Biosimilars And Follow-On Products In The United States: Adoption, Prices, And Users.

Biologic drugs account for a disproportionate share of the increase in pharmaceutical spending in the US and worldwide. Against this backdrop, many look to the expanding market for biosimilars-follow-on products to biologic drugs-as a vehicle for controlling pharmaceutical spending. This study explores the early years of entry of biosimilars and related follow-on products in the US. Using monthly sales data from the period 2005-19 for ten drug classes, we examine how quickly biosimilars/follow-on products gained market share and the subsequent trajectory of prevailing (national average invoice) prices. Our analysis suggests that although uptake has been slower than what is typically seen in generic drug markets, the most recent entrants have captured market share more rapidly than comparable earlier biosimilars/follow-on products. We also document that from biosimilar/follow-on products' time of entry, their lower prices help offset the overall trend in average annual reference-product price increases. Our findings can provide insight into future policy reforms aimed at increasing competition and use of biosimilars, leading to expanded patient access and significant cost savings.

Review times and adverse events for cardiovascular devices.

Shorter regulatory review times for high-risk cardiovascular devices correlate with the likelihood of reports of adverse events.

Resource use and costs associated with coeliac disease before and after diagnosis in 3,646 cases: results of a UK primary care database analysis.

BACKGROUND: Despite the considerable health impact of coeliac disease (CD), reliable estimates of the impact of diagnosis on health care use and costs are lacking. AIMS: To quantify the volume, type and costs, in a United Kingdom primary care setting, of healthcare resources used by individuals diagnosed with CD up to ten years before and after diagnosis, and to estimate medical costs associated with CD. METHODS: A cohort of 3,646 CD cases and a parallel cohort of 32,973 matched controls, extracted from the General Practice Research Database (GPRD) over the period 1987-2005 were used i) to evaluate the impact of diagnosis on the average resource use and costs of cases; ii) to assess direct healthcare costs due to CD by comparing average resource use and costs incurred by cases vs. controls. RESULTS: Average annual healthcare costs per patient increased by £310 (95% CI £299, £320) after diagnosis. CD cases experienced higher healthcare costs than controls both before diagnosis (mean difference £91; 95% CI: £86, £97) and after diagnosis (mean difference £354; 95% CI: £347, £361). These differences were driven mainly by higher test and referral costs before diagnosis, and by increased prescription costs after diagnosis. CONCLUSIONS: This study shows significant additional primary care costs associated with coeliac disease. It provides novel evidence that will assist researchers evaluating interventions in this area, and will challenge policymakers, clinicians, researchers and the public to develop strategies that maximise the health benefits of the resources associated with this disease.

Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood-brain barrier.

We investigated the expression and function of Abca1 in wild-type C57BL/6, abca1(+/+), and abca1(-/-) mice brain capillaries forming the blood-brain barrier (BBB). We first demonstrated by quantitative RT-PCR and Western immunoblot that Abca1 was expressed and enriched in the wild-type mouse brain capillaries. In abca1(-/-) mice, we reported that the lack of Abca1 resulted in an 1.6-fold increase of the Abcg4 expression level compared to abca1(+/+) mice. Next, using the in situ brain perfusion technique, we showed that the [(3)H]cholesterol brain uptake clearance (Cl(up), µl/s/g brain), was significantly increased (107%) in abca1(-/-) mice compared to abca1(+/+) mice, meaning that the deficiency of Abca1 conducted to a significant decrease of the cholesterol efflux at the BBB level. In addition, the co-perfusion of probucol (Abca1 inhibitor) with [(3)H]cholesterol resulted in an increase of [(3)H]cholesterol Cl(up) (115%) in abca1(+/+) but not in abca1(-/-) mice, meaning that probucol inhibited selectively the efflux function of Abca1. In conclusion, our results demonstrated that Abca1 was expressed in the mouse brain capillaries and that Abca1 functions as an efflux transporter through the mouse BBB.

Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases.

Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Huntington's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naïve mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 µM) was 0.15 ± 0.02 µL/g/s and was increased up to 0.34 ± 0.07 µL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.

Mapping the modified Rankin scale (mRS) measurement into the generic EuroQol (EQ-5D) health outcome.

BACKGROUND: Mapping disease-specific instruments into generic health outcomes or utility values is an expanding field of interest in health economics. This article constructs an algorithm to translate the modified Rankin scale (mRS) into EQ-5D utility values. METHODS: mRS and EQ-5D information was derived from stroke or transient ischemic attack (TIA) patients identified as part of the Oxford Vascular study (OXVASC). Ordinary least squares (OLS) regression was used to predict UK EQ-5D tariffs from mRS scores. An alternative method, using multinomial logistic regression with a Monte Carlo simulation approach (MLogit) to predict responses to each EQ-5D question, was also explored. The performance of the models was compared according to the magnitude of their predicted-to-actual mean EQ-5D tariff difference, their mean absolute and mean squared errors (MAE and MSE), and associated 95% confidence intervals (CIs). Out-of-sample validation was carried out in a subset of coronary disease and peripheral vascular disease (PVD) patients also identified as part of OXVASC but not used in the original estimation. RESULTS: The OLS and MLogit yielded similar MAE and MSE in the internal and external validation data sets. Both approaches also underestimated the uncertainty around the actual mean EQ-5D tariff producing tighter 95% CIs in both data sets. CONCLUSIONS: The choice of algorithm will be dependent on the study aim. Individuals outside the United Kingdom may find it more useful to use the multinomial results, which can be used with different country-specific tariff valuations. However, these algorithms should not replace prospective collection of utility data.

Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer's disease.

Combined evidence from neuroimaging and neuropathological studies shows that signs of vascular pathology and brain hypoperfusion develop early in Alzheimer's disease (AD). To investigate the functional implication of these abnormalities, we have studied the cerebrovascular volume and selected markers of blood-brain barrier (BBB) integrity in 11-month-old 3 x Tg-AD mice, using the in situ brain perfusion technique. The cerebrovascular volume of distribution of two vascular space markers, [3H]-inulin and [14C]-sucrose, was significantly lower (-26% and -27%, respectively; p < 0.01) in the brain of 3 x Tg-AD mice compared to non-transgenic littermates. The vascular volume reduction was significant in the hippocampus (p < 0.01), but not in the frontal cortex and cerebellum. However, the brain transport coefficient (Clup) of [14C]-D-glucose (1 microM) and [3H]-diazepam was similar between 3xTg-AD mice and controls, suggesting no difference in the functional integrity of the BBB. We also report a 32% increase (p < 0.001) in the thickness of basement membranes surrounding cortical microvessels along with a 20% increase (p < 0.05) of brain collagen content in 3xTg-AD mice compared to controls. The present data indicate that the cerebrovascular space is reduced in a mouse model of Abeta and tau accumulation, an observation consistent with the presence of cerebrovascular pathology in AD.

Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood-brain barrier: An in situ cerebral perfusion study.

Docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids are n-3 polyunsaturated fatty acids with a therapeutic potential for CNS diseases. Here, using an in situ brain perfusion technique in mice, we show that [(14)C]-DHA and [(14)C]-EPA readily cross the mouse blood-brain barrier (BBB) with brain transport coefficients (Clup) of 48+/-3microlg(-1)s(-1) and 52+/-4microlg(-1)s(-1), respectively. Mechanical capillary depletion of brain homogenates showed that less than 10% of [(14)C]-DHA or [(14)C]-EPA remained in endothelial cells of the brain vasculature, demonstrating that both molecules fully crossed the BBB. Addition of bovine serum albumin decreased the Clup of [(14)C]-DHA to 0.6+/-0.3microlg(-1)s(-1), indicating that binding to albumin reduced importantly, but not totally, the passage of DHA through the BBB. The Clup of [(14)C]-DHA or [(14)C]-EPA was not saturable at concentration up to 100microM, suggesting that these compounds crossed the BBB by simple diffusion. However, long-term high-DHA dietary consumption reduced the Clup of [(14)C]-DHA to 33+/-6microlg(-1)s(-1) (-20%, p<0.01). These results confirm that the brain uptake of DHA or EPA perfused with a physiological buffer is comparable to highly diffusible drugs like diazepam, and can be modulated by albumin binding and chronic dietary DHA intake.

Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study.

Analyses of brain phospholipid fatty acid profiles reveal a selective deficiency and enrichment in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. In order to account for this difference in brain fatty acid levels, we hypothesized that EPA is more rapidly beta-oxidized upon its entry into the brain. Wild-type C57BL/6 mice were perfused with either (14)C-EPA or (14)C-DHA via in situ cerebral perfusion for 40s, followed by a bicarbonate buffer to wash out the residual radiolabeled polyunsaturated fatty acid (PUFA) in the capillaries. (14)C-PUFA-perfused brains were extracted for chemical analyses of neutral lipid and phospholipid fatty acids. Based on the radioactivity in aqueous, total lipid, neutral lipid and phospholipid fractions, volume of distribution (V(D), microl/g) was calculated. The V(D) between (14)C-EPA- and (14)C-DHA-perfused samples was not statistically different for total lipid, neutral lipids or total phospholipids. However, the V(D) of (14)C-EPA in the aqueous fraction was 2.5 times higher than that of (14)C-DHA (p=0.025), suggesting a more extensive beta-oxidation than DHA. Furthermore, radiolabeled palmitoleic acid, a fatty acid that can be synthesized de novo, was detected in brain phospholipids from (14)C-EPA but not from (14)C-DHA-perfused mice suggesting that beta-oxidation products of EPA were recycled into endogenous fatty acid biosynthetic pathways. These findings suggest that low levels of EPA in brain phospholipids compared to DHA may be the result of its rapid beta-oxidation upon uptake by the brain.

In situ mouse carotid perfusion model: glucose and cholesterol transport in the eye and brain.

The in situ mouse brain perfusion method for measuring blood-brain barrier permeability was adapted to assess transport of solutes at the blood-brain and blood-eye barriers. The procedure was checked with radiolabeled markers in oxygenated bicarbonate-buffered fluid infused for 30 to 120 sec via a carotid artery. Vascular flow estimated with diazepam was 2.2-fold lower in the eye than in the brain. The vascular volume and the integrity markers sucrose and inulin indicated that a perfusion flow rate of 2.5 mL/min preserved the physical integrity of these organs. However, the brain vasculature integrity was more sensitive to acute perfusion pressure than the eye vasculature. The functional capacities of blood barriers were assessed with D-glucose; its transport followed Michaelis-Menten kinetics with an apparent K(m) of 7.6 mmol/L and a V(max) of 23 micromol/sec per g in the brain, and a K(m) of 22.9 mmol/L and a V(max) of 40 micromol/sec per g in the eye. The transport of cholesterol to the brain and eye was significantly enhanced by adding the Abca1 inhibitor probucol, suggesting an Abca1-mediated efflux at the mouse brain and eye blood barriers. Thus in situ carotid perfusion is suitable for elucidating transport processes at the blood-brain and blood-eye barriers.