Bivalirudin use in carotid endarterectomy in a patient with heparin-induced thrombocytopenia

OBJECTIVE: To describe the successful use of bivalirudin as the primary procedural anticoagulant in a patient with suspected heparin-induced thrombocytopenia (HIT) undergoing carotid endarterectomy (CEA). CASE SUMMARY: A 73-year-old white man presented for an elective CEA 3 weeks after emergent, on-pump coronary artery bypass grafting. Bivalirudin was used for procedural anticoagulation because of seropositivity for heparin-PF4 antibodies and a clinical history consistent with HIT. The dose was administered as a 0.75 mg/kg bolus and 1.75 mg/kg/h infusion as reported in percutaneous coronary intervention, based on review of the available bivalirudin literature. The dosage was adjusted for the patient's renal dysfunction. The outcome was successful, with the patient discharged home in 8 days without significant complications. DISCUSSION: During active HIT, when thrombocytopenia and heparin-PF4 antibodies are present, heparin therapy must be avoided. In patients with subacute HIT, when platelet counts have recovered but HIT antibodies are still present, it is also prudent to avoid heparin administration. In the case of a patient in whom anticoagulation is necessary but heparin use is contraindicated, a direct thrombin inhibitor, such as bivalirudin, may offer a viable alternative. Bivalirudin is not immunogenic and does not cross-react with the heparin-PF4 antibodies associated with HIT. To our knowledge, as of January 20, 2006, this is the first report of the use of bivalirudin for procedural anticoagulation during CEA in a patient with HIT antibodies and recent exposure to heparin. CONCLUSIONS: Further investigation is warranted to clarify the clinical benefits of bivalirudin for patients undergoing vascular surgery of the carotids, including potential advantages for vulnerable patient populations such as those with diagnosed or suspected HIT as well as those with renal dysfunction.     

Pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with normal or impaired renal function

BACKGROUND: Previous studies of the glycoprotein IIb-IIIa inhibitor eptifibatide have included patients with moderate renal impairment (serum creatinine concentrations, 2.0-4.0 mg/dL). In these patients, adjustment of the standard infusion dose (2.0 microg/kg.min) to 1.0 microg/kg.min was recommended on empiric grounds because approximately 50% of eptifibatide is cleared renally. OBJECTIVE: The present study was designed to assess teh pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with various levels of creatinine clearance (CrCl), a parameter that is a more accurate indicator of renal function than serum creatinine concentration to determine the appropriate dose adjustment in patients with reduced renal function. A secondary objective was to determine the tolerability of eptifibatide when administered to patients with decreased renal function. METHODS: This open-label study was concluded at 3 US sites experienced in conducting similar studies. Subjects with differing renal function (normal [group 1, CrCl > 80 mL/min], mild renal impairment [group 2, CrCl 51-80 mL/min], moderate renal impairment [group 3, CrCl 30-50 mL/min], or severe renal impairment [group 4, CrCl <30 mL/min]) received a 24-hour eptifibatide infusion of 2.0 microg/kg.min (groups 1, 2, and 3) or 1.0 microg/kg.min (group 4). The primary end point was the eptifibatide steady-state plasma concentration; the secondary end points included inhibition of platelet aggregation and eptifibatide clearance, terminal plasma half-life, and area under the plasma concentration-time curve. In addition to analyses performed for each group, pharmacokinetic models were estimated and eptifibatide clearance was related to CrCl as a continuous variable by linear regression. All adverse events were recorded, with particular attention to bleeding. RESULTS: Thirty-one subjects (21 men, 10 women; mean age, 58.5 years [range, 44-73 years]; mean body weight, 81.6 kg [range, 51.5-105.1 kg]; mean height, 162.9 cm [range, 150-183 cm]) were included in the study. A strong correlation was found between eptifibatide clearance and CrCl. A tree-based analytic model indicated that the optimal discrete break point for the purpose of dose adjustment was a CrCl of 55.85 mL/min, which was rounded to 50 mL/min for practical clinical reasons. In patients with moderate or severe renal impairment (CrCl < or = 50 mL/min), clearance rates and steady-state concentrations of eptifibatide were approximately 50% lower and almost 2-fold higher, respectively, than in patients with normal renal function or mild renal impairment (CrCl > 50 mL/min). Inhibition of platelet aggregation exceeded the clinically significant threshold of 80% in all groups. Five subjects had a mild bleeding event and 4 subjects experienced mild to moderate nonbleeding events, 2 of which were considered drug-related by the investigator. None of the events required intervention. CONCLUSIONS: In this study, moderate to severe renal impairment was associated with an approximately 50% reduction in total eptifibatide clearance and a corresponding doubling of plasma eptifibatide concentration. Based on these findings, in patients with moderately or severely impaired renal function (calculated CrCl < or =50 mL/min) who are scheduled for percutaneous coronary intervention or who have non-ST-segment elevation acute coronary syndromes, it is appropriate to reduce the infusion dose of eptifibatide by 50% (from 2 to 1 microg/kg.min). Because the bolus dose(s) is (are) used to establish the initial targeted plasma eptifibatide concentrations, which are independent of clearance, and given that the volume of distribution did not correlate with renal function, no adjustment of the bolus dose(s) is required.     

Bivalirudin: a direct thrombin inhibitor

BACKGROUND: Studies of the anticoagulant effects of hirudin, which is derived from the saliva of the leech Hirudo medicinalis, led to the development of compounds that can directly inhibit thrombin activity without the need for additional cofactors. One of these is the direct thrombin inhibitor bivalirudin, which has recently been approved by the US Food and Drug Administration for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. OBJECTIVE: This is a review of the pharmacologic properties, efficacy, tolerability, and potential cost-effectiveness of bivalirudin in the treatment of ischemic coronary syndromes. METHODS: Articles were identified by searches of MEDLINE (1966-September 2001), International Pharmaceutical Abstracts (1970-September 2001), and the Iowa Drug Information Service (1966-September 2001) using the terms bivalirudin and Hirulog. The reference lists of retrieved articles were also reviewed for relevant articles. RESULTS: Bivalirudin is a synthetic polypeptide that directly inhibits thrombin by binding simultaneously to its active catalytic site and its substrate recognition site. After intravenous administration, peak plasma concentrations occur in 2 minutes. In patients given a 1.0-mg/kg bolus followed by a 2.5-mg/kg per hour infusion, a median activated clotting time of 346 seconds is achieved with little interpatient or intrapatient variability. Clearance of bivalirudin occurs through a combination of renal elimination and proteolytic cleavage, and doses may need to be decreased in the presence of renal dysfunction. In patients undergoing percutaneous coronary interventions, bivalirudin has been associated with equivalent efficacy but lower bleeding rates (P < 0.001) than unfractionated heparin (UFH). Data from the Hirulog Early Reperfusion/Occlusion-2 study suggest no reduction in mortality with bivalirudin compared with heparin when either is added to aspirin and streptokinase in patients with acute myocardial infarction, despite a lower reinfarction rate (P < 0.001). Experience with bivalirudin in patients with unstable angina and heparin-induced thrombocytopenia (HIT), as well as in patients receiving glycoprotein IIb/IIIla inhibitors, is limited. The differences in bleeding rates between bivalirudin and heparin in published clinical trials probably reflect differences in levels of anticoagulation achieved in comparator groups. CONCLUSIONS: Given its high cost, bivalirudin should be reserved for use as an alternative to UFH, primarily in patients with HIT, until clinical trials have more clearly demonstrated its benefits in terms of efficacy or safety.     

Bivalirudin: a review of the pharmacology and clinical application

Among the current agents in the class of direct thrombin inhibitors, bivalirudin (Angiomax(?), The Medicines Company, NJ, USA) has seen increased use in cardiovascular medicine over the past decade through its primary indication as an anticoagulant used during percutaneous coronary interventions. Bivalirudin has been further investigated and used as the anticoagulation strategy in the setting of cardiac and endovascular surgical procedures and is frequently utilized in the management of patients with heparin-induced thrombocytopenia. In comparison with heparin, bivalirudin exhibits a low immunogenic profile and provides similar or reduced major bleeding rates as well as a predictable degree of anticoagulation that is dose related. Bivalirudin primarily undergoes dual elimination via proteolytic cleavage and renal elimination, and requires dose adjustment in the setting of severe renal dysfunction. Given the body of supportive data, bivalirudin is likely to continue to figure prominently as a reliable and efficient anticoagulation strategy. Additional agents in the class of direct thrombin inhibitors are under investigation and may find increasing clinical use.     

Bivalirudin: a review of the pharmacology and clinical application

Among the current agents in the class of direct thrombin inhibitors, bivalirudin (Angiomax^®, The Medicines Company, NJ, USA) has seen increased use in cardiovascular medicine over the past decade through its primary indication as an anticoagulant used during percutaneous coronary interventions. Bivalirudin has been further investigated and used as the anticoagulation strategy in the setting of cardiac and endovascular surgical procedures and is frequently utilized in the management of patients with heparin-induced thrombocytopenia. In comparison with heparin, bivalirudin exhibits a low immunogenic profile and provides similar or reduced major bleeding rates as well as a predictable degree of anticoagulation that is dose related. Bivalirudin primarily undergoes dual elimination via proteolytic cleavage and renal elimination, and requires dose adjustment in the setting of severe renal dysfunction. Given the body of supportive data, bivalirudin is likely to continue to figure prominently as a reliable and efficient anticoagulation strategy. Additional agents in the class of direct thrombin inhibitors are under investigation and may find increasing clinical use.     

Pharmacology and clinical use of bivalirudin

OBJECTIVE: To review the primary literature describing the pharmacology and clinical uses of bivalirudin. DATA SOURCES: A MEDLINE search (January 1966-May 2001) was conducted that used bivalirudin, hirulog, and direct thrombin inhibitor as key words. References from retrieved articles and unpublished information acquired from the manufacturer and the Internet were also used. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, and clinical efficacy of bivalirudin were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the pharmacology and clinical use of bivalirudin. Given the paucity of data pertaining to the clinical use of bivalirudin, most articles were used, including abstracts and communications with the manufacturer. DATA SYNTHESIS: Bivalirudin is a direct thrombin inhibitor that inactivates both unbound and fibrin-bound thrombin. Bivalirudin rapidly induces anticoagulation and has a relatively short duration of action. Bivalirudin displays linear kinetics and is primarily eliminated renally. Bivalirudin was proven effective in preventing postprocedural ischemic complications in patients with unstable or postinfarction angina who received percutaneous transluminal coronary angioplasty (PTCA). Yet, further investigations that include less critically ill patients and use the current clinical practice of administering glycoprotein IIb/IIIa antagonists and/or inserting intracoronary stents are needed to fully evaluate its efficacy. Bivalirudin has also induced early patency in patients with myocardial infarction in combination with streptokinase, but its use with newer thrombolytics needs to be studied. Bivalirudin has been used in patients with immunologically mediated, heparin-induced thrombocytopenia (HIT) without complications. Bleeding is the major adverse effect and occurs more commonly in patients with renal dysfunction. CONCLUSIONS: At present, bivalirudin is worthy of consideration in patients requiring PTCA who have HIT. Advocating the routine use of bivalirudin in patients experiencing an acute coronary syndrome or HIT is premature.     

Pharmacokinetics of enoxaparin in patients undergoing percutaneous coronary intervention with and without glycoprotein IIb/IIIa therapy

The pharmacokinetic profile of enoxaparin was established in a substudy involving 1054 patients undergoing percutaneous coronary intervention. Patients enrolled in the National Investigators Collaborating on Enoxaparin 1 (NICE-1) trial received enoxaparin as a 1.0-mg/kg intravenous bolus. Patients enrolled in the NICE-4 trial received enoxaparin as a 0.75-mg/kg intravenous bolus followed by abciximab as a 0.25-mg/kg bolus and a 0.125-mcg/kg/min 12-hour infusion. Blood samples were collected at six time points over 12 hours and analyzed for plasma anti-Xa, anti-IIa, and Heptest (Haemachem Inc., St. Louis, MO) activity using specific and sensitive assay methods. Data were similar in both trials. Plasma anti-Xa, anti-IIa, and Heptest activity peaked shortly after the enoxaparin bolus and declined in parallel over the ensuing 12 hours. Area under the curve and peak activity were greatest for Heptest activity and least for anti-IIa activity. Values for clearance, volume of distribution, volume of distribution at steady state, and elimination rate constant were on the order of 10 mL/h/kg, 48 mL/kg, 45 mL/kg, and 0.22/h, respectively. These measures suggest that the use of abciximab in combination with enoxaparin during percutaneous coronary intervention is unlikely to affect the pharmacokinetics of enoxaparin.     

Effect of renal impairment on the pharmacokinetics of cibenzoline

Sixteen subjects completed an open-label study designed to assess the effect of renal impairment on the disposition of cibenzoline. The study included 10 patients with mild or moderate renal impairment creatinine clearance less than 60 ml/min/70 kg) and six healthy subjects in the same age range, each of whom received a single 130 mg oral dose of cibenzoline. The pharmacokinetic parameters observed in the healthy volunteers were similar to those reported previously. Maximum plasma concentration, time of maximum concentration, and apparent volume of distribution after single doses in patients with renal impairment were in the same range as those observed in healthy volunteers. The elimination half-life increased with decreasing renal function from a mean value of approximately 8 hours in healthy volunteers to more than 20 hours in patients with moderate renal impairment. Renal clearance and the fraction of the dose excreted unchanged in the urine decreased with decreasing creatinine clearance. The results of this study suggest that the dosage of cibenzoline should be reduced or the dosage interval increased in patients with reduced renal function to avoid excessive drug accumulation.     

Pharmacokinetics of recombinant human superoxide dismutase in healthy volunteers.

We studied the pharmacokinetics and effects of recombinant human superoxide dismutase (rhSOD) in 32 normal human volunteers after intravenous bolus doses from 1 mg/kg to 45 mg/kg in a single-blind, placebo-controlled, crossover design. The drug was well tolerated. Neither cardiovascular nor renal function, such as the echocardiographically determined cardiac index, insulin or para-aminohippurate clearance, or the urinary excretion of beta 2-microglobulin or N-acetylglucosaminidase, was affected. Pharmacokinetic analysis by use of noncompartmental methods showed an overall half-life of rhSOD to be about 4 hours for doses from 3 mg/kg to 45 mg/kg. The peak concentrations ranged from 24 to 837 mg/L, and urinary excretion increased from 3% to 57% of total dose after single intravenous bolus administrations of the drug from 1 mg/kg to 45 mg/kg. The mean renal clearance of rhSOD initially increased with dose then plateaued at the highest dose, whereas the nonrenal clearance decreased with dose to a plateau; total clearance remained essentially constant. The progressive increase in renal clearance may be explained by saturation of the tubular reabsorption and degradation of the protein, a mechanism previously described in animal models.     

Pharmacokinetics and pharmacodynamics of ranitidine after burn injury.

The pharmacokinetics and pharmacodynamics of ranitidine were studied in 10 hypermetabolic burned patients with normal creatinine clearance and compared with healthy volunteers. Ranitidine was administered as a single 50 mg intravenous bolus and multiple blood samples were obtained up to 10 hours after the dose for determination of plasma ranitidine concentrations. Gastric pH in burned patients was monitored by way of a nasogastric tube. Burned patients exhibited significantly higher (p less than 0.01) ranitidine clearance (mean +/- SD; 10.80 +/- 2.38 versus 7.53 +/- 1.71 ml/min/kg) and steady-state distribution volume (1.63 +/- 0.13 versus 1.16 +/- 0.33 L/kg). Within an hour of administration of drug the gastric pH was greater than or equal to 4.0 in all but one patient. This pH was maintained for at least 6 hours. In five patients the pH was greater than or equal to 4.0 throughout the 10-hour study. Thus, despite increased ranitidine clearance, the recommended dose of ranitidine maintained gastric pH greater than or equal to 4.0 throughout the normal dosing interval in the majority of patients. Dosage adjustment reported for many other drugs after burn injury may not be necessary for ranitidine.     

Pharmacokinetics of cefepime in subjects with renal insufficiency

The pharmacokinetics of intravenously administered cefepime (1000 mg over 30 minutes) were studied in 5 healthy volunteers and 20 patients with various degrees of renal impairment. Cefepime concentrations in plasma, urine, and hemodialysate were assayed using reverse-phase HPLC with ultraviolet detection. Mean peak plasma concentrations of cefepime at the end of 30-minute infusion ranges from 63.5 to 73.9 micrograms/ml and were not affected by the degree of renal impairment. The half-life of cefepime was approximately 2.3 hours in subjects with normal kidney function; it increased proportionately as renal function decreased. Significant linear relationships between total body clearance and creatinine clearance, as well as renal clearance and creatinine clearance, were observed. The mean volume of distribution at steady state in healthy volunteers was 20.5 liters and was not significantly altered in subjects with renal insufficiency. The mean cumulative urinary recovery of cefepime in healthy volunteers was 82.9% of the administered dose and significantly decreased in subjects with creatinine clearance less than 30 ml/min. Hemodialysis significantly shortened the elimination half-life from 13.5 hours during the predialysis period to 2.3 hours during the dialysis period. Cefepime dosage should be reduced in proportion to the decline in creatinine clearance.     

Development of an optimal furosemide infusion strategy in infants with modeling and simulation

BACKGROUND: The optimal dosing strategy for continuous intravenous furosemide infusion is unknown in pediatric patients. Eighteen patients less than 1 year old were studied after cardiac surgery during routine clinical care. The current strategy starts with a continuous infusion of 0.1 mg/kg x h, which may be adapted. METHODS: A pharmacokinetic-pharmacodynamic model was developed that linked furosemide dose to furosemide serum concentrations, renal function (creatinine clearance), and urine output. Various regimens were simulated that adapt according to urine production. The modified dosing schedule was prospectively tested in a subsequent population of 18 pediatric patients after cardiac surgery. RESULTS: Data from the follow-up study suggest that urine production is more controlled for the proposed regimen. CONCLUSIONS: Both the modeling and simulation results and the follow-up study indicated that a bolus dose of 1 mg/kg followed 6 hours later with a 1- or 2-mg/kg loading dose and a 0.2-mg/kg x. h intravenous infusion provides a rational starting point for furosemide therapy after cardiac surgery in pediatric patients less than 1 year old. Adjustment of this regimen every 12 hours in steps of 0.1 mg/kg x h on the basis of clinical assessment should lead to adequate control over urinary output.     

Pharmacokinetics of intravenous amdinocillin in healthy subjects and patients with renal insufficiency.

Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14- to 18-h period. Although the clearance from plasma and the half-life of amdinocillin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis.     

Dosing strategy in patients with renal failure receiving enoxaparin for the treatment of non-ST-segment elevation acute coronary syndrome

BACKGROUND: Enoxaparin therapy is recommended for the initial treatment of patients with non-ST-segment elevation acute coronary syndrome. However, little dosing information is available regarding the use of enoxaparin in patients with renal impairment. METHODS: We conducted a population pharmacokinetic analysis using anti-Xa activities measured in 532 patients (normal renal function in 34%, mild renal impairment in 36%, moderate renal impairment in 20%, and severe renal impairment in 10%) receiving subcutaneous enoxaparin (mean weight-corrected dose [+/-SD], 0.83 +/- 0.19 mg x kg(-1) x 12 h(-1) for an acute coronary syndrome. Simulations were then performed to develop a dosing strategy for patients with renal impairment. RESULTS: A 1-compartment model with first-order kinetics best fit the data. The covariate analysis showed that enoxaparin clearance was related to renal function and volume of distribution to total body weight. Enoxaparin clearance was decreased by 31% in patients with moderate renal impairment and by 44% in patients with severe renal impairment, resulting in a significant accumulation with the use of the standard 1 mg . kg(-1) x 12 h(-1) dosing regimen. Simulations showed that a first unadjusted dose of 1 mg/kg followed by a regimen of 0.8 mg . kg(-1) x 12 h(-1) in patients with moderate renal impairment or 0.66 mg . kg(-1) x 12 h(-)1 in patients with severe renal impairment should avoid accumulation of enoxaparin and keep peak anti-Xa activities between 0.5 and 1.2 IU/mL for a large majority of patients. CONCLUSIONS: An enoxaparin dosage reduction should be considered in acute coronary syndrome patients with creatinine clearance lower than 50 mL/min. A simple dosing protocol for enoxaparin to avoid significant accumulation in patients with moderate or severe renal impairment is proposed.     

Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function

The pharmacokinetics of 14C-labeled glyburide were studied in 13 men with varying degrees of renal impairment. Patients received a single, 5 mg oral dose of glyburide as a solution (10 microCi/ml/mg) after a high-carbohydrate breakfast. Serial plasma and breath samples were collected for 48 hours and urine and feces were collected for 5 to 7 days. Patients with normal to moderately impaired renal function (creatinine clearance [CLCR] of 29 to 131 ml/min/1.7 m2) had glyburide plasma t1/2 values of 2.0 to 5.0 hours, with no relationship between CLCR and glyburide clearance. One subject with severe renal impairment (CLCR = 5 ml/min/1.7 m2) had decreased glyburide clearance that resulted in a t1/2 of 11 hours. The elimination of metabolites was more dependent on renal status but was only significantly affected in the patient with severe renal impairment.     

Pharmacokinetics and pharmacodynamics of recombinant soluble thrombomodulin in disseminated intravascular coagulation patients with renal impairment

Recombinant human soluble thrombomodulin (TM-α) was recently developed as an anticoagulant for patients with disseminated intravascular coagulation (DIC). However, the pharmacokinetics and pharmacodynamics of TM-α in DIC patients with severe renal impairment have not yet been elucidated. We investigated the pharmacokinetics and pharmacodynamics of TM-α in DIC patients with severe renal impairment. Eleven DIC patients with severe renal impairment (creatinine clearance <30 mL/min) and 10 DIC patients without severe renal impairment (creatinine clearance ≥30 mL/min) were included in this study. In all patients, a dose of 380 U/kg of TM-α was administered during a 30-min infusion. Blood samples were taken before the start of the first TM-α administration, and at 0.5, 2, 4, 8, and 24 h after the start of administration. Although the clearance of TM-α in the patients with renal impairment was 80% of that in the patients without renal impairment, none of the pharmacokinetic values were significantly different between the groups. In the pharmacokinetic simulation, however, the trough levels of TM-α increased gradually in the patients with renal impairment when the same dose of TM-α was repeatedly administered. After the administration of TM-α, the prothrombinase activities in the patients in both groups were sufficiently inhibited during the observation period. Although the pharmacokinetic values in DIC patients with severe renal impairment were only slightly different from those in DIC patients without severe renal impairment, we need to pay attention to the elevation of the trough levels of TM-α when the same dose of TM-α is repeatedly administered.     

Pharmacokinetics, safety, and tolerability of ascending single intravenous doses of oritavancin administered to healthy human subjects

Oritavancin (LY333328 diphosphate) is a novel glycopeptide antimicrobial agent with potent microbiological activity in vitro against Gram-positive bacteria. A single-dose, open-label, noncontrolled, dose-escalation study in 11 healthy human subjects was carried out to evaluate the safety and pharmacokinetics of oritavancin. One subject at each dose level received a single intravenous dose of 0.02, 0.03, 0.05, 0.08, 0.125, 0.20, and 0.325 mg/kg infused over 1 hour and four subjects each received a single-dose of 0.5 mg/kg. Safety and tolerability were evaluated by monitoring adverse events and laboratory parameters. Oritavancin pharmacokinetics were assessed by blood, urine, and fecal sampling. The plasma concentrations of oritavancin after the end of infusion followed a multiexponential decline over a 2-week period. Median (range) C(max) for the 0.5 mg/kg dose group was 6.5 (4.7-7.6) microg/mL. In every subject, plasma concentrations declined to < or =10% of the C(max) within 24 hours. Following a short, constant-rate infusion, the pharmacokinetics of oritavancin were linear across a total dose range from 3.66-44.6 mg. Renal clearance was approximately 0.457 mL/min. The mean (range) plasma terminal half-life of oritavancin was 195.4 (135.8-273.8) hours across all dose levels from 0.05-0.5 mg/kg. Less than 5% and 1% of administered drug were recovered in the urine and feces, respectively, after 7 days. This first time in man evaluation of oritavancin revealed that single doses of oritavancin of up to and including 0.5 mg/kg were safe and well tolerated. Although no clinically relevant changes in renal, hepatic and hematologic indices from baseline were observed, five subjects did manifest asymptomatic and transient elevations of hepatic transaminase concentrations. Because this study was not placebo-controlled and enrolled a small number of subjects, the safety and pharmacokinetic profiles of oritavancin need to be confirmed in additional studies.     

Pharmacokinetics of telbivudine in subjects with various degrees of renal impairment

This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL(CR)), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL(R)), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL(R) and CL(CR). In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of approximately 45%, representing a approximately 23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.     

Pharmacokinetics of sparfloxacin in patients with renal impairment.

Sparfloxacin is a fluoroquinolone antimicrobial agent with a broad spectrum of activity and long elimination half-life. Because its single-dose pharmacokinetics are altered by renal impairment, the present study was undertaken to determine the effects of moderate or severe renal insufficiency on the multidose pharmacokinetic characteristics of and tolerance to sparfloxacin. The pharmacokinetic characteristics of sparfloxacin were assessed in 32 subjects (15 men, 17 women) with (1) normal renal function (creatinine clearance [CLcr]> or = 250 mL/min per 1.73 m2) and a mean age of 52.6 years and mean weight of 70.4 kg; (2) moderate renal insufficiency (CLcr 30-49 mL/min per 1.73 m2) and a mean age of 54.4 years and mean weight of 67.8 kg; and (3) severe renal insufficiency (CLcr 10-29 mL/min per 1.73 m2) and a mean age of 50.8 years and mean weight of 73.1 kg. The first 2 groups received a 400-mg loading dose on day 1 followed by 200 mg once daily for 9 days; subjects with severe renal insufficiency received a 400-mg loading dose on day 1 followed by 200 mg every 48 hours on days 3, 5, 7, and 9. The plasma and urinary pharmacokinetics of sparfloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTc) interval and for adverse events. Renal insufficiency altered the steady-state pharmacokinetic variables of sparfloxacin and its glucuronide metabolite, reducing their renal clearances and increasing both maximum plasma concentration and area under the plasma concentration-time curve. Mean steady-state plasma sparfloxacin concentrations in subjects with severe renal insufficiency (48-hour dosing interval) were comparable to those in subjects with normal renal function (24-hour dosing interval). However, mean plasma sparfloxacin concentrations in patients with moderate renal insufficiency were 2 to 3 times greater than the corresponding concentrations in subjects with normal renal function receiving the same dosage regimen. The QTc interval was slightly increased in all groups (the greatest increases were 14, 14, and 6 milliseconds in the groups with normal renal function and moderately and severely impaired renal function, respectively, at 5.5 hours post-dose on day 9 or 10) but similar among subjects with normal renal function or with renal insufficiency. Sparfloxacin was well tolerated. Thus sparfloxacin clearance is reduced and plasma concentrations raised by moderate or severe renal insufficiency. These increases do not appear to augment drug effects on the QTc interval or enhance the risk for adverse events. These results suggest that alternate-day dosing (48-hour dosing interval) following a double loading dose on day 1 should be used in patients with severe renal insufficiency and may be appropriate for patients with moderate renal insufficiency.     

Pharmacokinetics and pharmacodynamics of atrial natriuretic peptide after bolus and infusion administration in the isolated perfused rat kidney

We used the isolated perfused rat kidney to test the hypothesis that the renal pharmacokinetics and pharmacodynamics of atrial natriuretic peptide (ANP) are saturable and dependent on the method of administration. Wistar rat kidneys were perfused for 90 min after a bolus dose or continuous infusion of 45, 180, 450 ng of ANP. ANP clearance ranged from 3.27 to 2.28 ml/min after bolus administration. ANP clearance fell after infusion, resulting in a disproportionate increase in the ANP concentration with increasing infusion rate. The ANP half-life was unaffected by dose in the bolus group averaging 18 min. Increasing the ANP dose also increased the amount of Na excreted into the urine, but there were no differences between experimental groups. However, the area under the curve responsible for the natriuresis was 36 to 41% lower after infusion. Exogenous creatinine clearance, renal perfusion pressure and flow and renal vascular resistance were not affected. We conclude that the renal pharmacokinetics of ANP are saturable and are altered by the method of administration due to a down regulation of the ANP receptor. Furthermore, infusion of ANP should result in a greater net natriuresis due to resulting greater ANP concentrations at steady state and an apparent increased sensitivity of the kidney to ANP after infusion.