Therapeutic drug monitoring of gabapentin in various indications.

OBJECTIVES: Gabapentin has been increasingly used in various indications in recent years. Despite variable pharmacokinetics, therapeutic drug monitoring (TDM) is scarcely described in other indications than epilepsy. The aim of the study was to investigate the use and pharmacokinetic variability of gabapentin in epilepsy and non-epilepsy indications and to further evaluate the use of TDM in patients with restless legs syndrome (RLS). MATERIALS & METHODS: Population-based data from the Norwegian Prescription Database, retrospective TDM data from the section for Clinical Pharmacology, the National Center for Epilepsy, Norway, and prospective observational data on patients with RLS were used. RESULTS: The use of gabapentin increased by 30% from 2014 to 2017 (32 181 to 42 675 users). TDM data from 120 patients showed a 22-fold pharmacokinetic variability in concentration/dose ratios, and this ratio was elevated in elderly patients (≥65 years). The majority of elderly used gabapentin for non-epilepsy indications. In patients with RLS, intake in the evening/night only was common due to nocturnal symptoms, in contrast to regular dosing regimens in epilepsy. Thus, drug fasting concentrations do not reflect concentrations at the time of required therapeutic effect. TDM was still found useful in most patients to support dosage increase or evaluate adverse effects. CONCLUSION: Due to extensive pharmacokinetic variability, TDM can benefit patients using gabapentin. Challenges with applying TDM in new indications such as RLS include different dosage regimens and consequently different interpretation of serum concentrations. Thus, TDM should be requested on clear clinical grounds and the service tailored according to the therapeutic indication.

Blood GHB concentrations and results of medical examinations in 25 car drivers in Norway.

PURPOSE: information on the clinical effects associated with whole blood gamma-hydroxybutyrate (GHB) concentrations is sparse. We have investigated possible relationships between GHB blood concentrations and clinical effects in car drivers. METHODS: in Norway, the police stop car drivers suspected of drug-driving. Medical doctors perform a clinical test of impairment (CTI) and blood samples are screened for drugs/medicines by immunological, enzymatic and chromatographic methods at the Division of Forensic Toxicology and Drug Abuse. GHB is a part of our extended drug-testing programme. GHB is standardly measured as GBL by gas chromatographic method. All the results were stored in a database. This database was searched between 2000 and 2007 for car drivers positive only for GHB, called GHB-drivers. A control group with a completely negative blood analysis, including GHB, called control-drivers, was included in the study. RESULTS: twenty-five car drivers had only GHB in their blood. The police reported that 78% showed unsafe driving behaviour and seven were involved in car accidents, without serious injury. A total of 61% of the drivers were found to be sleepy or in an even more reduced state of consciousness. The median GHB blood concentration was 1,262 (range 592-2,191) µmol/L, measured a median of 69 min after the police had stopped the driver from driving. The GHB blood concentration tended to increase with increasing impairment and reduced consciousness. Clinical findings were normal- to large-sized pupils (86%), impairment as the final conclusion (84%), impaired balance/nystagmus (62 and 54%, respectively), congested/shiny conjunctiva (67%), apathetic, aggressive or abnormal behaviour (65%), reduced short-term memory (67%), reduced/absent pupillar reaction to light (65%), heart rate ≤ 70 beats/min (56%), and some level of reduced consciousness (56%). In the control-drivers, 15.6% were found by the medical doctors to have reduced consciousness or impaired. CONCLUSIONS: the median GHB blood concentration of the 25 car drivers was high. Most drivers had clinical impairment that was not explainable by injuries, with depressive effects on the central nervous system and sympathomimetic effects on eyes. Effects on impairment and consciousness tended to be concentration-dependent. The number of drivers who were impaired or had reduced consciousness was highly increased in GHB-drivers compared to controls. Based on these results, we conclude that the GHB-drivers most probably drove in an unsafe manner due to impairment by GHB.

Determination of digoxin and digitoxin in whole blood.

A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method has been developed and validated for the determination of digoxin and digitoxin in whole blood samples in autopsy cases. Samples were prepared by liquid-liquid extraction (LLE) with ethyl acetate/heptane/dichloromethane (3:1:1). LC separation was achieved using an Atlantis dC(18)-column (2.1 x 50 mm, 3 microm). The time between injections was 11 min. Mass detection was performed by positive ion mode electrospray LC-MS-MS on the ammonium adducts with two transitions for each analyte and one for the internal standard (digoxin-d(3)). Within-day precision was between 8.3 and 10.8%, between-day precision was between 8.7 and 14.2% and accuracy (bias) was between -17.3 and 11.5%. LOQ was 0.1 nmol/L (0.08 ng/mL), with an accuracy and precision of 19% and -17% (digoxin) and 18% and 3% (digitoxin). Matrix effects ranged from 104 to 117%. Good qualitative correlation with previous findings was achieved for 38 autopsy cases. The median (range, number of cases) B-digitoxin and B-digoxin found with the LC-MS-MS method in this very limited material were 9.3 (3.4-23.8, n = 24) and 5.6 (3.4-26.5, n = 4) nmol/L, respectively.