Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis.

PURPOSE: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis. METHODS: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier NCT01435174 at Clinicaltrials.gov). Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters. RESULTS: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%. CONCLUSIONS: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population.

Acetaminophen clearance during ex vivo continuous renal replacement therapies.

Intravenous acetaminophen is an adjuvant to opioid use in critically ill and surgical patients requiring continuous renal replacement therapy (CRRT). The objective of this study was to determine the ex vivo transmembrane clearance of intravenous acetaminophen during continuous hemofiltration and hemodialysis. Transmembrane clearance was assessed using a validated ex vivo bovine blood model for CRRT using an F8 or HF1400 hemodiafilter. Ultrafiltrate and dialysate flow rates were 1, 2, and 3 L/h. Urea and acetaminophen clearances were calculated and compared. Acetaminophen was readily cleared by continuous hemofiltration with both hemodiafilters. Acetaminophen clearance rates were 92-98% of ultrafiltrate production rates. Similarly, dialytic acetaminophen clearances approximated dialysate flow rates for both hemodiafilters. Acetaminophen is readily cleared by CRRT. Patients receiving CRRT and acetaminophen may require increased doses for adequate pain control.

Vibration enhances clearance of solutes with varying molecular weights during in vitro hemodialysis.

This proof of concept pilot study was performed to determine whether vibration can increase solute clearance when applied to an in vitro dialysis model. Urea, creatinine, gentamicin, and vancomycin transmembrane clearances were calculated at a blood flow rate of 200 ml/min, dialysate flow rates of 2 and 8 L/hr, and no concurrent ultrafiltration at various vibration intensities. Dialyzer integrity was determined by measuring transmembrane pressure, filter drop pressure, and albumin clearance, and by visually inspecting the dialysate. Comparing the highest vibration modality with no vibration, the median percentage increase in urea, creatinine, gentamicin, and vancomycin clearance was 18% (all p < 0.005). The transmembrane clearance of albumin was negligible for all experiments. When measuring transmembrane pressure and filter drop pressure, no significant differences were found between nonvibration and vibration dialysis. The addition of vibration during dialysis increased transmembrane clearance for solutes with molecular weights of 60-1450 Daltons.

Medication dosing in critically ill patients with acute kidney injury treated with renal replacement therapy.

Critically ill patients with acute kidney injury may be treated with a variety of renal replacement therapies (RRTs). Each of these RRTs has profound yet differing effects on drug dosing. Although the doses of some drugs can be titrated to an immediately observable pharmacodynamic effect, the effects of many drugs, such as antibiotics for example, are not immediately apparent. Attainment of desired pharmacodynamic response is a complex interplay between patient, RRT, and pharmacokinetic factors. In the case of antibiotics, microorganism-specific factors also must be considered. Rational and effective drug dosing in this clinical setting cannot occur until all these issues are addressed by the clinician. Failure to account for the pharmacokinetic influences of critical illness, kidney disease, and choice of intermittent hemodialysis or prolonged intermittent or continuous RRT can contribute to the high mortality rates seen in these patients. Pharmacotherapy considerations for each of these therapies are addressed in this article by applying them to a patient case.