 μg (severe hepatic impairment only) once daily in the morning. Lack of effect was defined as an upper 90% confidence limit of the Cmax and AUC geometric mean impaired:healthy ratios (GMRs) of <2. ResultsStudy participants included patients with severe renal impairment (n = 9) or with mild (n = 9), moderate (n = 9), or severe (n = 8) hepatic impairment, together with matched healthy subjects (n = 9 per study). Lack of effect of severe renal impairment was demonstrated with FF (GMRs [90% CI]: Cmax, 0.96 [0.57–1.61]; AUC0–24, 0.91 [0.60–1.38]) and VI (Cmax, 0.70 [0.49–1.00]; AUC0–24, 1.56 [1.27–1.92]). Day-7 dose-normalized FF AUC0–24 was greater in the groups with mild, moderate, and severe hepatic impairment than in healthy subjects (GMRs [90% CI]: 1.34 [0.82–2.20], 1.83 [1.11–2.99], and 1.75 [1.05–2.91], respectively); lack of effect was not demonstrated. There was no effect of hepatic impairment on dose-normalized VI Cmax or AUC0–24. Apart from reduced serum cortisol weighted mean (0–24 hour) in patients with moderate hepatic impairment (34% reduction [90% CI, 11%–51%] compared with healthy subjects), there was no evidence of a difference in heart rate, serum potassium, or 24-hour serum cortisol between patients with severe renal impairment of any hepatic impairment and healthy subjects. No safety concerns were identified in any of the groups with impairment or their matched healthy controls. ConclusionsSevere renal impairment had no apparent clinically relevant effects on the pharmacokinetic or pharmacodynamic properties or tolerability of FF/VI. Hepatic impairment had no apparent effect on VI systemic exposure but increased FF exposure. Fluticasone furoate was associated with reduced serum cortisol in patients with moderate hepatic impairment. These data suggest that caution should be exercised when prescribing FF/VI in patients with moderate or severe hepatic impairment due to a risk for unwanted systemic corticosteroid effects associated with increased FF systemic exposure. Clinicaltrials.gov identifiers: NCT01266941 and NCT01266980.

Influence of Severe Renal Impairment on the Pharmacokinetics of Clazosentan

The purpose of this open-label, parallel-group study was to investigate the effect of severe renal impairment on the pharmacokinetics (PK), tolerability, and safety of clazosentan, an intravenous endothelin receptor antagonist. Clazosentan was administered as a continuous intravenous infusion of 1 mg/h for a period of 6 hours in 9 subjects with severe renal impairment (group A) and 8 healthy subjects (group B) (creatinine clearance <30 mL/min and >80 mL/min, respectively). The subjects in both groups were well matched for sex, body mass index, and age (±10 years). The PK parameters of clazosentan were calculated by both model-independent and model-dependent methods. The differences in the PK parameters between the subjects with severe renal impairment and healthy subjects were minor. The geometric means for area under the curve (AUC) during the infusion, AUC(0-t), (AUC from zero to time t of the last measured concentration above the limit of quantification) AUC(0-∞) (AUC from zero to infinity), and concentration at steady state were 7%, 8%, 8%, and 8%, respectively, higher in group A than in group B. The results obtained after 2-compartmental modeling were in agreement with those obtained after noncompartmental analysis. Administration of clazosentan was well tolerated in both groups. The data suggest that there is no need for dose adjustment of clazosentan in patients with renal impairment.

Pharmacokinetics and Safety of Sunitinib Malate in Subjects With Impaired Renal Function

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.

Sunitinib pharmacokinetic (PK) and safety data in subjects with renal impairment and on hemodialysis

2578 Background: Sunitinib malate (SU) is an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This study assessed the effect of severe renal impairment and hemodialysis on the PK and safety of SU and its primary active metabolite (SU12662) following a single dose of SU. Methods: In an open-label, single-dose, parallel-group study, subjects with normal renal function (n=8; CLcr >80 mL/min), severe renal impairment (n=8; CLcr <30 mL/min), and end-stage renal disease (ESRD) requiring hemodialysis (n=8) received SU 50 mg po. Serial blood samples were collected over 480 h for quantification of plasma concentrations of SU and SU12662 using a validated LC/MS/MS assay. For ESRD subjects, hemodialysis was started after collection of the 48-h sample. Safety was monitored throughout the study. Results: All 24 subjects completed the study. The preliminary mean±SD PK parameters for SU and SU12662 are presented below. A single dose of SU was found to be well tolerated when administered to subjects with severe renal impairment or ESRD; no serious adverse events were reported. Conclusions: Based on preliminary plasma concentration data, the PK of SU and SU12662 in subjects with severe renal impairment appeared similar to that in subjects with normal renal function. Plasma exposure to SU and SU12662 appeared lower in subjects with ESRD compared with subjects with normal renal function or severe renal impairment. PK parameter Normal (n=8) Severe (n=8) ESRD (n=8) SU Cmax, ng/mL 26.1±6.5 24.6±9.7 16.1±3.1 AUC0–48, ng·h/mL 809±58 764±322 489±97 AUC0-∞, ng·h/mL 1,921±531 1,814±1091 1,013±290 t1/2, h 83±12 84±20 72±17 SU12662 Cmax, ng/mL 5.7±1.3 4.7±1.7 4.1±1.2 AUC0- 48, ng·h/mL 196±31 153±66 135±27 AUC0-∞, ng·h/mL 778±109 627±262 538±116 t1/2, h 130±21 126±24 114±19 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Inc Pfizer Inc

Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administration.

To assess the influence of severe renal impairment on azimilide pharmacokinetics. A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22-28 and 10 days, respectively. Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h-1 kg-1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h-1 kg-1, 95% confidence interval on the ratio 0.67, 1.36) was observed. Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.

Liver function and anesthetic metabolism in rats with chronic renal impairment.

Patients and rats with chronic renal insufficiency (CRI) anesthetized with enflurane do not have significantly greater increases in postoperative serum inorganic fluoride levels when compared with subjects with normal renal function. The authors chose to investigate whether this observation is due to decreased anesthetic metabolism, secondary to the renal disease. Thus, male Fischer 344 rats with surgically induced CRI were studied to determine the effect of severe renal impairment: first, on in vivo hepatic function as measured by a serum liver enzyme profile, and second, on in vitro hepatic metabolism as indicated by microsomal anesthetic defluorination rates and cytochrome P-450 levels. Rats were operated on in two stages, 1 week apart, and assigned to one of three groups. Group 1 rats had a capsule stripping of each kidney. Group 2 rats had a capsule stripping of one kidney and then a nephrectomy of the other. Group 3 rats had the upper and lower poles of one kidney excised and then a nephrectomy of the other. There was no change in renal function in rats from Group 1 and 2. Chronic renal insufficiency in Group 3 rats was manifested by threefold elevations in serum creatinine and urea nitrogen levels and reciprocal decreases in clearances. After 89-98 days, blood was obtained for a serum liver enzyme profile and rats were killed for determination of in vitro hepatic metabolism. There were no changes suggestive of hepatic damage.(ABSTRACT TRUNCATED AT 250 WORDS)