Jane Vella-Brincat

Are Gentamicin and/or Vancomycin Associated with Ototoxicity in the Neonate? A Retrospective Audit

Background: Aminoglycoside-induced ototoxicity has been reported in neonates but its incidence is poorly defined, whereas vancomycin-induced ototoxicity has not been reported in neonates. Objective: To compare hearing test results in infants in a neonatal intensive care unit (NICU) who were or were not treated with extended interval gentamicin dosing and/or standard vancomycin dosing. Method:A database of otoacoustic emissions (OAE), over a 5-year period of NICU admissions, was combined with databases of gentamicin and vancomycin dosing to compare patients treated or not treated with these antibiotics.Results:A total of 2,347 OAE results was available. OAE failure rates were: no gentamicin and no vancomycin (noGnoV), 7% (85/1,233); gentamicin but no vancomycin (GnoV), 4% (42/949); vancomycin but no gentamicin (VnoG), 22% (9/41) and gentamicin and vancomycin (GandV), 14% (17/124). Compared to noGnoV there was a decreased risk of OAE failure in GnoV (p = 0.022, OR 0.64, 95% CI 0.44–0.94) and an increased risk in VnoG (p = 0.003, OR 3.46, 95% CI 1.54–7.75) and GandV, (p = 0.006, OR 2.20, 95% CI 1.26–3.83). Conclusions:Gentamicin, as used and evaluated in this audit, showed no evidence of an increased risk of ototoxicity; what was observed was a statistically significant decrease in OAE failure rate. Vancomycin, by contrast, was associated with ototoxicity.

Eight years' experience of an extended-interval dosing protocol for gentamicin in neonates

BACKGROUND Dosing of gentamicin in neonates in Christchurch has been carried out since 2000 using a locally developed extended-interval dosing protocol. All dosing data have been recorded in a database. AIMS The aims of this study were to analyse the database to determine what percentage of neonates achieved target values for C(max), C(min) and AUC, and to use the pharmacokinetic values of gentamicin to simulate new dosing protocols. METHODS C(max), C(min) and AUC were compared with target values. Clearance (CL), volume of distribution (V) and half-life (t(1/2)) were estimated, and used to produce new predictive dosing protocols that were tested and compared with the results of the original protocol. RESULTS Gentamicin concentrations from 1461 individual doses were recorded in the database. Four hundred and eight were excluded. Of the remaining 1053, 84% achieved the target C(max) (>10 mg/L), 77% the target C(min) (<1 mg/L) and 63% the target AUC (within 80% to 125%). The number achieving target C(max) and C(min) values was improved markedly by prolonging the dosing intervals, but not by altering the predictive equations. Since the majority of the neonates only received a single dose of gentamicin, a new V-based model was also tested, and performed well. CL (L/kg) increased, while V (L/kg) and t(1/2) (h) both decreased with respect to weight. CONCLUSIONS Extending the dose interval improved the success in achieving target C(max) and C(min), while revision of the dosing equation did not. A V-based model provides an alternative approach to the first dose of gentamicin in neonates.

Perspective on dabigatran etexilate dosing: why not follow standard pharmacological principles?

Individualized drug dosing is a major pursuit in clinical pharmacology. The principal covariates that determine drug maintenance dose rates are the renal and hepatic function of the individual [1]. The process of dose individualization is most clear for drugs that are renally cleared as there are established indices that can be employed to gauge renal function and thus guide dosing. Pharmaceutical companies tend to promote a ‘one size fits all’ approach in the interests of simplicity. In the following commentary, we review the approach to dabigatran etexilate, a renally eliminated drug that was initially promoted by its manufacturer as having ‘one dose for all’. We aim to show that although guidelines have evolved that take renal function into account to some extent, these are applied insufficiently, not always logically and without consistency between indications. Guidelines have also eschewed monitoring of clotting function. This has happened despite the excellent pharmacokinetic and pharmacodynamic data (mostly from the manufacturer) that supports individualized dosing in relation to renal function using standard pharmacological principles, and anticoagulant monitoring in selected patients.

Dosing of dabigatran etexilate in relation to renal function and drug interactions at a tertiary hospital

Plasma concentrations of the anticoagulant dabigatran are correlated with clinical outcomes, and are affected by renal function, intestinal P‐glycoprotein (P‐gp) activity and stomach acidity.

Prescribing and monitoring clozapine in Christchurch

Objective: The aim of the study was to identify the pattern of usage of clozapine in Christchurch, New Zealand, including daily dose, indication and use of drug concentration monitoring. Method: Patients (n=353) were identified retrospectively from the pharmacy computer system. Data gathered included patient demographics, the daily clozapine dose and the number of occasions that clozapine drug concentration monitoring occurred. In addition, each psychiatrist who had prescribed clozapine was surveyed, regarding their indications for the use of clozapine and their use of clozapine drug concentration monitoring. Results: The majority (63%) of patients on clozapine were male. The mean age of the patients was 43 years (range 15–88 years). The mean daily dose of clozapine was 325 mg (range 12.5–900 mg). Patients over the age of 65 years were on a significantly lower dose (mean=143 mg, 95% CI=103–183 mg) compared with those under 65 years of age (mean=350 mg, 95% CI=330–370 mg). The median duration of treatment on clozapine was 4 years. Fifty-one percent of patients had undergone drug concentration monitoring, the majority on multiple occasions. In females, increasing age correlated with an increase in dose-corrected plasma clozapine concentrations (r2=0.29, p<0.001). This was not demonstrated in the male population. Of the psychiatrists surveyed, 44% prescribed clozapine for unlicensed indications and 79% used clozapine drug concentration monitoring in their patients. This was most commonly performed to assess compliance or confirm toxicity. Conclusions: The mean daily dose of clozapine of 325 mg was similar to that found in other studies. An age-related decline in dose was observed, probably due to different indications, with many of the elderly patients receiving clozapine for Parkinsonian related symptoms. There was also an age-related decline apparent in clearance in females. Clozapine was often used for unlicensed indications, and a clear majority of psychiatrists use drug concentration monitoring.

Gentamicin and renal function: lessons from 15 years' experience of a pharmacokinetic service for extended interval dosing of gentamicin.

Background: Extended interval dosing (EID) of gentamicin most commonly involves dosing every 24 hours, but patients with impaired renal function may require a longer dose interval. This study examines a large database of patients treated with gentamicin from 1996 to 2010 to see how many patients with renal impairment would have benefited from dose intervals >24 hours and to define the incidence of nephrotoxicity. Methods: All patients aged ≥16 years who had received gentamicin by EID over the 14-year period and had concentration data available were examined. End points included the numbers (%) achieving the target peak concentration [predicted maximum gentamicin concentration (Cmax)] >10 mg/L, the target trough concentration at 24 hours [predicted minimum gentamicin concentration (Cmin24)] <0.5 mg/L, and the target area under the curve over 24 hours of 70–100 mg/L·h. How these related to various creatinine clearance (CLcr) groupings was also examined, as was the number who developed nephrotoxicity (increase in creatinine of ≥0.04 mmol/L). Results: After exclusions, information was available on 4523 patients. Of these, 96% achieved the target Cmax, 83% the target Cmin24, and 54% the target area under the curve over 24 hours. Of the 73% of patients with CLcr ≥60 mL/min, 98% and 97% achieved the target Cmax and Cmin24, respectively. Of the 19% of patients with CLcr of 40–59 mL/min, 94% and 61% achieved the target Cmax and Cmin24, respectively. Of the 8% of patients with CLcr of 20–39 mL/min, 83% and 15% achieved the target Cmax and Cmin24, respectively. Nephrotoxicity, “probably” because of gentamicin, was observed in approximately 4% of the patients studied, which was irreversible in 25% of these (ie, 1% overall). Conclusions: Extending the dose interval of gentamicin to >24 hours is useful in patients with renal impairment to achieve the aims of EID. These results support initial dose intervals for gentamicin of 24, 36, and 48 hours for patients with CLcr ≥60, 40–59, and 20–39 mL/min, respectively. Irreversible nephrotoxicity was observed in approximately 1% of the patients studied.

The Pharmacokinetics and Pharmacogenetics of the Antiemetic Cyclizine in Palliative Care Patients

CONTEXT Cyclizine, an antihistaminic antiemetic, is commonly used in palliative care. Its pharmacokinetics have been poorly studied, and its metabolic pathway is unknown but may involve the genetically controlled cytochrome P450 2D6 (CYP2D6). If this is the case, the metabolic ratio of cyclizine to norcyclizine and efficacy/adverse effects may vary between patients according to their CYP2D6 genotype. OBJECTIVES To deduce the pharmacokinetics and antiemetic/sedative effects of cyclizine and relate these and its metabolic ratio to the CYP2D6 genotype in palliative care patients. METHODS Palliative care patients initiated on continuous cyclizine subcutaneous (SC) infusions had blood samples taken and efficacy/toxicity scores measured during the approach to steady state. Another group of patients at steady state receiving oral cyclizine had a single blood sample taken. Samples were analyzed to elucidate pharmacokinetic parameters and CYP2D6 genetics. RESULTS SC dosing group: The median (interquartile range) cyclizine half-life, volume of distribution, and clearance were 13 (7-48) hours, 23 (12-30)L/kg, and 15 (11-26)mL/min/kg, respectively. Nausea and sedation scores were 3.0 (1.2-5.7) and 5.0 (2.6-8.1), respectively, overall and did not vary with genotype (P=0.76 and 0.11, respectively). The median overall metabolic ratio at steady state was 4.9 (3.8-9.2) and did vary with CYP2D6 genotype (P=0.02). Oral dosing group: The median metabolic ratio was 2.1 (1.5-2.9) and did not vary with CYP2D6 genotype (P=0.37). CONCLUSION Palliative care patients have similar cyclizine pharmacokinetics to those reported in other patient groups. Cyclizine metabolism to norcyclizine may include CYP2D6 as the metabolic ratio varied with CYP2D6 genotype in the SC group.

Quantification of cyclizine and norcyclizine in human plasma by liquid chromatography–tandem mass spectrometry (LC–MS/MS)

A rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for quantification of cyclizine and its main metabolite norcyclizine in human plasma. Samples were prepared by protein precipitation with acetonitrile and cinnarizine was used as internal standard (recovery >87%). The analytes were eluted from a C8 50 mm×2.0 mm analytical column using a linear gradient of methanol and 0.05% formic acid with a total analysis time of 4 min. Analytes were detected by MS/MS using electrospray ionisation in the positive mode with multiple reactions monitoring (MRM) of the precursor ion/product ion transitions 267.2/167.2 for cyclizine and 253.2/167.2 for norcyclizine. Matrix effects were negligible. Standard curves for cyclizine and norcyclizine were linear (r(2)≥0.996) over the range 2-200 ng/mL, with 2 ng/mL representing the lower limit of quantification. Relative standard deviations were <14% for intra- and inter-day precision and the accuracy was within ±8%. The assay was successfully applied to a clinical study.

Audit of antipsychotic polypharmacy in Christchurch.

I was pleased to read that Allnutt and O’Driscoll now acknowledge that the NSW Clinical Risk Assessment and Management Training Program can play little or no role in the prevention of homicide in NSW. I also defend myself against the suggestion that my criticism of their document was improper. The document I cited was widely distributed, included an internet address, and did not have a disclaimer regarding draft status.

Regional variation in antipsychotic and antidepressant dispensing in New Zealand

Antipsychotic and antidepressant agents are the mainstay of treatment for schizophrenia/psychoses and moderate to severe depression, respectively. In New Zealand, PHARMAC is responsible for ensuring that patients have access to cost effective medicines and subsidises 13 oral and six long-acting depot antipsychotics, and 17 antidepressants. 1 Community medicines are funded by the District Health Boards (DHBs) in accordance with the Pharmaceutical Schedule. 1 Data for all community subsidised dispensing of pharmaceuticals are stored in a data warehouse managed by New Zealand Health Information Service.