Cees Neef

Cost-effectiveness of therapeutic drug monitoring: a systematic review

There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked interpatient pharmacokinetic variability. Individualized therapy with such drugs requires therapeutic drug monitoring (TDM) to obtain the desired clinical effects safely. Cost-effectiveness analysis in health care is still at an early stage of development, especially for TDM. A systematic review was carried out to document studies that have addressed the cost-effectiveness of TDM. The Cochrane database and Medline were searched. References identified by this approach were then searched manually for relevant articles. Very few studies have been performed that document the cost-effectiveness of TDM, and TDM has been demonstrated to be cost-effective only for aminoglycosides. For the other classes of drugs that are monitored, the rationale for TDM has been supported, but appropriate cost-effectiveness analyses have not been performed. Because the use of many of these drugs without TDM would increase the risk of under- or overdosing, emphasis should not be placed solely on cost-effectiveness but rather on how such interventions can be applied in the most cost-effective and clinically useful manner.

Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin

Because clinical data about the therapeutic consequences of polymorphic oxidation of simvastatin by CYP2D6 have not been well reported, we sought to investigate the possible link between polymorphism of CYP2D6 and the efficacy and tolerability of simvastatin treatment in a group of 88 patients with hypercholesterolemia.

Therapeutic drug monitoring of everolimus using the dried blood spot method in combination with liquid chromatography–mass spectrometry

An assay of everolimus based on finger prick sampling and consecutive application as a blood spot on sampling paper has been developed. We explored several methods [K. Hoogtanders, J. van der Heijden, M. Christiaans, P. Edelbroek, J. van Hooff, L. Stolk, J. Pharm. Biomed. Anal. 44 (2006) 658-664; A. Allanson, M. Cotton, J. Tettey, et al., J. Pharm. Biomed. Anal. 44 (2007) 963-969] and developed a new method, namely the impregnation of sampling paper with a solution of plasma-protein, formic acid and ammonium acetate, in combination with the extraction of the blood spot by filter filtration. This kind of sample preparation provides new possibilities for blood spot sampling especially if analytes are adsorbed to the paper. The dried blood spot was analysed using the HPLC-electrospray-tandem mass spectrometry method, with 32-desmethoxyrapamycin as the internal standard. The working range of our study was 2-30 microg/l. Within this range, intra-and inter-assay variability for precision and accuracy was <15%. Everolimus blood spot samples proved stable for 3 days at 60 degrees C and for 32 days at 4 degrees C. Everolimus concentrations of one stable out-patient were compared after both blood spot sampling and conventional venous sampling on various occasions. Results indicate that this new method is promising for therapeutic drug monitoring in stable renal transplant patients.

Staphylococcus aureus biofilm formation at the physiologic glucose concentration depends on the S. aureus lineage

BackgroundSince bacteria embedded in biofilms are far more difficult to eradicate than planktonic infections, it would be useful to know whether certain Staphylococcus aureus lineages are especially involved in strong biofilm formation. For this reason, in vitro biofilm formation of 228 clinical S. aureus isolates of distinct clonal lineages was investigated.ResultsAt 0.1% glucose, more than 60% of the S. aureus strains associated with multilocus sequence typing (MLST) clonal complex (CC)8 produced large amounts of biomass, compared to 0-7% for various other clonal lineages. Additionally, S. aureus bloodstream isolates associated with MLST CC8 and CC7 had similar biofilm forming capacities as their commensal counterparts. Furthermore, strong biofilm formation could not be attributed to a specific accessory gene regulator (agr) genotype, as suggested previously. The agr genotypes were strictly associated with the clonal lineages. Moreover, strong biofilm formation was not related to slime formation. Congo red agar (CRA) screening is therefore not useful as a qualitative screening method for biofilm formation.ConclusionThe adherence to polystyrene surfaces under physiologic glucose concentration (0.1%) was dependent on the clonal lineage. Strains associated with MLST CC8 were markedly more often classified as strong biofilm former at glucose concentrations of 0%, 0.1% and 0.25%.The present study reveals that the MLST CC8 associated genetic background was a predisposing factor for strong biofilm formation in vitro, under all tested glucose concentrations.

Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial.

Background: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug with a quaternary ammonium structure not able to cross the blood-brain barrier in considerable amounts. Therefore, glycopyrrolate exhibits minimal central side effects, which may be an advantage in patients with PD, of whom a significant portion already experience cognitive deficits. Objective: To determine the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD. Methods: We conducted a 4-week, randomized, double-blind, placebo-controlled, crossover trial with oral glycopyrrolate 1 mg 3 times daily in 23 patients with PD. The severity of the sialorrhea was scored on a daily basis by the patients or a caregiver with a sialorrhea scoring scale ranging from 1 (no sialorrhea) to 9 (profuse sialorrhea). Results: The mean (SD) sialorrhea score improved from 4.6 (1.7) with placebo to 3.8 (1.6) with glycopyrrolate (p = 0.011). Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% vs 1 patient (4.3%) with placebo (p = 0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. Conclusions: Oral glycopyrrolate 1 mg 3 times daily is an effective and safe therapy for sialorrhea in Parkinson disease. Classification of evidence: This study provides Class I evidence that glycopyrrolate 1 mg 3 times daily is more effective than placebo in reducing sialorrhea in patients with Parkinson disease during a 4-week study.

Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs

Background:Potential drug–drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment.Methods:A search was conducted in a computer-based medication prescription system for dispensing oral anticancer drugs to outpatients in three Dutch centres. Potential drug–drug interactions were identified using electronic (Drug Interaction Fact software) and manual screening methods (peer-reviewed reports).Results:In the 898 patients included in the study, 1359 PDDIs were identified in 426 patients (46%, 95% confidence interval (CI)=42–50%). In 143 patients (16%), a major PDDI was identified. The drug classes most frequently involved in a major PDDI were coumarins and opioids. The majority of cases concerned central nervous system interactions, PDDIs that can cause gastrointestinal toxicity and prolongation of QT intervals. In multivariate analysis, concomitant use of more drugs (odds ratio (OR)=1.66, 95% CI=1.54–1.78, P<0001) and genito-urinary cancer (OR=0.25, 95% CI=0.12–0.52, P<0001) were risk factors.Conclusion:Potential drug–drug interactions are very common among cancer patients on oral cancer therapy. Physicians and pharmacists should be more aware of these potential interactions.

Review article: the prevalence and clinical relevance of cytochrome P450 polymorphisms

Background  Most drugs currently used in clinical practice are effective in only 25% to 60% of patients, while adverse drug reactions (ADRs) as a consequence of treatment are estimated to cost billions of US dollars and tens of thousands of deaths.

An interaction between cytostatic and anticonvulsant drugs

A young woman with epilepsy had tonic‐clonic seizures during antineoplastic therapy with adriamycin and cisplatin. During two courses of cytostatic drug administration peak and trough plasma levels of phenytoin, carbamazepine, and valproate sodium were measured. Lower plasma levels of carbamazepine and valproate sodium were observed after 2 days of antineoplastic therapy. Normal plasma levels of these drugs were found 2 to 3 days after the last cisplatin dose. Impaired absorption or accelerated elimination might explain these results. Phenytoin levels were reduced to 37% of the original values, although the drug was given intravenously. Changed Michaelis‐Menten parameters suggest that cisplatin increases the metabolic rate of phenytoin. Another explanation for the decreased drug levels might be an increased volume of distribution. Calculation of this volume from peak and trough levels showed an increase of the volume of distribution during and after chemotherapy.

Use of dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus and risk of fracture

INTRODUCTION Although patients with type 2 diabetes mellitus have an increased bone mineral density as compared to healthy patients, their risk of fracture is elevated. Incretins, new anti-diabetic drugs, may have a protective effect on bone mineral density. However, data on the effect of incretins on fracture risk are limited. Therefore the aim of this study was to investigate the association between the use of DPP4-I and the risk of fracture. METHODS A retrospective population based cohort study, using data from the Clinical Practice Research Datalink (CPRD) database (2007-2012), was conducted. Patients (N=216,816) with at least one prescription for a non-insulin anti-diabetic drug (NIAD), aged 18+ during data collection, were matched to one control patient. Cox proportional hazards models were used to estimate the hazard ratio of any fracture in DPP4 inhibitor (DPP4-I) users versus controls and versus other NIAD patients. Time-dependent adjustments were made for age, sex, life style, comorbidity and drug use. RESULTS The actual duration of DPP4-I use was 1.3years. There was no different risk of fracture comparing current DPP4-I users to controls (adjusted hazard ratio (adj. HR) 0.89, 95% confidence interval (CI) 0.71-1.13). There was also no increased risk comparing current DPP4-I users to other NIAD users, adj. HR 1.03 (95% CI 0.92-1.15). CONCLUSIONS DPP4-I use was not associated with fracture risk compared to controls and to other NIAD users. However, the duration of DPP4-I use in our database might have been too short to show an association with fracture risk.

Assessing Medication Adherence Simultaneously by Electronic Monitoring and Pill Count in Patients With Mild-to-Moderate Hypertension

BACKGROUND Poor adherence to antihypertensive medication is one of the major problems in the treatment of hypertension. Electronic monitoring is currently considered to be the gold standard for assessing adherence, but it may trigger patients to open the pill bottle without taking medication or to take out more than prescribed. In adjunct to electronic monitoring, pill count could be a valuable tool for exploring adherence patterns, and their effects on blood pressure reduction. METHODS Among a total of 228 patients with mild-to-moderate hypertension, adherence to treatment was measured by means of both the Medication Event Monitoring System (MEMS) and pill count. Patients were followed-up for seven visits over a period of 1 year. At each visit to the physicians office, patients adherence was assessed by both methods. RESULTS Adherence is defined as the percentage of days with correct dosing; median adherence according to MEMS was lower than median adherence according to pill count (91.6 vs. 96.1; P < 0.001). Both methods agreed in defining patients as adherent in 107 (47%) and nonadherent in 33 (14%) patients. Thirty-one (14%) patients were adherent only by MEMS and 59 (25%) patients only by pill count. At the end of the study, patients in the four categories reached comparable blood pressure values and reductions. CONCLUSIONS Pill count could be a useful adjunct to electronic monitoring in assessing adherence patterns. Although deviant intake behavior occurred frequently, the effect on achieved blood pressure and blood pressure reduction was not remarkable.