E.J.J. Berm

Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature

Objective Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature. Methods A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies’ overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument. Results We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing. Conclusions Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests’ efficacy remains of utmost importance.

A clinical validation study for application of DBS in therapeutic drug monitoring of antidepressants

BACKGROUND A bridging study of plasma and DBS concentrations for therapeutic drug monitoring of antidepressants was performed. RESULTS & METHODOLOGY: Potassium-based hematocrit analysis was included. In addition, we defined acceptance criteria based on the differences between individual data points of plasma and DBS concentrations. These criteria were applied to test acceptability of error found in predicted nortriptyline plasma concentrations. Potassium-based hematocrit predicted a negative bias for DBS concentrations of amitriptyline, but not for the other compounds. To predict plasma concentrations of antidepressants based on DBS concentrations, a factor of 0.8, 0.65, 0.84 and 0.78 was found for nortriptyline, desmethylclomipramine, venlafaxine and desmethylvenlafaxine, respectively. DISCUSSION & CONCLUSION Application of the factor and newly formulated acceptance criteria demonstrated prediction of nortriptyline plasma concentrations based on DBS concentrations.

A Model Based Cost-Effectiveness Analysis of Routine Genotyping for CYP2D6 among Older, Depressed Inpatients Starting Nortriptyline Pharmacotherapy

Objective Genotyping for CYP2D6 has the potential to predict differences in metabolism of nortriptyline. This information could optimize pharmacotherapy. We determined the costs and effects of routine genotyping for old aged Dutch depressed inpatients. Methods With a decision-tree, we modelled the first 12 weeks of nortriptyline therapy. Direct costs of genotyping, hospitalization, therapeutic drug monitoring and drugs were included. Based on genotype, patients could be correctly, sub-, or supratherapeutically dosed. Improvement from sub- or supratherapeutically dosed patients to correctly dosed patients was simulated, assuming that genotyping would prevent under- or overdosing of patients. In the base case, this improvement was assumed to be 35%. A probabilistic sensitivity analysis (PSA) was performed to determine uncertainty around the incremental cost-effectiveness ratio (ICER). Results In the base case analysis, costs for genotyping were assumed €200 per test with a corresponding ICER at €1 333 000 per QALY. To reach a €50 000 per QALY cut-off, genotyping costs should be decreased towards €40 per test. At genotyping test costs < €35 per test, genotyping was dominant. At test costs of €17 per test there was a 95% probability that genotyping was cost-effective at €50 000 per QALY. Conclusions CYP2D6 genotyping was not cost-effective at current genotyping costs at a €50 000 per QALY threshold, however at test costs below €40, genotyping could be costs-effective.

Relation between genotype, phenotype and therapeutic drug concentrations of nortriptyline or venlafaxine users in old age psychiatry

Bisphenol A (BPA) is a high production volume chemical. It is used to produce polycarbonate (PC) plastics and other polymeric materials, and also for the production of special papers (e.g. thermal paper). PC is used for tableware (plates and mugs), BPA-based epoxy-phenolic resins are used as coatings for canned food and beverages. Human exposure is by food via the oral route and by thermal papers via the dermal route. The presystemic elimination of BPA requires calculating internal exposure for the assessment of exposure via several routes. Animal toxicity studies have been performed by the oral route and in some instances by subcutaneous route. Internal doses rather than the administered doses have to be calculated using the human equivalent dose (HED) approach. Here we assess BPA exposures occurring during prolonged medical procedures via the intravenous route by medical devices. From a paper reporting on urinary BPA concentrations in premature and newborn babies in neonatal intensive care units we calculated the urinary BPA excretion as a measure of the daily dose. The geometric mean of the urinary BPA excretion was 3.05 μg/day with a maximum of 94.6 μg/day for prematurely born infants in neonatal intensive care units. Assuming an exposure from medical devices exclusively via the intravenous route, we employed physiologically based toxicokinetic (PBTK) modelling to calculate from the urinary BPA excretions the serum concentrations of unconjugated BPA in newborns and compared these concentrations with those for older children and adults. Based on the urinary excretions of 3.05 μg/day (geometric mean) and 94.6 μg/day (maximum), the predicted steady-state concentrations in blood were 19 ng/ml and 600 ng/ml for newborns, 14 ng/ml and 440 ng/ml for 3 months, 4 ng/ml and 120 ng/ml for e 6 months and 1.5 years old, and 1.35 ng/ml and 42 ng/ml for adults. Converting the steady state concentrations into AUCs, the AUCs exceed the AUC related to the currently used temporary TDI of 5 μg/kg/day. Two aspects should be noted: (i) the TDI is meant for life-long exposure whereas exposure in a neonatal intensive care unit is a special situation for a limited time period, and (ii) the health benefits of the medical interventions needs to be taken into consideration.