Current prices versus minimum costs of production for CFTR modulators.

BACKGROUND: While the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of the world's richest countries. Despite this, there is currently limited evidence regarding global access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment. METHODS: Minimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries. RESULTS: Costs of production for elexacaftor/tezacaftor/ivacaftor are estimated at $5,676 [$4,628-6,723] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for elexacaftor/tezacaftor/ivacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients worldwide would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion. CONCLUSIONS: Elexacaftor/tezacaftor/ivacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy, thereby exacerbating existing inequalities in CF care. Urgent action is needed to increase the availability of triple combination treatment worldwide. One strategy based on previous success is originator-issued voluntary licenses.

African Environmental Ethics: Keys to Sustainable Development Through Agroecological Villages.

This essay proposes African-based ethical solutions to profound human problems and a working African model to address those problems. The model promotes sustainability through advanced agroecological and information communication technologies. The essay's first section reviews the ethical ground of that model in the work of the Senegalese scholar, Cheikh Anta Diop. The essay's second section examines an applied African model for translating African ethical speculation into practice. Deeply immersed in European and African ethics, Godfrey Nzamujo developed the Songhaï Centers to solve the problem of rural poverty in seventeen African countries. Harnessing advanced technologies within a holistic agroecological ecosystem, Nzamujo's villages furnish education spanning the fields of ethics, information communication technology, microbiology, international development, and mechanical, electrical, civil and biological engineering in a community-based and centered development enterprise. The essay proposes a global consortium of ecovillages based on Nzamujo's model. The final section explores funding methods for the consortium. The conclusion contemplates a return to Africa to supplement environmental ethics that enhance life's future on earth.

Minimum costs to manufacture new treatments for COVID-19.

INTRODUCTION: 'Repurposing' existing drugs to treat COVID-19 is vital to reducing mortality and controlling the pandemic. Several promising drugs have been identified and are in various stages of clinical trials globally. If efficacy of these drugs is demonstrated, rapid, mass availability at an affordable cost would be essential to ensuring equity and access especially amongst low- and middle-income economies. METHODS: Minimum costs of production were estimated from the costs of active pharmaceutical ingredients using established methodology, which had good predictive accuracy for medicines for hepatitis C and HIV amongst others. Data were extracted from global export shipment records or analysis of the route of chemical synthesis. The estimated costs were compared with list prices from a range of countries where pricing data were available. RESULTS: Minimum estimated costs of production were US $0.93/day for remdesivir, $1.45/day for favipiravir, $0.08/day for hydroxychloroquine, $0.02/day for chloroquine, $0.10/day for azithromycin, $0.28/day for lopinavir/ritonavir, $0.39/day for sofosbuvir/daclatasvir and $1.09/day for pirfenidone. Costs of production ranged between $0.30 and $31 per treatment course (10-28 days). Current prices of these drugs were far higher than the costs of production, particularly in the US. CONCLUSIONS: Should repurposed drugs demonstrate efficacy against COVID-19, they could be manufactured profitably at very low costs, for much less than current list prices. Estimations for the minimum production costs can strengthen price negotiations and help ensure affordable access to vital treatment for COVID-19 at low prices globally.

Estimated generic prices for novel treatments for drug-resistant tuberculosis.

Background: The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course. Objectives: To estimate generic prices for novel TB drugs that would be achievable given large-scale competitive manufacture. Methods: Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The projected costs for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarity. Generic prices for bedaquiline, delamanid and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis and per-step yields. Costing algorithms reflected variable regulatory requirements and efficiency of scale based on demand, and were validated by testing predictive ability against widely available TB medicines. Results: Estimated generic prices were US$8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$34/month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4-$11/month for clofazimine and $4-$8/month for moxifloxacin. The estimated generic prices were 87%-94% lower than the current lowest available prices for bedaquiline, 95%-98% for delamanid and 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current costs $734-$1799), $53-$276 for pretomanid-based three-drug regimens and $238-$507 for a delamanid-based four-drug regimen. Conclusions: Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets.

Rapid reductions in prices for generic sofosbuvir and daclatasvir to treat hepatitis C.

OBJECTIVES: Novel treatments for hepatitis C demonstrate high cure rates, but current high prices can be a barrier to rapid global treatment scale-up. Generic competition can rapidly lower drug prices. Using data on exports of raw materials in 2015, we calculated currently feasible generic prices of sofosbuvir and daclatasvir. METHODS: Data on per-kilogram prices of sofosbuvir and daclatasvir active pharmaceutical ingredients (API) exported from India were extracted from an online database. To the cost of the amount of API needed for a 12-week treatment course, we added cost estimates for formulation (40%), packaging (US$0.35/month), and a mark-up (50%). RESULTS: Between 1 January and 15 October 2015, over 5 tons of sofosbuvir were exported, with prices decreasing by US$702/kg/month, and observed prices of US$2501/kg in early September. Over the same period, 84 kg of daclatasvir were exported, with prices decreasing by US$1664/kg/month to US$1897/kg. Using the price estimation algorithm, we estimated the price of a generic sofosbuvir-daclatasvir combination regimen at US$200 per patient for a 12-week treatment course. CONCLUSION: The costs of generic production of sofosbuvir and daclatasvir are rapidly decreasing. Sofosbuvir-daclatasvir combination treatment could be produced for US$200 per patient per 12-week course.

Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment.

OBJECTIVE: To calculate sustainable generic prices for 4 tyrosine kinase inhibitors (TKIs). BACKGROUND: TKIs have proven survival benefits in the treatment of several cancers, including chronic myeloid leukaemia, breast, liver, renal and lung cancer. However, current high prices are a barrier to treatment. Mass production of low-cost generic antiretrovirals has led to over 13 million people being on HIV/AIDS treatment worldwide. This analysis estimates target prices for generic TKIs, assuming similar methods of mass production. METHODS: Four TKIs with patent expiry dates in the next 5 years were selected for analysis: imatinib, erlotinib, lapatinib and sorafenib. Chemistry, dosing, published data on per-kilogram pricing for commercial transactions of active pharmaceutical ingredient (API), and quotes from manufacturers were used to estimate costs of production. Analysis included costs of excipients, formulation, packaging, shipping and a 50% profit margin. Target prices were compared with current prices. Global numbers of patients eligible for treatment with each TKI were estimated. RESULTS: API costs per kg were $347-$746 for imatinib, $2470 for erlotinib, $4671 for lapatinib, and $3000 for sorafenib. Basing on annual dose requirements, costs of formulation/packaging and a 50% profit margin, target generic prices per person-year were $128-$216 for imatinib, $240 for erlotinib, $1450 for sorafenib, and $4020 for lapatinib. Over 1 million people would be newly eligible to start treatment with these TKIs annually. CONCLUSIONS: Mass generic production of several TKIs could achieve treatment prices in the range of $128-$4020 per person-year, versus current US prices of $75161-$139,138. Generic TKIs could allow significant savings and scaling-up of treatment globally, for over 1 million eligible patients.

Cheminfomatic-based Drug Discovery of Human Tyrosine Kinase Inhibitors.

Receptor Tyrosine Kinases (RTKs) are essential components for regulating cell-cell signaling and communication events in cell growth, proliferation, differentiation, survival and metabolism. Deregulation of RTKs and their associated signaling pathways can lead to a wide variety of human diseases such as immunodeficiency, diabetes, arterosclerosis, psoriasis and cancer. Thus RTKs have become one of the most important drug targets families in recent decade. Pharmaceutical companies have dedicated their research efforts towards the discovery of small-molecule inhibitors of RTKs, many of which had been approved by the U.S. Food and Drug Administration (US FDA) or are currently in clinical trials. The great successes in the development of small-molecule inhibitors of RTKs are largely attributed to the use of modern cheminformatic approaches to identifying lead scaffolds. Those include the quantitative structure-activity relationship (QSAR) modeling, as well as the structure-, and ligand-based pharmacophore modeling techniques in this case. Herein we inspected the literature thoroughly in an effort to conduct a comparative analysis of major findings regarding the essential structure-activity relationships (SARs)/pharmacophore features of known active RTK inhibitors, most of which were collected from cheminformatic modeling approaches.

Competition, Selectivity and Efficacy of Analogs of A-84543 for Nicotinic Acetylcholine Receptors with Repositioning of Pyridine Nitrogen.

Nicotinic acetylcholine receptors (nAChRs) play a crucial role in a number of clinically relevant mental and neurological pathways, as well as autonomic and immune functions. The development of subtype-selective ligands for nAChRs therefore is potentially useful for targeted therapeutic management of conditions where nAChRs are involved. We tested if selectivity for a particular nAChR subtype can be achieved through small structural modifications of a lead compound containing the nicotinic pharmacophore by changing the distance between the electronegative elements. For this purpose, analogs of A-84543 were designed, synthesized and characterized as potentially new nAChR subtype-selective ligands. Compounds were tested for their binding properties in rat cerebral cortical tissue homogenates, and subtype-selectivity was determined using stably transfected HEK cells expressing different nAChR subtypes. All compounds synthesized were found to competitively displace [(3)H]-epibatidine ([(3)H]EB) from the nAChR binding site. Of all the analogues, H-11MNH showed highest affinity for nAChRs compared to a ~ fivefold to tenfold lower affinity of A-84543. All other compounds had affinities >10,000 nM. Both A-84543 and H-11MNH have highest affinity for α2ß2 and α4ß2 nAChRs and show moderate affinity for ß4- and α7-containing receptors. H-11MNH was found to be a full agonist with high potency at α3ß4, while A-84543 is a partial agonist with low potency. Based on their unique pharmacological binding properties we suggest that A-84543 and its desmethylpyrrolidine analog can be useful as pharmacological ligands for studying nAChRs if selective pharmacological and/or genetic tools are used to mask the function of other receptors subtypes.

Analysis of minimum target prices for production of entecavir to treat hepatitis B in high- and low-income countries.

BACKGROUND: In 2013, an estimated 686,000 people died from hepatitis B virus (HBV) infection worldwide. Mass treatment programmes for hepatitis B will require very low drug costs. International treatment guidelines recommend first-line monotherapy with either entecavir or tenofovir disoproxil fumarate (TDF). While the basic patent on TDF expires in 2017/8, entecavir is already generic in several countries, including the US. The chemical structure of entecavir is related to abacavir, which costs <$200 per person-year in low-income countries. METHODS: The clinical efficacy, chemical structures, daily doses, routes of chemical synthesis, costs of raw materials and patent expiry dates were analysed for entecavir and TDF. Costs of sustainable, generic production were calculated for entecavir, and compared with published originator and generic prices in high- and low-income countries. RESULTS: With a daily dose of 0.5 mg, one year's supply of entecavir treatment requires <0.2 g of active pharmaceutical ingredient (API) per person, estimated to cost $4/year, based on quotations of API production from generic suppliers. With an additional $20 per year for formulation/packaging and a 50% profit margin, entecavir was estimated to cost a minimum of $36/person-year, substantially lower than current originator and generic prices. Entecavir is no longer under patent protection in the USA, China, Brazil and South Africa, with European expiry in 2017. Given differences in daily dosing, production volumes for entecavir would be 600 times lower than TDF (300 mg once daily) for treating the same numbers of patients. CONCLUSIONS: Mass treatment for hepatitis B with generic entecavir could be achieved at very low cost in all countries, provided that important projections can be met in terms of pricing for the API and finished dosage form.

Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey.

Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President's Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent.

Survival ethics in the real world: the research university and sustainable development.

We discuss how academically-based interdisciplinary teams can address the extreme challenges of the world's poorest by increasing access to the basic necessities of life. The essay's first part illustrates the evolving commitment of research universities to develop ethical solutions for populations whose survival is at risk and whose quality of life is deeply impaired. The second part proposes a rationale for university responsibility to solve the problems of impoverished populations at a geographical remove. It also presents a framework for integrating science, engineering and ethics in the efforts of multidisciplinary teams dedicated to this task. The essay's third part illustrates the efforts of Howard University researchers to join forces with African university colleagues in fleshing out a model for sustainable and ethical global development.

4,7-Dichloro-quinoline.

The two mol-ecules in the asymmetric unit of the title compound, C(9)H(5)Cl(2)N, are both essentially planar (r.m.s. deviations for all non-H atoms = 0.014 and 0.026 Å). There are no close C-H⋯Cl contacts.

7-Chloro-4-(piperazin-1-yl)quinoline.

There are two mol-ecules in the asymmetric unit (Z' = 2) of the title compound, C(13)H(14)ClN(3), Each mol-ecule is linked by N-H⋯N hydrogen bonds to another of the same type in a chain in [110]. The crystal studied was a non-merohedral twin with components 0.622 (2) and 0.378 (2).

Extraction and physicochemical characterization of a new polysaccharide obtained from the fresh fruits of abelmoschus esculentus.

This paper is the first multi-scale characterization of the fluidize-dried gum extracted from the fresh fruits of the plant Abelmoschus esculentus. It describes the physical, thermal, sorptional and functional properties of this natural gum. Elemental analysis, scanning electron microscopy (SEM), particle size analysis, X-ray powder diffraction (XPRD), thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), fourier transmittance infra red (FT-IR), and nuclear magnetic resonance (NMR) spectroscopy were used to characterize the gum sample. Abelmoschus Esculentus Gum (AEG) had a glass transition temperature (Tg) of 70°C and no melting peak. It showed a 14.91% loss in weight at 195°C. X-ray diffractogram showed numerous broad halos for AEG. Elemental analysis showed that AEG contains 39.5, 7.3, 51.8, and 1.4% carbon, hydrogen, oxygen and nitrogen respectively. The results obtained in this study established the fundamental characteristics of AEG and suggests its potential application in the food, cosmetic and pharmaceutical sectors.

Microreactors for continuous processing ­ How close to commercial utility?

Microreactor technology holds great promise for simplifying process chemistry. The design of microreactors inherently simplifies heat transfer and flow. Continuous processing on a commercial scale is also achievable using these reactors, providing significant improvements in efficiency compared with batch processing. Two-phase reactions with liquid-gas and liquid-solid phases present difficulties for microreactor-based processing; however, advances in reactor design are providing some solutions to such challenges. The potential efficiencies provided by microreactors suggest that this technology will be adopted increasingly for widespread commercial applications, particularly following greater investment by companies and further improvements in engineering.

Oral sustained release tablets of zidovudine using binary blends of natural and synthetic polymers.

Oral sustained release matrix tablets of zidovudine (ZDV) were prepared using different types, proportions and blends of carbopol 71G (C71) and a plant gum obtained from Abelmoschus esculentus (AEG). The effect of various formulation factors like polymer proportion, polymer type and pH of the dissolution medium on the in vitro release of the drug was studied, using the half change technique, in 900 ml of dissolution medium, at 100 rpm. Release kinetics were analyzed using Zero-order, Higuchi's square-root and Ritger-Peppas' empirical equations. In vitro release performance as revealed by the time taken for 70% of the drug to be released (t70%), showed that the release rate decreased with increase in polymer proportion. Matrix tablets containing 10 and 20% AEG were found to exhibit immediate-release characteristics. Matrix tablets containing 30% AEG showed t70% value of 204 min and extended the release up to 5 h, while matrix tablets containing 30% carbopol showed t70% value of 234 min and extended the release up to 6 h. Three blends of AEG and C71 at the ratio of 1:2, 2:1 and 1:3 showed t70% values of 132, 312 and 102 min respectively and extended the release up to 8 h. Mathematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets followed Fickian and anomalous release. Drug release from matrix tablets of zidovudine containing blends of AEG and C71 demonstrates the advantage of blending a natural and synthetic polymer over single polymer use.

Near-infrared investigations of novel anti-HIV tenofovir liposomes.

Near-infrared (NIR) approaches is considered one of the most well-studied process analyzers evolving from the process analytical technology initiatives. The objective of this study was to evaluate NIR spectroscopy and imaging to assess individual components within a novel tenofovir liposomal formulation. By varying stearylamine, as a positive charge imparting agent, five batches were prepared by the thin film method. Each formulation was characterized in terms of drug entrapment efficiency, release characteristics, particle sizing, and zeta potential. Drug excipients compatibility was tested using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results showed an increase in drug entrapment and a slower drug release by increasing the incorporated percentage of stearylamine. The compatibility testing revealed a significant interaction between the drug and some of the investigated excipients. The developed NIR calibration model was able to assess drug, phospholipid, and stearylamine levels along the batches. The calibration and prediction plots were linear with correlation coefficients of more than 0.9. The root square standard errors of calibration and prediction did not attain 5% of the measured values confirming the accuracy of the model. In contrast, NIR spectral imaging was capable of clearly distinguishing the different batches, both qualitatively and quantitatively. A linear relationship was obtained correlating the actual drug entrapped and the predicted values obtained from the partial least squares images.

A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations.

It has been roughly 25 years since the threat posed by human immunodeficiency virus type 1 (HIV-1) became widely known. The cumulative death toll from HIV/AIDS is now greater than 25 million. There are approximately 33 million people living worldwide with this disease, of whom about 68% (22.5 million) live in sub-Saharan Africa (http://www.avert.org/worldstats.htm). A number of antiretroviral (ARV) drugs have been approved for treatment of HIV/AIDS. Inhibitors of HIV reverse transcriptase (RTIs) include the nucleoside/nucleotide drugs zidovudine, lamivudine, abacavir, didanosine, stavudine, emtricitabine and tenofovir disoproxil fumarate. Non-nucleoside RTIs include nevirapine, efavirenz and etravirine. Inhibitors of HIV protease (PIs) include saquinavir, ritonavir, lopinavir, nelfinavir, indinavir, fosamprenavir and atazanavir. Enfuvirtide inhibits the HIV fusion protein. The CCR5 chemokine antagonist maraviroc and the integrase inhibitor raltegravir were very recently approved by the US FDA. Fixed-dose combinations (FDCs) have been formulated to increase tolerability, convenience and compliance. First-line drug combinations are offered to treatment-naive patients, while second-line drugs are reserved for those who no longer respond adequately to first-line therapy. In developing countries a modest but increasing fraction of those infected have access to ARVs. The Clinton HIV/AIDS Initiative estimates that 2.4 million of the nearly 8 million individuals needing treatment in developing nations have access to some drugs. First-line FDCs used in resource-poor settings are largely combinations of two nucleoside RTIs and a non-nucleoside RTI or PI. The effectiveness of these combinations decreases over time, requiring a switch to combinations that retain potency in the presence of viral resistance. Increasing access to second-line FDCs and new developments in first-line ARV therapy are cost challenges. In high-income countries the cost of ARV therapy is largely irrelevant, except for "advanced salvage" drugs such as enfuvirtide. In resource-poor settings cost is a huge factor that limits drug access, resulting in high rates of new infection and subsequent mortality. IP coverage, where granted, can keep access prices for essential ARVs higher than would otherwise be the case. Large, innovator companies have made drugs available at prices very close to the cost of manufacturing for "lowest income" countries. Generic providers in India and elsewhere provide the largest supply of drugs for the developing world. The recent issuance of Voluntary and Compulsory Licenses (VLs, CLs) through the World Trade Organization's TRIP (Treaty Respecting Intellectual Property) provisions arguably contribute to bringing down access prices. The utilization of improved science, pooled purchasing and intelligent procurement practices all definitely contribute to access. This work surveys the production processes for several critical ARVs. These are discussed in terms of scale up, raw material/intermediates and active pharmaceutical ingredient (API) costs. In some cases new routes to APIs or critical intermediates are needed. Based on potential new chemistries, there are significant opportunities to reduce cost for a number of critical ARVs.