An integrated approach to evaluate different tetracycline derivatives for formulary decisions

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Stenotrophomonas maltophilia has emerged as a critical opportunistic pathogen associated with significant morbidity and mortality. Tetracycline derivatives have been recognized as alternative treatment options, but they have varied pharmacokinetic properties. An integrated approach to different tetracycline derivatives for formulary decisions is reported. Methods The minimum inhibitory concentration (MIC) data from clonally diverse bloodstream S. maltophilia isolates were examined, along with the pharmacokinetic profiles of 4 tetracycline derivatives, to predict achievable pharmacodynamic exposures with standard intravenous dosing regimens. Antimicrobial therapy was assessed using the ratio of daily drug acquisition cost relative to the ratio of the free-drug area under the time-concentration curve (fAUC) to the 90th percentile for minimum inhibitory concentration (MIC) values for isolates (fAUC/MIC90). Results In our analysis, minocycline had the greatest fAUC/MIC90. Doxycycline was the most financially preferred agent, as calculated using 2020 average wholesale price for base-case estimates of drug acquisition cost. Conclusion An integrated evaluation for antimicrobial formulary decision-making addressed local susceptibility data, pharmacokinetics, pharmacodynamics, dosing regimens, and drug acquisition costs. This comprehensive method is more objective than the conventional approach and warrants validation.

Brentuximab vedotin in adult patients with HL CD30+ at high risk of relapse or progression following ASCT: a cost-analysis in Italy

Introduction: In Hodgkin Lymphoma (HL), the early administration of brentuximab vedotin (BV) represents a highly effective treatment to consolidate patients after autologous stem cell transplantation (ASCT). For this indication, the Summary of Product Characteristics (SPC) reports a lower medical resource utilization in BV vs. placebo. This study aimed at assessing costs accrued by using BV in consolidation after ASCT and compare them with the resource consumption associated with the main options today used in Italy for HL. Methods and results: A cost-analysis based on patients at high risk of relapse (HL CD30+-HR) after ASCT was developed by collecting data about health care consumption (drugs and monitoring). The model is described by two arms, "A," where BV is used as consolidation therapy after ASCT, and "B", where patients are treated only at the time of relapse. A 3-year time horizon and the Italian National Health System perspective were adopted. All data inputs for the analysis were sourced from the available literature and official list prices. The simulation was integrated by sensitivity analysis. The introduction of BV as consolidation therapy would allow savings in terms of drug acquisition and resource consumption. Over a 3-year time frame, the Consolidation arm’s overall expenditure was 137,059€ vs. 225,418€ in the Non-consolidation arm. Early after the ASCT, BV administration guarantees a long period free from relapses (5-year PFS is not reached), thus reducing the clinical and economic burden of the subsequent therapies needed to treat further relapses. Conclusions: The present pharmacoeconomic analysis shows that the introduction of BV as consolidation therapy after ASCT represents a sustainable expenditure for the National Healthcare System (NHS) and a cost-saving paradigm when compared with the drug mainly used for treating the relapses.

Single-Agent Oral Vinorelbine in the Treatment of Pediatric Progressive Optic Pathway Glioma: A Single Institutional Experience

Purpose: The vinca alkaloids’ activity against pediatric low-grade glioma (PLGG) is well established. The goal of the present study is to describe our experience with oral vinorelbine in patients with progressive optic pathway glioma (OPG), not only regarding the clinical response, but also the cost benefit using an oral medication. Methods: Patients under 21 years of age with unresectable and/or progressive OPG were eligible. Oral vinorelbine was administered at a dose of 90mg/m2 daily on days 0, 8 and 22, in a scheme of 4 weekly cycles for a total of 18 cycles (54 doses). Results: From 2013 to 2018, sixteen patients were enrolled onto the study, with a median age of 9,1 years (range 4,6-17,8y). The most common histology was pilocytic astrocytoma (88,8%). Best response to chemotherapy was reviewed with a response rate (complete, partial, or minor response) of 30% for the patients treated exclusively with the oral drug. Five-year event-free survival (EFS) rate was 43.4%. Six patients had to change to intravenous vinorelbine due to gastrointestinal toxicity, vomiting grade III. None of the patients showed neurotoxicity. The total cost including drug acquisition, administration and toxicity management was lower with the oral formulation comparing to IV one. Conclusion: Single-agent oral vinorelbine seems to have some clinical activity in the management of recurrent or refractory pediatric OPG, being an interesting and cost-effective option, minding that gastrointestinal toxicity may be limiting and a combination of antiemetics should be considered in this treatment regimen.

Budget Impact Analysis of prolonged-release buprenorphine depot-formulation for the management of patients affected by opioid use disorder

Background: Opioid use disorder (OUD) is a disorder associated with significant rate of morbidity and mortality. Frequent clinic attendance for supervised consumption of sublingual buprenorphine is common. Prolonged-release buprenorphine (PRB) allows a management based on weekly or monthly subcutaneous injections, thus limiting the burdens of clinic attendance and the risks associated with sublingual formulations. Objective: To determine the price level of PRB that allows to obtain a neutral impact from the point of view of the economic resources absorbed, in comparison with the alternatives currently available in the Italian context for the management of patients suffering from OUD. Methods: The analysis assumes a daily PRB cost of €8.526 (neutral cost). The analysis aims to determine the economic impact associated with the introduction of PRB in the Italian context for the management of OUD patients. Results are expressed in terms of differential resourced absorbed in the alternative scenarios. A one-way sensitivity analysis was also carried out to test the robustness of the results. Results: The introduction of PRB implies an increase in the drug acquisition costs over the 5-year time horizon of €19.563.019,13: such costs are fully compensated by the other cost driver considered in the analysis (drug tests provided, health professionals’ time destined to the provision of the treatment, indirect costs, for savings equal to €6.167.026,94, €9.106.824,67 and €4.289.167,53 respectively) demonstrating its effectiveness in particular by an organizational point of view. Lower price levels for PRB would imply significant savings for the SSN. Conclusions: PRB resulted to be associated to a lower level of resources’ absorption in the Italian sector as compared with the available alternatives thus allowing to re-allocate health founds to other fields of the care sector ensuring greater safety for patients and a decreased misuse and diversion rate.

Costs comparison of treating diabetic macular edema with aflibercept, ranibizumab or dexamethasone at 1 year in France (INVICOST study)

Purpose: INVICOST, a medico-economic analysis, compared costs of managing treatment-naive patients with diabetic macular edema (DME) receiving intravitreal injections (IVIs) of aflibercept (AFL), dexamethasone implant (DXI) or ranibizumab (RAN) over 1 year. Methods: Healthcare resource use and associated costs were estimated using individual patient data from INVICTUS, a prospective, open-label, monocentric study. Healthcare costs comprised direct medical costs such as drug acquisition and administration, consultations and ophthalmological procedures. Costs were assessed from the French National Health Insurance perspective using published national tariffs expressed in 2019 euros. Results: Of the 60 treated eyes, 48 had no treatment switch; 14 received AFL, 19 received DXI and 15 received RAN. AFL-treated eyes received an average of 6.5 IVIs, DXI-treated patients received 2 IVIs and RAN-treated received 6.8 IVIs. All treated eyes received an initial prescription for adjunctive ocular medications and 349 follow-up procedures were performed including an average of 3.9 optical coherence tomography and 3.2 retinography procedures per eye. Average total direct cost of per-eye treatment was €4516 (€1128–€8257). Average cost was €5782 for eyes treated with AFL, €2779 with DXI and €5536 with RAN. Drug therapy was the cost driver: €4394 (76%) for AFL, €1915 for DXI (69%) and €4268 (77%) for RAN. Conclusion: The difference in total treatment cost is largely explained by the significantly lower frequency of IVI and annual cost of therapy with DXI, compared with AFL and RAN. INVICOST is the first study comparing treatment costs with AFL, DXI and RAN in France in current clinical practice.

Cryochemical Production of Drug Nanoforms: Particle Size and Crystal Phase Control of the Antibacterial Medication 2,3-Quinoxalinedimethanol-1,4-dioxide (Dioxidine)

Increasing the effectiveness of known, well-tested drugs is a promising low-cost alternative to the search for new drug molecular forms. Powerful approaches to solve this problem are (a) an active drug particle size reduction down to the nanoscale and (b) thermodynamically metastable but kinetically stable crystal modifications of drug acquisition. The combined cryochemical method has been used for size and structural modifications of the antibacterial drug 2,3-quinoxalinedimethanol-1,4-dioxide (dioxidine). The main stage of the proposed technique includes the formation of a molecular vapor of the drug substance, combined with a carrier gas (CO2) flow, followed by a fast condensation of the drug substance and CO2 molecules on a cooled-by-liquid nitrogen surface of preparative cryostate. It was established that the molecular chemical structure of the drug substance remained unchanged during cryochemical modification; however, it led to a significant decrease of the drug particles’ size down to nanosizes and changes in the crystal structures of the solid drug nanoforms obtained. Varying carrier gas (CO2) flow led to changes in their solid phase composition. A higher dissolution rate and changes in antibacterial activity were demonstrated for cryomodified dioxidine samples in comparison to the properties of the initial pharmacopeia dioxidine.

A two-year mirror-image study of the effect of treatment with paliperidone and aripiprazole long-acting injections on need for inpatient care and home treatment intervention

AimsTo evaluate the effect of the use of aripiprazole and paliperidone long acting injections on healthcare resource useBackgroundLong acting injections of second-generation antipsychotics such as paliperidone and aripiprazole have become more commonly prescribed over the past decade. They have much higher acquisition costs when compared to first generation depot antipsychotics. It is therefore essential to demonstrate their tolerability and cost-effectiveness.MethodWe undertook an observational, retrospective two-year mirror study for all patients who started treatment with paliperidone long acting injection between January and June 2016 (n = 47) or aripiprazole long acting injection between April 2014 and July 2017 (n = 93). Clinical notes were examined to determine the number of admissions, inpatient days, home treatment episodes and number of home treatment days, in the 12 months preceding and following the commencement of the long acting injection.Result70% remained on paliperidone and 62% remained on aripiprazole at the end of the one-year period.There was a significant reduction in occupied bed days in those treated with paliperidone from 78.2 days in the year before this treatment was started to 25.4 days in the year after (p = 0.002). There was a significant reduction in occupied bed days in those treated with aripiprazole from 66.51 days to 32.7 days (p = 0.0006).There was no significant reduction in days spent under the care of home treatment teams for individuals treated with either of these medicines.ConclusionTreatment with either paliperidone or aripiprazole long-acting injection was associated with a reduction in admissions and occupied bed days of a magnitude that delivered an overall cost-saving despite the high drug acquisition costs. It remains to be determined how these reductions compare with other second-generation long-acting injections and first-generation depot antipsychotics.

U.S. budget impact analysis of biosimilar versus originator intravenous rituximab for the treatment of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

e18820 Background: Rituximab-abbs is an anti-CD20 monoclonal antibody and an important immuno-oncology agent for the treatment of B-cell malignancies NHL (diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma [FL]) and CLL. It is also indicated for patients with RA, GPA, and MPA. Rituximab-abbs was the first rituximab biosimilar approved in the US and is expected to reduce drug acquisition costs. This budget impact model (BIM) estimated the impact of replacing a share of originator rituximab (IV-R-REF) use with rituximab-abbs (IV-R-BIOSIM) for NHL (DLBCL and FL), CLL, RA, GPA, and MPA. The objective was to project incremental annual cost differences between IV-R-BIOSIM and IV-R-REF for a hypothetical 1-million-member US healthcare insured (Medicare) population. Methods: An illustrative BIM estimated changes in 1-year drug and administration costs for an increased IV-R-BIOSIM uptake from 17.5% to 22.0%. Values for epidemiology, market share distribution, drug dosing, administration, and costs were derived from scientific literature, product labels, and publicly available cost resources. Dosing was based on a mean patient body surface area of 1.8 m2. Annual dose counts per patient were: 10 untreated FL with maintenance; 8 untreated FL (without maintenance), relapsed/refractory FL, or untreated DLBCL; 6 CLL, and 4 for RA, GPA, or MPA. All treatments were assumed to infuse over 3 hours. Drug acquisition and administration costs were from 2020 Average Sales Price pricing file and Centers for Medicare and Medicaid Services Physician Fee Schedule. Patient cost share was based on 2020 Medicare Part B 20% cost-share for office visits and drug products. Univariate sensitivity analyses were conducted. A scenario analysis was performed to project 2-year costs for extended FL maintenance treatment. Results: Estimated total annual plan incremental savings for a 1-million-member payer after the utilization shift were $312,379, equating to $0.31 per enrolled member per year (PMPY). Per-patient incremental drug cost savings with IV-R-BIOSIM for 1-year were $5,474–$12,924 (Table). The model was most sensitive to IV-R-REF cost and proportion of patients with RA. Conclusions: This analysis estimated annual savings of over $310,000 ($0.31 PMPY) for a 1-million-member US payer following a 4.5% utilization shift from IV-R-REF to IV-R-BIOSIM, demonstrating that IV-R-BIOSIM may confer considerable economic benefits vs originator rituximab.[Table: see text]

U.S. budget impactanalysis of body surface area (BSA)dosing for a rituximab biosimilar vsflat-fixed-dosing for subcutaneous rituximab in non-Hodgkin lymphoma (NHL)and chronic lymphocytic leukemia (CLL).

e18822 Background: The first rituximab biosimilar approved in the US, rituximab-abbs, is a CD20-directed monoclonal antibody that is expected to significantly reduce drug acquisition costs. This economic analysis evaluated budgetary impact of BSA-based rituximab-abbs (IV-R-BIOSIM) vs flat-fixed rituximab/hyaluronidase human subcutaneous injection (SC-R) dosing in NHL (diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL]) and CLL. The objective was to project incremental cost differences per patient between IV-R-BIOSIM and SC-R from a US healthcare insured (Medicare) population. Methods: An illustrative BIM estimated 1-year costs for IV-R-BIOSIM and SC-R. The model assumed equal efficacy and safety between products. Values for epidemiology, market share distribution, drug dosing, administration, and costs were derived from scientific literature, product labels, and publicly available cost resources. Costs for the first infused rituximab (IV-R) dose were excluded for appropriate comparison. IV-R-BIOSIM doses used BSAs of 1.6 m2, 1.8 m2, infusion duration was 3 hours. Annual dose counts of IV-R-BIOSIM or SC-R were: 9 untreated FL with maintenance; 7 untreated FL (without maintenance), relapsed/refractory FL, or untreated DLBCL; 5 CLL. Drug acquisition and administration costs were from 2020 Average Sales Price pricing file and Centers for Medicare and Medicaid Services Physician Fee Schedule. Patient cost share was 2020 Medicare Part B 20% cost-share for office visits and drugs. A scenario analysis was also performed to estimate FL maintenance costs for 2-year dosing. Results: Estimated 1-year savings with IV-R-BIOSIM for 1.8 m2 BSA dosing were $1,067–$6,893 with variability between indications (Table). For 1.6 m2 BSA dosing, estimated 1-year savings with IV-R-BIOSIM were $3,819–$10,856. Estimated 2-year savings with IV-R-BIOSIM for FL maintenance dosing were $9,191 for 1.8 m2 BSA dosing and $14,475 for 1.6 m2 BSA dosing. Savings of up to $1,900 were seen for higher-than-average BSA dosing, regardless of regimen. Conclusions: These findings demonstrate the potential economic benefits of replacing a proportion of SC-R use with BSA-based IV-R-BIOSIM from a US payer perspective, especially when lower BSA dosing is used. Savings are driven by drug costs and may increase with IV-R-BIOSIM as patient BSA decreases due to static costs with SC-R doses. These data also suggest that drug wastage may occur with SC-R in lower BSA patients.[Table: see text]

U.S. budget impact analysis of an intravenousrituximab biosimilar versus subcutaneous rituximab for the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).

e18821 Background: Rituximab-abbs is a CD20-directed monoclonal antibody and the first rituximab biosimilar approved in the US, expected to significantly reduce drug acquisition costs. This budget impact model (BIM) estimated budgetary impact of replacing a proportion of rituximab/hyaluronidase human subcutaneous injection (SC-R) utilization for NHL (diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL]) and CLL with rituximab-abbs (IV-R-BIOSIM). The objective was to project incremental cost differences between IV-R-BIOSIM and SC-R over one year for a hypothetical 5-million-member US healthcare insured (Medicare) population. Methods: An illustrative BIM was developed to estimate 1-year drug and administration costs for a one-quarter shift in SC-R market utilization to IV-R-BIOSIM, with equal efficacy and safety assumed. Values for epidemiology, market share, drug dosing, administration, and costs were derived from scientific literature, product labels, and publicly available cost resources. Infused rituximab (IV-R) dosing assumed a mean body surface area (BSA) of 1.8m2. Annual dose counts of IV-R-BIOSIM or SC-R per patient were: 10 untreated FL with maintenance; 8 untreated FL (without maintenance), relapsed/refractory FL, or untreated DLBCL; 6 CLL. IV-R infusion duration was 3 hours. Drug acquisition and infusion/subcutaneous administration costs were from 2020 Average Sales Price pricing file and Centers for Medicare and Medicaid Services Physician Fee Schedule. SC-R costs included an initial IV-R originator dose. Patient cost share was based on 2020 Medicare Part B 20% cost-share for office visits and drugs. Univariate sensitivity analyses were conducted. A scenario analysis used 2-year dosing to estimate costs for further FL maintenance treatment. Results: For a 5-million-member insured population, an estimated 972 patients would receive rituximab for NHL or CLL; 49 would receive SC-R. Estimated total incremental savings for one year for a 13-patient shift from SC-R to IV-R-BIOSIM were $57,864, equating to $0.02 per enrolled member per year (PMPY). Per-patient incremental annual savings with IV-R-BIOSIM for one year ranged between $2,359–$8,186 (Table). The model was most sensitive to low or high BSA dosing and proportion of patients with CLL. Conclusions: This BIM estimated annual savings of over $57,000 ($0.02 PMPY) for a 5-million-member US payer following a 25% shift of current SC-R use to IV-R-BIOSIM. These findings demonstrate the potential economic benefits of IV-R-BIOSIM vs SC-R that may result in expanded access to rituximab therapy.[Table: see text]