Projecting the impact of delayed access to elexacaftor/tezacaftor/ivacaftor for people with Cystic Fibrosis.

BACKGROUND: Therapies that target the underlying defect in Cystic Fibrosis (CF) will likely impact the future characteristics of the CF population and healthcare utilization. The objectives of this study were to estimate the potential impact of elexacaftor/tezacaftor/ivacaftor on morbidity and mortality, and the impact of delayed access. METHOD: A microsimulation transition model was applied to Canadian CF Registry data to forecast lung disease severity, pulmonary exacerbations, deaths and transplants to 2030 under three scenarios: 1) no availability of elexacaftor/tezacaftor/ivacaftor, 2) availability in 2021 ('early') or 3) availability in 2025 ('delayed'). Published Phase III data on treatment effects were used to estimate transition rates between disease severity states. RESULTS: Under specific assumptions regarding disease state and treatment effect applied to the Canadian CF population it is projected that by 2030, early introduction of elexacaftor/tezacaftor/ivacaftor is expected to reduce the number of individuals with severe lung disease by 60% (95% CI 55.3; 63.9), increase the number of individuals with mild lung disease by 18% (95%CI 18.2; 19.0) and reduce the number of pulmonary exacerbations by 19% (95%CI 18.9; 19.5). Earlier introduction of elexacaftor/tezacaftor/ivacaftor could reduce deaths by 15% (95% 13.2; 18.4) and improve the median age of survival by 9.2 years (7.5; 10.8) over a 10-year period. The expected benefits of therapy are cumulative, therefore delayed access to elexacaftor/tezacaftor/ivacaftor will result in preventable health care utilization and deaths. CONCLUSIONS: Delayed access to elexacaftor/tezacaftor/ivacaftor will have a negative impact on lung health and survival in the CF population.

Doctor Shopping Behavior for Zolpidem Among Insomnia Patients in Taiwan: A Nationwide Population-Based Study.

OBJECTIVES: Although zolpidem is listed as a controlled drug in Taiwan, patients' behavior has not been restricted and has led to the problem of doctor shopping behavior (DSB), leading to overutilization of medical resources and excess spending. The National Health Insurance Administration in Taiwan has instituted a new policy to regulate physicians' prescribing behavior and decrease DSB. This retrospective study aimed to analyze the DSB for zolpidem by insomnia patients and assess related factors. DESIGN AND PARTICIPANTS: Data were extracted from the Longitudinal Health Insurance Database in Taiwan. Individuals with a diagnosis of insomnia who received more than one prescription of zolpidem in 2008 were followed for 24 mo. Doctor shopping was defined as ≥ 2 prescriptions by different doctors within ≥ 1 day overlapping in the duration of therapy. The percentage of zolpidem obtained through doctor shopping was used as an indicator of the DSB of each patient. RESULTS: Among the 6,947 insomnia patients who were prescribed zolpidem, 1,652 exhibited DSB (23.78%). The average dose of zolpidem dispensed for each patient during 24 mo was 244.21 daily defined doses. The doctor shopping indicator (DSI) was 0.20 (standard deviation, 0.23) among patients with DSB. Younger age, chronic diseases, high number of diseases, higher premium status, high socioeconomic status, and fewer people served per practicing physicians were all factors significantly related to doctor shopping behavior. CONCLUSION: Doctor shopping for zolpidem appears to be an important issue in Taiwan. Implementing a proper referral system with efficient data exchange by physician or pharmacist-led medication reconciliation process might reduce DSB.

Impact of restricting access to high-cost medications for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, and its incidence is increasing in the West, including the UK, with the increasing burden of chronic liver disease. Until recently, systemic treatment options for advanced disease were limited. However, randomized clinical trials have demonstrated that the multikinase inhibitor sorafenib prolongs survival in appropriately selected patients, and this drug has become the standard of care for patients with advanced HCC. However, a single-technology appraisal by the NICE recommended that the UK National Health Service should not fund sorafenib on the grounds of cost-effectiveness. A number of other novel agents and combinations are currently in clinical trials, the results of which may further expand the treatment options and indications for systemic therapy in HCC. This review discusses the impact of restricting access to high-cost medications for patients with HCC in the UK, and describes potential strategies and future directions that may improve the cost-effectiveness of such drugs. It also describes the potential impact, pending national guidance, of variations in local funding decision-making on patient outcomes.

Availability of insecticidal molecules to control Aedes albopictus (Skuse).

Following the implementation of the Directive 98/8/CE a few changes in the availability of insecticidal molecules to control Ae. albopictus have been outlined. Available products for larvicidal treatments will predominantly be based upon two growth regulators (diflubenzuron and pyriproxyfen). For the control of the adult forms there will mostly be active ingredients belonging to the pyrethroid group. Importance of surveillance for the onset of tolerance or resistance phenomena.

Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons.

The sensory neuron-specific sodium channel Na(v)1.8 and p38 mitogen-activated protein kinase are potential therapeutic targets within nociceptive dorsal root ganglion (DRG) neurons in inflammatory, and possibly neuropathic, pain. Na(v)1.8 channels within nociceptive DRG neurons contribute most of the inward current underlying the depolarizing phase of action potentials. Nerve injury and inflammation of peripheral tissues cause p38 activation in DRG neurons, a process that may contribute to nociceptive neuron hyperexcitability, which is associated with pain. However, how substrates of activated p38 contribute to DRG neuron hyperexcitability is currently not well understood. We report here, for the first time, that Na(v)1.8 and p38 are colocalized in DRG neurons, that Na(v)1.8 within DRG neurons is a substrate for p38, and that direct phosphorylation of the Na(v)1.8 channel by p38 regulates its function in these neurons. We show that direct phosphorylation of Na(v)1.8 at two p38 phospho-acceptor serine residues on the L1 loop (S551 and S556) causes an increase in Na(v)1.8 current density that is not accompanied by changes in gating properties of the channel. Our study suggests a mechanism by which activated p38 contributes to inflammatory, and possibly neuropathic, pain through a p38-mediated increase of Na(v)1.8 current density.

Phase I and pharmacodynamic study of Triapine, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia.

In a phase I study, 24 patients with refractory leukemia received Triapine, a novel ribonucleotide reductase (RR) inhibitor, as a continuous intravenous infusion over 96 h beginning on days 1 and 15 or days 1 and 8. On the days 1 and 15 regimen, the starting dose was 120 mg/m(2) per day, and the maximum tolerated dose (MTD) was 160 mg/m(2) per day. Three of eight patients receiving 160 mg/m(2) per day in the first course, and one patient escalated to this dose in a second course, developed hepatic dose-limiting toxicity (DLT). For the days 1 and 8 regimen, the first 96 h infusion was administered at a fixed dose of 140 mg/m(2) per day. The dose of the second infusion beginning on day 8 was escalated from 120 to 160 mg/m(2) per day without observing DLT. No objective responses occurred. Over 70% of patients had a >50% reduction in white blood cell counts. The steady-state levels of Triapine were between 0.6 and 1 microM. As expected from the in vitro studies, at these plasma concentrations there was a decline in dATP and dGTP pools and a decrease in DNA synthetic capacity of the circulating leukemia cells. Based on these clinical, pharmacokinetic, and pharmacodynamic data, Triapine warrants further study in patients with hematologic malignancies.

Indinavir (Crixivan) access and distribution.

AIDS: Merck's indinavir (Crixivan) will be available in limited supplies through the end of the year until the company's new production facilities open. Merck established a complex distribution system to ensure that patients who begin indinavir treatment will be able to continue uninterrupted use of the drug. The company will temporarily use only one mail-order pharmacy, Stadtlanders, to track and fill all orders for the drug. The complex distribution system and some of its potential problems are described. Indinavir costs $5,820 per year, which may be covered by medical insurance. In some cases, Merck will work with patients on finding payment sources.^ieng

Nevirapine expanded access.

AIDS: Boehringer-Ingelheim Pharmaceuticals is offering an expanded access program for its non-nucleoside reverse transcriptase inhibitor, nevirapine (Viramune). Criteria for inclusion are that participants be at least 13 years old, with a CD4 count below 50, and be intolerant to currently approved HIV treatments. The company expects to file an application for accelerated approval of nevirapine with the Food and Drug Administration (FDA) by March 1996.^ieng

Getting your space on the magic crixi-van.

AIDS: The Food and Drug Administration (FDA) approved the use of indinavir, Merck's protease inhibitor, for treatment of HIV infection in adults. Because FDA approval was quicker than the manufacturer expected, there will be problems producing and distributing the drug. Merck contracted with Stadtlander's Pharmacy, a mail-order buyer's club, to manage indinavir distribution. Activists are complaining that the program will be awkward and unworkable. The factory retail price for indinavir will be $4,380 per year. Merck established a financial assistance program for patients who are uninsured or unable to qualify for other programs. Alternative ways of getting the drug under this program are also explained.^ieng

Merck expanded access program August 11, 1995 deadline.

AIDS: People with fewer than 50 T4 cells may register before August 11, 1995 to be considered for Crixivan, a protease inhibitor made by Merck. The registration number is 1-800-497-8383. Due to limited drug supply, a lottery will be necessary if more than 1,100 people apply. Potential participants must be at least 18 years of age; are permitted to have taken/be taking 3TC, d4T, ddI, ddC or AZT; must have more than 50,000 platelets; may not have acute hepatitis; and may not be pregnant. Those not selected via lottery will be placed on a waiting list.^ieng

Protease inhibitor: Roche lottery deadline July 21.

AIDS: Hoffmann-La Roche has announced details of the Invirase International Compassionate Treatment Program, which will distribute saquinavir (brand name, Invirase), a protease inhibitor. Saquinavir will be made available to 2,280 U.S. patients with a CD4 (T-helper) count under 300 who no longer benefit from approved antiretroviral drugs (AZT, ddI, ddC, and d4T), and who meet other criteria. Sixty percent of the slots will be reserved for persons with a T-helper count under fifty. In addition, Roche has set up a lottery in case more people apply for the drug. Physicians must enter their patients by July 21, 1995. The author notes, however, that previous data on saquinavir at the suggested dosage levels to be used in this program have not been significant. The drug appears to be safe and effective, but at larger doses. Roche may make saquinavir a better drug by using new data to show doctors how to use it more effectively. There are concerns that patients using saquinavir alone are more likely to develop resistance to it, which means they may not be able to benefit from future protease inhibitors. However, Roche claims that new data shows that saquinavir does not cause resistance to other protease inhibitors, and that the development of resistance to saquinavir itself can be reduced by using it in combination with AZT.^ieng

Merck protease inhibitor available to persons with CD4 count 50 or less--must register by August 11.

AIDS: Merck & Co. has announced an expanded-access program to make Crixivan (generic name, indinavir sulfate), its experimental protease inhibitor, available to persons with a CD4 (T-helper) count of 50 or below. The new program will allow 1,100 people in the U.S. and 650 people from other countries to obtain the drug, formerly known as MK-639 and L-735,524. U.S. participants must register by August 11, 1995; those registered after that date will be placed on a waiting list. To be eligible, participants must have a CD4 count less than 50, be at least 18 years old, cannot have hepatitis, and cannot be pregnant or breastfeeding. Required laboratory tests, paid for by Merck, will fulfill additional entry criteria. Patients are allowed to combine the Crixivan with most other drugs. Patients in the open-label study will be treated by their own doctors.^ieng

Treatment briefs.

AIDS: Merck & Co. has announced it will launch a sizable expanded access program for its protease inhibitor compound MK-639. This is surprising since less than a month earlier it claimed it could not make any substantial quantity of the drug available for at least another year. Citing limits of its present 3TC production, Glaxo has established a quota system of 350 new enrollments per week in its 3TC/AZT combination study. Some believe this is a way Glaxo has found to limit a financial commitment when it is spending $16 billion to buy out Burroughs Wellcome. The Food and Drug Administration (FDA) is expected to approve the 3TC/AZT combination next Fall. Genentech has announced it will supply its human nerve growth factor (NGF) to a government-sponsored trial (ACTG 291) of the compound in AIDS-related peripheral sensory neuropathy. NGF promises to actually reverse the nerve damage caused by extended dosages of such anti-HIV drugs as ddI, d4T, and especially, ddC.^ieng