RESUMO
Background: Transthyretin amyloid polyneuropathy (ATTR-PN) is a fatal disease associated with substantial burden of illness. Three therapies are approved by the European Medicines Agency for the management of this rare disease. The aim of this study was to compare the total annual treatment specific cost per-patient associated with ATTR-PN in Spain.Methods: An Excel-based patient burden and cost estimator tool was developed to itemize direct and indirect costs related to treatment with inotersen, patisiran, and tafamidis in the context of ATTR-PN. The product labels and feedback from five Spanish ATTR-PN experts were used to inform resource use and cost inputs.Results: Marked differences in costs were observed between the three therapies. The need for patisiran- and inotersen-treated patients to visit hospitals for pre-treatment, administration, and monitoring was associated with increased patient burden and costs compared to those treated with tafamidis. Drug acquisition costs per-patient per-year were 291,076 (inotersen), 427,250 (patisiran) and 129,737 (tafamidis) and accounted for the majority of total costs. Overall, the total annual per-patient costs were lowest for patients treated with tafamidis (137,954), followed by inotersen (308,358), and patisiran (458,771).Conclusions: Treating patients with tafamidis leads to substantially lower costs and patient burden than with inotersen or patisiran.
Assuntos
Neuropatias Amiloides Familiares/terapia , Benzoxazóis/administração & dosagem , Efeitos Psicossociais da Doença , Oligonucleotídeos/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Neuropatias Amiloides Familiares/economia , Benzoxazóis/economia , Custos de Medicamentos/estatística & dados numéricos , Custos de Cuidados de Saúde/estatística & dados numéricos , Hospitalização/economia , Humanos , Oligonucleotídeos/economia , RNA Interferente Pequeno/economia , EspanhaRESUMO
The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can be particularly challenging to perform in patients with severe scoliosis and/or previous spine fusion surgeries. We developed a protocol for the administration of nusinersen in pediatric patients, which includes a decision-tree algorithm that categorizes patients according to the estimated technical difficulty for the intrathecal administration. Complex spine patients were defined as those with a Cobb angle greater than 50° and/or a history of spinal surgery, while the rest of patients were considered non-complex. Nusinersen was successfully administered through a conventional non-CT-guided lumbar puncture in all 14 non-complex spine patients (110 out of 110 procedures; 100%). The feasibility of the intrathecal injection in the 15 complex spine patients was assessed by 3D CT. Administration was considered unfeasible in 7 out of these 15 patients according to imaging. In the 8 complex spine patients in whom the administration was considered feasible, conventional non-CT-guided lumbar punctures were successful only in 19 out of 53 procedures (36%). The remaining 34 procedures (64%) were guided by CT scan, all successful. Our work demonstrates that a cut-off point of 50° in Cobb angle and history of spinal surgery can reliably be used to anticipate the need for CT guidance in nusinersen administration.
Assuntos
Algoritmos , Árvores de Decisões , Injeções Espinhais/métodos , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/administração & dosagem , Radiografia Intervencionista/métodos , Adolescente , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Imageamento Tridimensional , Lactente , Masculino , Atrofia Muscular Espinal/complicações , Procedimentos Neurocirúrgicos , Escoliose/complicações , Escoliose/cirurgia , Tomografia Computadorizada por Raios X/métodosRESUMO
Inotersen (TEGSEDI™) is a 2'-O-(2-methoxyethyl)-modified antisense oligonucleotide, intended for treating hereditary transthyretin (TTR) amyloidosis with polyneuropathy. The potential immunogenicity (IM) response to inotersen was evaluated in chronic nonclinical safety studies and the pivotal phase 2/3 clinical study. The evaluation was designed to assess the characteristics of antidrug antibodies (ADAs) and their effects on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety in animals and humans. No immunogenic response was observed after long-term treatment with inotersen in mice. In monkeys, the incidence rate of IM to inotersen appeared to be dose dependent, with 28.6%-50.0% of animals developing ADAs after 36 weeks of treatment. This was characterized as late onset (median onset of 185 days) with low titers (median titer of 8, or 400 if minimum required dilution of 50 is included). The overall incidence rate of patients who developed ADAs was 30% after 65 weeks of treatment with median onset of 203 days and median peak titer of 300. IM had minimal effect on plasma peak (Cmax) and total exposure (i.e. area under curve, AUC) of inotersen, but showed elevated plasma trough levels in both IM-positive animals and humans. However, ADAs had no effect on tissue exposure, TTR messenger RNA, or plasma TTR levels in the long-term monkey study. Similarly, IM showed no effect on plasma TTR levels in clinical studies. Thus, ADAs antibodies were binding antibodies, but not neutralizing antibodies. Finally, no association was observed between IM and toxicity findings (eg, platelet, complement activation, and histopathology findings) in the inotersen 9-month monkey study. In humans, no difference was observed in hematology, including platelets, kidney function tests, or incidence of adverse events between IM-positive and -negative patients. Overall, IM showed no effect on toxicity or safety of inotersen evaluated in both monkeys and humans. ClinicalTrials.gov Identifier: NCT01737398.
Assuntos
Doença de Charcot-Marie-Tooth/tratamento farmacológico , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos/administração & dosagem , Oligorribonucleotídeos/administração & dosagem , Pré-Albumina/genética , Animais , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Anti-Idiotípicos/imunologia , Plaquetas/imunologia , Doença de Charcot-Marie-Tooth/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Haplorrinos , Humanos , Imunogenicidade da Vacina/genética , Imunogenicidade da Vacina/imunologia , Testes de Função Renal , Masculino , Camundongos , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/sangue , Oligonucleotídeos Antissenso/farmacocinética , Oligorribonucleotídeos/efeitos adversos , Oligorribonucleotídeos/sangue , Oligorribonucleotídeos/farmacocinética , Pré-Albumina/antagonistas & inibidores , Pré-Albumina/imunologiaRESUMO
Four decades have passed since oligonucleotides were first used to manipulate gene expression. There were few FDA approvals prior to 2016, mostly of drugs that eventually exhibited poor performance in the market. The aura of their younger siRNA relatives had also faded during the past 15 years. However, several FDA approvals have occurred in the past 4 years, restoring hope that a new era has dawned in oligonucleotide/siRNA clinical therapeutics. Here, we review the field of oligonucleotide therapeutics and provide an update on FDA approvals of oligonucleotides from 2017 until the second quarter of 2019. We take into consideration the ethical issues looming over the still somewhat limited efficacy of these molecules, the toxicity of treatment, and the exorbitant cost of these therapeutic agents, which limits accessibility for many.
Assuntos
Oligonucleotídeos/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Custos de Medicamentos , Humanos , Oligonucleotídeos/economia , Oligonucleotídeos/genética , Oligonucleotídeos/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos , United States Food and Drug AdministrationRESUMO
The mechanisms of antisense oligonucleotide-induced liver toxicity are still poorly understood. Assessment of the hepatic safety profile is currently mostly investigated directly in rodent studies. A predictive preclinical in vitro model that is capturing liver liabilities of antisense oligonucleotides can be of great help to be used as a first filter in the screening process of therapeutic oligonucleotides. We describe here an in vitro cytotoxicity assay using freshly isolated mouse hepatocytes or cryopreserved human hepatocytes that recapitulates the hepatotoxic profile of antisense oligonucleotides previously observed in rodents and can be used for the prioritization of molecules prior to in vivo testing.
Assuntos
Hepatócitos/efeitos dos fármacos , Oligonucleotídeos/efeitos adversos , Animais , Biomarcadores , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Camundongos , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/farmacologiaRESUMO
PURPOSE: To examine diagnostic reference levels (DRL) and achievable doses (AD) of image-guided and size-specific dose estimates (SSDE) and organ and effective doses of CT-guided intrathecal nusinersen administration to adult patients with spinal muscular atrophy (SMA). METHODS: This study involved a total of 60 image-guided intrathecal nusinersen treatments between August 2017 and June 2018. Patient cohort comprised 14 adult patients with the following SMA types: type 2 (n = 9) and type 3 (n = 5) with a mean age of 33.6 years (age range 25-57 years). DRL, AD, SSDE, organ, and effective doses were assessed with a dose-monitoring program based on the Monte Carlo simulation techniques. RESULTS: DRL and AD for computed tomography are summarised as follows: in terms of CT-dose index (CTDIvol), DRL 56.4 mGy and AD 36.7 mGy; in terms of dose-length product (DLP), DRL 233.1 mGy cm and AD 120.1 mGy cm. DRL and AD for fluoroscopic guidance were distributed as follows: in terms of dose-area product (DAP), DRL 239.1 µGy m2 and AD 135.2 mGy cm2. Mean SSDE was 9.2 mGy. Mean effective dose of the CT-guided injections was 2.5 mSv (median 2.0 mSv, IQR 1.3-3.2 mSv). Highest organ doses in the primary beam of radiation were the small intestine 12.9 mSv, large intestine 9.5 mSv, and ovaries 3.6 mSv. CONCLUSION: Radiation exposure of SMA patients measured as DRLs is generally not higher compared with patients without SMA despite severe anatomical hazards. Dose monitoring data may allow clinicians to stratify radiation risk, identify organs at risk, and adopt measures for specific radiation dose reduction.
Assuntos
Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/administração & dosagem , Radiografia Intervencionista/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Exposição à RadiaçãoAssuntos
Técnicas de Apoio para a Decisão , Alocação de Recursos para a Atenção à Saúde/ética , Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Ética Médica , Hospitais/ética , Humanos , Lactente , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/economia , Estados UnidosRESUMO
Cure SMA is dedicated to the treatment and cure of spinal muscular atrophy (SMA)-a disease affecting motor neurons, that robs patients of their ability to walk, eat and even breathe. Since 1984, we have directed and invested in comprehensive research that has shaped the scientific community's understanding of SMA. On 23 December, 2016, the Food and Drug Administration (FDA) announced approval of Spinraza, a treatment developed by Biogen and Ionis, making it the first-ever approved therapy for SMA. Cure SMA provided early research funding in 2003 leading to the discovery of ISS-N1 sequence, now targeted by Spinraza. We are pleased that our strategy of providing seed funding for research to either identify new therapeutic strategies or de-risk early stage ones, has proven successful with Spinraza's approval. The approval of Spinraza provides great hope to the SMA community and represents decades of hard work and perseverance by families, researchers, pharmaceutical companies and the FDA. Our hope is that Spinraza is the leading edge of a robust drug pipeline, and with our deep expertise in every aspect of SMA, we remain committed to do everything we can to support research and drug development to achieve the greatest possible effect for each and every SMA patient.
Assuntos
Terapia Genética/métodos , Atrofia Muscular Espinal/terapia , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos/administração & dosagem , Ensaios Clínicos como Assunto , Terapia Genética/economia , Terapia Genética/legislação & jurisprudência , Humanos , Atrofia Muscular Espinal/genética , Estados Unidos , United States Food and Drug AdministrationRESUMO
Approval of Spinraza (nusinersen) for treatment of spinal muscular atrophy prompts consideration of a number of ethical issues that arise whenever a new treatment is proposed for a serious condition, especially one that is rare and can devastatingly affect children. Patients, families, clinicians, researchers, institutions and policymakers all must take account of the ways that newly available treatments affect informed and shared decision-making about therapeutic and research options. The issues to consider include: addressing what is still uncertain and unknown; the possibility that potential benefits will be exaggerated and potential harms underemphasized in the media, by advocacy organizations, and in consent forms and processes; the high cost of many novel drugs and biologics; the effects of including conditions of variable phenotype in state-mandated newborn screening panels; and how new treatments can change the standard of care, altering what is and is not known about a disorder and posing challenges for decision-making at both individual and policy levels. The good news that Spinraza brings thus requires additional attention to its ethical and policy implications, to improve counseling and shared decision-making about treatment and research options for patients and all involved in their care.
Assuntos
Terapia Genética/ética , Atrofia Muscular Espinal/terapia , Custos e Análise de Custo , Terapia Genética/economia , Terapia Genética/legislação & jurisprudência , Terapia Genética/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Atrofia Muscular Espinal/genética , Oligonucleotídeos/administração & dosagemRESUMO
Non-human primates (NHPs) are currently considered to be the non-rodent species of choice for the preclinical safety assessment of single-stranded oligonucleotide (SSO) drugs. We evaluated minipigs as a potential alternative to NHPs to test the safety of this class of compounds. Four different phosphorothioated locked nucleic acid-based SSOs (3 antisense and 1 anti-miR), all with known safety profiles, were administered to minipigs using similar study designs and read-outs as in earlier NHP studies with the same compounds. The studies included toxicokinetic investigations, in-life monitoring, clinical and anatomic pathology. In the minipig, we demonstrated target engagement by the SSOs where relevant, and a similar toxicokinetic behavior in plasma, kidney, and liver when compared with NHPs. Clinical tolerability was similar between minipig and NHPs. For the first time, we showed similar and dose-dependent effects on the coagulation and complement cascade after intravenous dosing similar to those observed in NHPs. Similar to NHPs, morphological changes were seen in proximal tubular epithelial cells of the kidney, Kupffer cells, hepatocytes, and lymph nodes. Minipigs appeared more sensitive to the high-dose kidney toxicity of most of the selected SSOs than NHPs. No new target organ or off-target toxicities were identified in the minipig. The minipig did not predict the clinical features of human injection site reactions better than the NHPs, but histopathological similarities were observed between minipigs and NHPs. We conclude that there is no impediment, as default, to the use of minipigs as the non-rodent species in SSO candidate non-clinical safety packages.
Assuntos
Modelos Animais , Oligonucleotídeos/toxicidade , Porco Miniatura , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/farmacocinética , Suínos , Distribuição Tecidual , ToxicocinéticaRESUMO
Intravaginal delivery offers an effective option for localized, targeted, and potent microbicide delivery. However, an understanding of the physiological factors that impact intravaginal delivery must be considered to develop the next generation of microbicides. In this review, a comprehensive discussion of the opportunities and challenges of intravaginal delivery are highlighted, in the context of the intravaginal environment and currently utilized dosage forms. After a subsequent discussion of the stages of microbicide development, the intravaginal delivery of proteins and oligonucleotides is addressed, with specific application to HSV and HIV. Future directions may include the integration of more targeted delivery modalities to virus and host cells, in addition to the use of biological agents to affect specific genes and proteins involved in infection. More versatile and multipurpose solutions are envisioned that integrate new biologicals and materials into potentially synergistic combinations to achieve these goals.
Assuntos
Anti-Infecciosos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Técnicas de Transferência de Genes , Oligonucleotídeos/uso terapêutico , Proteínas/uso terapêutico , Doenças Virais Sexualmente Transmissíveis/tratamento farmacológico , Doenças Virais Sexualmente Transmissíveis/prevenção & controle , Administração Intravaginal , Anti-Infecciosos/economia , Anti-Infecciosos/uso terapêutico , Feminino , Humanos , Nanopartículas/administração & dosagem , Nanopartículas/uso terapêutico , Oligonucleotídeos/administração & dosagem , Proteínas/administração & dosagemRESUMO
This white paper summarizes the current consensus of the Reproductive Subcommittee of the Oligonucleotide Safety Working Group on strategies to assess potential reproductive and/or developmental toxicities of therapeutic oligonucleotides (ONs). The unique product characteristics of ONs require considerations when planning developmental and reproductive toxicology studies, including (a) chemical characteristics, (b) assessment of intended and unintended mechanism of action, and (c) the optimal exposure, including dosing regimen. Because experience across the various classes of ONs as defined by their chemical backbone is relatively limited, best practices cannot be defined. Rather, points to consider are provided to help in the design of science-based reproductive safety evaluation programs based upon product attributes.
Assuntos
Aptidão Genética/efeitos dos fármacos , Guias como Assunto , Oligonucleotídeos/farmacocinética , Reprodução/efeitos dos fármacos , Animais , Biomarcadores Farmacológicos/análise , Vias de Administração de Medicamentos , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Animais , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/toxicidadeRESUMO
Over the past decade, oligonucleotide-based therapeutics such as antisense oligonucleotides and small interfering RNAs (siRNAs) have been developed extensively. For example, mipomersen (Kynamro; ISIS Pharmaceuticals), which is a second-generation antisense oligonucleotide administered by subcutaneous injection, has recently been approved by the FDA for the treatment of homozygous familial hypercholesterolemia. On the other hands, methods for the evaluation of quality, efficacy and safety of oligonucleotide therapeutics have not been fully discussed. Furthermore, the regulatory guidance specific for oligonucleotide therapeutics has not been established yet. Under these circumstances, we started to collaborate with Osaka University and PMDA to discuss regulatory science focused on oligonucleotide therapeutics. Through the collaboration, we would like to propose the possible design of quality evaluation and preclinical safety-evaluation of oligonucleotide therapeutics.
Assuntos
Oligorribonucleotídeos Antissenso , Farmacovigilância , RNA Interferente Pequeno , Pesquisa Translacional Biomédica , Comportamento Cooperativo , Aprovação de Drogas , Órgãos Governamentais , Administração de Serviços de Saúde , Humanos , Injeções Subcutâneas , Oligonucleotídeos/administração & dosagemAssuntos
Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticolesterolemiantes/economia , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/economia , LDL-Colesterol/sangue , Aprovação de Drogas , Fígado Gorduroso/induzido quimicamente , Humanos , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/economia , Vigilância de Produtos Comercializados , Doenças Raras/tratamento farmacológico , Estados Unidos , United States Food and Drug AdministrationAssuntos
Aprovação de Drogas , Sistemas de Liberação de Medicamentos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Apolipoproteínas/biossíntese , Indústria Farmacêutica , Humanos , Linfoma de Células B/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/administração & dosagem , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacocinética , Tionucleotídeos/uso terapêuticoAssuntos
Asma/tratamento farmacológico , Terapia de Alvo Molecular , Administração por Inalação , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Indústria Farmacêutica , Humanos , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/uso terapêutico , Transdução de Sinais , Resultado do TratamentoRESUMO
Abetimus sodium is an oligonucleotide-based investigational drug designed to treat patients with lupus nephritis by specifically reducing anti-double-stranded DNA antibody levels. The safety and pharmacokinetics of abetimus were evaluated in 24 healthy volunteers at intravenous doses of 600 mg, 1200 mg, and 2400 mg. The mean half-life ranged from 0.8 to 1.5 hours. Maximum exposure assessed by maximum observed plasma concentration was dose proportional. Total exposure assessed by area under the plasma concentration-time curve was dose proportional between 1200-mg and 2400-mg doses and greater than proportionate between the 600-mg and 1200-mg doses. Abetimus was well tolerated in all dose groups, with adverse events observed in 33.3% (2/6) of placebo subjects and 16.7% (3/18) subjects receiving abetimus. No clinically significant effects were observed on laboratory values, vital signs, or electrocardiogram, with the exception of a transient, dose-dependent, prolongation in activated partial thromboplastin time. In vitro coagulation studies suggested that the effect on activated partial thromboplastin time was attributable to a nonspecific interaction rather than specific factor depletion. Exposure to abetimus at intravenous doses of 600 mg, 1200 mg, and 2400 mg was well tolerated. Total exposure assessed by area under the plasma concentration-time curve was greater than dose proportional across the dose range of 600 mg to 2400 mg.
Assuntos
Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Coagulação Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Injeções Intravenosas , Masculino , Oligonucleotídeos/administração & dosagem , Tempo de Tromboplastina Parcial , Tempo de ProtrombinaRESUMO
PURPOSE: Intramural delivery of a P-32 radiolabeled oligonucleotide (ODN) using an infiltrating catheter has been proposed recently to potentially reduce restenosis in coronary arteries and tested on a limited number of human subjects. However, because of the low efficiency of drug retention (approximately 2-5%) after the initial washout period from this technique, the dose levels to nontarget organs may be significant and thus may require a detailed investigation. The radiation dose distributions resulting from this technique is investigated using the MIRD formalism and Monte Carlo calculations. MATERIALS AND METHODS: The total activity of the P-32 ODN to be injected during treatment to deliver a therapeutic dose of approximately 30 Gy to the arterial wall is estimated taking into account the drug delivery efficacy of the infiltrating device (approximately 2-5% typical). Using pharmacokinetic data for P-32 ODN, we estimate the dose to healthy organs resulting from the systemic fraction that is released into the circulatory system during washout (>95% typical). Variabilities in the biological parameters are also identified as important sources of error in the prescribed dose. RESULTS: A limitation to this technique is the poor accuracy in delivering the prescribed dose due to variability in the amount of drug delivered. Dose to organs is also an important limitation. For example, our calculation indicate that approximately 37 MBq (1 mCi) of P-32 labeled ODN are needed to deliver 30 Gy to the arterial wall assuming a delivery efficiency of 2-5% and a 24-h residence time. This may result in doses of approximately 1 Gy to the spleen and 0.2-0.4 Gy to the liver, kidneys and lungs (95% confidence interval). CONCLUSION: This novel therapy suffers from serious limitations. It is doubtful that a therapeutic dose can be delivered accurately, safely and effectively to the arterial wall because of the poor delivery efficacy and extreme variability found in drug delivery experiments. Also, dose levels to healthy organs appears to be too high to recommend the use of this technique in human experiments.