reflexões e contribuições à farmacologia

Reflexões e Contribuições à Farmacologia

Gilberto De Nucci

Desenvolvimento de um MedicamentoDesenvolvimento de um Medicamento

Aumento escalonado Aumento escalonado da doseda doseAumento escalonado Aumento escalonado da doseda dose

TolerânciaTolerânciaTolerânciaTolerância

In vitro PK/PDIn vitro PK/PDAnimal PK/PDAnimal PK/PDIn vitro PK/PDIn vitro PK/PDAnimal PK/PDAnimal PK/PD

Dose (Conc)Dose (Conc)Resposta clínicaResposta clínicaDose (Conc)Dose (Conc)Resposta clínicaResposta clínica

EficáciaEficáciaEficáciaEficácia

Seleção da DoseSeleção da DoseSeleção da DoseSeleção da Dose

Vols sadiosVols sadiosVols sadiosVols sadios

População PK/PDPopulação PK/PDGrandes ensaios clínicosGrandes ensaios clínicosPopulação PK/PDPopulação PK/PDGrandes ensaios clínicosGrandes ensaios clínicos

PK/PD em populaçãoPK/PD em populaçãoespeciaisespeciaisPK/PD em populaçãoPK/PD em populaçãoespeciaisespeciais

Vigilância Vigilância pós-pós-mercadomercado

Vigilância Vigilância pós-pós-mercadomercado

Fase IFase IFase IFase I

Testes Clínicos (Humanas)Testes Clínicos (Humanas)Testes Clínicos (Humanas)Testes Clínicos (Humanas)

Testes Pré-clínicosTestes Pré-clínicosTestes Pré-clínicosTestes Pré-clínicos

Fase IIFase IIFase IIFase II

Fase IIIFase IIIFase IIIFase IIIFase IVFase IVFase IVFase IV

Poucos pctesPoucos pctesPoucos pctesPoucos pctes

Muitos pctesMuitos pctesMuitos pctesMuitos pctesPopulaçãoPopulaçãoPopulaçãoPopulação

Testes em animaisTestes em animaisTestes em animaisTestes em animais

Vols sadiosVols sadiosVols sadiosVols sadios

Fase 0Fase 0Fase 0Fase 0

We found that the methodological quality of the included studies was poor. Issues such as randomization, masked treatment allocation, blinded outcome assessment, and intention to treat analyses, which are very important issues and are now generally required in clinical studies, were especially neglected in these

animal experiments. Surprisingly, 1 study reported a double-blind assessment of effectiveness.

Ames TestAmes Test ( (Salmonella typhimuriumSalmonella typhimurium))

Bacterial reverse mutation assays are widely used to evaluate the Bacterial reverse mutation assays are widely used to evaluate the mutagenic potential of chemicals, formulations, or extracts. The most mutagenic potential of chemicals, formulations, or extracts. The most common assay involves the use of amino acid-requiring strains of common assay involves the use of amino acid-requiring strains of Salmonella typhimuriumSalmonella typhimurium and is commonly referred to as the "Ames Test". and is commonly referred to as the "Ames Test".

In the absence of an external amino acid source (histidine for In the absence of an external amino acid source (histidine for SalmonellaSalmonella), ), the cells cannot grow to form colonies unless a reversion of the mutation the cells cannot grow to form colonies unless a reversion of the mutation allows the synthesis of the amino acid to resume.allows the synthesis of the amino acid to resume.

Spontaneous reversions occur with each of the strains. However, some Spontaneous reversions occur with each of the strains. However, some compounds induce a mutagenic response and thereby increase the number compounds induce a mutagenic response and thereby increase the number of revertant colonies substantially over the spontaneous reversion levelof revertant colonies substantially over the spontaneous reversion level..

The bacterial reverse mutation assay involves the The bacterial reverse mutation assay involves the measurement of revertant colony frequencies that measurement of revertant colony frequencies that are obtained when are obtained when SalmonellaSalmonella strains are treated strains are treated in the presence and absence of a test article. in the presence and absence of a test article.

Positive and negative controls are included for Positive and negative controls are included for each strain tested. Metabolic activation using rat each strain tested. Metabolic activation using rat liver S9 is included to mimic the liver S9 is included to mimic the in vivoin vivo activity of activity of the liver enzymes in transforming some pro-the liver enzymes in transforming some pro-mutagens to mutagensmutagens to mutagens

São Paulo, 20 de setembro de 2000 n.606/00.

Antiinflamatório 100% brasileiro

Pesquisadores do ICB desenvolvem primeiro antiinflamatório totalmente sintetizado no País. O novo medicamento, além de possuir boa atividade farmacológica, apresenta grande capacidade muco-protetora.

The Best Model for Humans is Human — How to

Accelerate Early Drug Development Safely

Mark Seymour

Altern Lab Anim. 2009 Sep;37 Suppl 1:61-5.

Classificação de estudos

• Aleatorizado (randomizado) ou não-aleatorizado.• Aberto, simples-cego, duplo-cego, triplo-cego.• Superioridade ou não-inferioridade• Paralelo, cruzado.• Controlado ou não-controlado.

• Aleatorizado (randomizado) ou não-aleatorizado.• Aberto, simples-cego, duplo-cego, triplo-cego.• Superioridade ou não-inferioridade• Paralelo, cruzado.• Controlado ou não-controlado.

Bíblia Sagrada

Bíblia Sagrada – Tradução da CNBB – 5° edição – pag 1109 (Daniel 1-2)

“Perhaps the most famous historical example of a planned controlled, comparative, clinical trial is from the eighteenth century: that where Lind (1753) found oranges and lemons to be the most effective of six dietary treatments for scurvy on board ships.” - Textbook of Clinical Trials. 2004: p03.

In 2003 Graham Sutton searched HMS Salisbury’s original papers, both the captain’s log and the separate roll-call. “However the weekly roll-call shows at most one or two, and usually none, as sick during this entire voyage”.

“Lind was well aware that it was impractical to carry citrus fruits on long sea voyages because (…) oranges and lemons are liable to spoil. (…) Lind therefore devised a system of almost boiling purified citrus juice, so that 24 oranges or lemons were reduced to a few ounces. (…) Lind’s rob (fruit syrup) was later shown to be ineffective in preventing scurvy (now known because he had boiled the heat-labile ascorbic acid).“ - Nutr Rev. 2009 Jun;67(6):315-32.

Testes Clínicos• Fase 0 – voluntários sadios (microdosagem) – não é regulatória

• Fase I – voluntários sadios

• Fase II – pacientes para prova conceitual

• Fase III – grande número de pacientes – estudos multicêntricos

• Fase IV – vigilância pós-mercado – pesquisa sobre novas indicações

• Fase 0 – voluntários sadios (microdosagem) – não é regulatória

• Fase I – voluntários sadios

• Fase II – pacientes para prova conceitual

• Fase III – grande número de pacientes – estudos multicêntricos

• Fase IV – vigilância pós-mercado – pesquisa sobre novas indicações

“Assumed to be stripped clean of human bias, the masked (blind) RCT is accepted as the gold standard and thus above scrutiny as a potential source of systematic error” - J Clin Epidemiol. 2001 Jun;54(6):541-9.

J Clin Psychopharmacol. 1997 Oct;17(5):407-18.

Am J Psychiatry 2006; 163:185–194

Medicina baseada em evidência é considerada como consenso nas diretrizes de tratamento médico. Entretanto, isso pode ser válido se a evidência for completa.

N Engl J Med 2008;358:252-60

Lancet. 1993 Feb 13;341(8842):418-22.

Control Clin Trials. 1997 Oct;18(5):431-44.

Treatment A Treatment B

78% (273/350) 83% (289/350)

Kidney Stones


Large Stones

Group 373% (192/263)

Group 469% (55/80)

Kidney Stones


Small Stones

Group 193% (81/87)

Group 287% (234/270)

Kidney Stones


Small StonesGroup 1

93% (81/87)Group 2

87% (234/270)

Large StonesGroup 3

73% (192/263)Group 4

69% (55/80)

Both 78% (273/350) 83% (289/350)

Kidney Stones

J Clin Epidemiol. 1995 Jan;48(1):71-9.

Meta-analysis: statistical alchemy for the 21st century.

Feinstein AR.

The p-value for each study is > 0.20 but the p-value for summary effect is <0.02

Introduction to Meta-Analysis – Fig 28.1

Impact of streptokinase on mortality (adapted from Lauet al., 1992)

Introduction to Meta-Analysis – Fig 2.1

Couto L.T; et al. Analysis of five streptokinase formulations using the euglobulin lysis test and the plasminogen activation assay. Braz J Med Biol Res 2004;37:1889–1894.

Conclusion

These data show that the commercially available clinical streptokinase formulations vary significantly in their in vitro activity. Whether these differences have clinical implications needs to be investigated.

CONCLUSION:

There are wide variations in the activity, purity, and composition

of the available streptokinase preparations.

A methodological drawback of the work by Hermentin et al.9 (which the authors acknowledge) is the assessment of only one sample per batch of SK, limiting the generalizability of the results. Moreover, the authors have a direct interest in publicizing their findings, as the SK formulation produced and distributed by their employer showed an exemplary profile in their analyses. Despite these limits, the data by Hermentin et al.9 appear reliable, as they are supported by another report, from an independent academic institution, using rigorous methods of analysis, which also describes marked differences in the activity of five commercially available SK formulations.10

•9. Hermentin P.; et al. Eur Heart J 2005;26:933–940.

•10. Couto LT.; et al. Braz J Med Biol Res 2004;37:1889–1894.

Int J STD AIDS. 1999 Jan;10(1):8-16.

Circumcision and HIV infection: review of the literature and meta-analysis.Van Howe RS.

SourceDepartment of Pediatrics, Marshfield Clinic, Lakeland Center, USA. [email protected]

AbstractThirty-five articles and a number of abstracts have been published in the medical literature looking at the relationship between male circumcision and HIV infection. Study designs have included geographical analysis, studies of high-risk patients, partner studies and random population surveys. Most of the studies have been conducted in Africa. A meta-analysis was performed on the 29 published articles where data were available. When the raw data are combined, a man with a circumcised penis is at greater risk of acquiring and transmitting HIV than a man with a non-circumcised penis (odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01-1.12). Based on the studies published to date, recommending routine circumcision as a prophylactic measure to prevent HIV infection in Africa, or elsewhere, is scientifically unfounded.

PIP:This article reviews the literature on circumcision and HIV infection. Recent studies show raw figures suggesting circumcised men to be at greater risk for HIV infection. Circumcised men have been found to also have more sexual partners. Findings explain that circumcision may be responsible for the increased number of partners, and therefore, the increased risk. In Africa, the use of dirty instruments and mass ritual events, including group circumcision, may increase the number of young boys developing HIV infections. Based on the studies published in the scientific literature, it is incorrect to assert that circumcision prevents HIV infection. Moreover, even if studies showing circumcision to be beneficial are accurate, the risk from circumcision outweighs any small benefit it may have. Thus, promoting circumcision as protection against HIV infection would lead to the belief that circumcised men are being protected from contracting AIDS, which would result in increased HIV infections.

Int J STD AIDS. 2000 Mar;11(3):137-42.

Circumcision in men and the prevention of HIV infection: a 'meta-analysis' revisited.O'Farrell N, Egger M.

SourceDepartment of Genitourinary Medicine, Milne Clinic, Bristol Royal Infirmary, UK.

AbstractThere is debate on the role of male circumcision in HIV transmission. Most case-control and cohort studies from Africa have shown an association between a lack of circumcision and an increased risk of HIV infection in men. The evidence is conflicting, however, with cross-sectional surveys from Tanzania and Rwanda either showing no relationship or an association in the opposite direction. A recent review and meta-analysis of the literature concluded that the risk of HIV infection was lower in uncircumcised men (combined odds ratio 0.94, 95% confidence interval 0.89 to 0.99). However, the analysis was performed by simply pooling the data from 33 diverse studies, which is an inappropriate method for combining studies. We re-analysed the data, stratifying by study, and found that an intact foreskin was associated with an increased risk of HIV infection: combined odds ratio 1.43 (1.32 to 1.54) with a fixed effect model and 1.67 (1.25 to 2.24) with a random effect model. There was significant between-study heterogeneity (P<0.0001) which was partly explained by stronger associations in studies in high-risk groups. The results from this re-analysis thus support the contention that male circumcision may offer protection against HIV infection, particularly in high-risk groups where genital ulcers and other STDs 'drive' the HIV epidemic. A systematic review is required to clarify this issue. Such a review should be based on an extensive search for relevant studies, published and unpublished, and should include a careful assessment of the design and methodological quality of studies. Much emphasis should be given to the exploration of possible sources of heterogeneity. In view of the continued high prevalence and incidence of HIV in many countries in sub-Saharan Africa, the question of whether circumcision could contribute to prevent infections is of great importance, and a sound systematic review of the available evidence should be performed without delay.

Comment onThe following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface controlCircumcision and HIV infection: review of the literature and meta-analysis. [Int J STD AIDS. 1999]

Why Most Published Research Findings Are False

John P. A. Ioannidis

Summary There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

Intention-to-Treat Analysis

Includes all randomized patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol

(Lloyd) Fisher et al., 1990

- Intention to treat analysis is a euphemism not to include all events in all patients from randomised until study completion.

- Intention to treat analysis leads to missing data, which is one of the most catastrophic problems facing clinical trials today.

- Missing data is a cancer growing on the clinical trial community.

What is meant by intention to treat analysis? Survey of published randomised controlled trials

Sally Hollis, Fiona Campbell

Abstract Objectives To assess the methodological quality of intention to treat analysis as reported in randomised controlled trials in four large medical journals.

Conclusions The intention to treat approach is often inadequately

described and inadequately applied. Authors should explicitly describe the handling of deviations from randomised allocation and missing responses and discuss the potential effect of any missing response. Readers should critically assess the validity of reported intention to treat analyses.

BMJ 1999;319:670–4

Far better an approximate answer to the right question, which is often vague, than

an exact answer to the wrong question, which can always be made precise.

John W. Tukey (1962)

Fase I para moléculas sintéticas e biológicas para o tratamento do câncer

Objetivos da Fase I

• Farmacocinética

• Tolerabilidade

• Toxicidade

• Escalonamento de dose para Fase II

• Avaliar aspectos Farmacodinâmmicos

A phase I trial of the bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC3095 in patients with advanced solid

malignancies

G. Schwartsmann, L. P. DiLeone, M. Horowitz, D. Schunemann, A. Cancella, A. S. Pereira, M. Richter, F. Souza, A. Brondani da Rocha, F. H. Souza, P. Pohlmann, G. De

Nucci.

Purpose: To determine the safety and feasibility of the administration of RC-3095 by daily subcutaneous injections in patients with advanced and refractory solid malignancies.

Methods: Twenty-five patients received RC-3095 once or twice-daily at doses ranging from 8 to 96 ug/kg. Dose was escalated in groups of 3–5 patients per dose level.

Invest New Drugs (2006) 24:403–412.

A dose-escalation phase I trial of nimotuzumab,

an antibody against the epidermal growth factor receptor, in patients with advanced solid malignancies

Benoit You, Anthony Brade, Joao M. Magalhaes, Lillian L. Siu, Amit Oza, Sonya Lovell, Lisa Wang, David W. Hedley, Leonardo V. Nicacio, Eric X. Chen.

Objective: The primary objective of the trial was to assess the pharma- codynamic effects of nimotuzumab in tumor and skin tissues. Hence, no dose escalation above 800 mg was planned. This study did not aim at determining a recommended dose for phase 2 trial.

Invest New Drugs (2011) 29:996–1003.

A dose-escalation phase I trial of nimotuzumab,

an antibody against the epidermal growth factor receptor, in patients with advanced solid

malignancies

Eligibility: The 17 patients enrolled onto this study had histologically or cytologically documented solid tumors either refractory to standard therapy or for which no curative therapy exists.

Administration: Nimotuzumab was administered intravenously every week over 30 min after administration of 50 mg of diphenhydramine on an outpatient basis. Each cycle was defined as 6 weeks and treatment was continued until disease progression, occurance of intolerable toxicity, or patient’s withdrawal of consent. No routine antiemetic prophylaxis was mandated.

Invest New Drugs (2011) 29:996–1003.

Invest New Drugs (2011) 29:996–1003.

Metabolism and disposition of imatinib mesylate in healthy volunteers

Hans-Peter Gschwind, Ulrike Pfaar, Felix Waldmeier, Markus Zollinger, Claudia Sayer, Peter Zbinden, Michael Hayes, Rolf Pokorny, Michael Seiberling, Monique Ben-Am,

Bin Peng and Gerhard Gross

Purpose: To investigate the disposition and biotransformation of imatinib mesylate in 4 male healthy volunteers after a single oral dose of 239 mg of 14C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588.

Int J Pharm Med (2006) 20:159-165.

Int J Pharm Med (2006) 20:159-165.

Advantages of Microdosing

First of all, microdosing requires minute quantities of the drug for safety testing. A microdose is so small that when administered to human subjects, it is not intended to produce any pharmacologic action; hence, the risk of adverse events is less.

A smaller toxicology package is required. As per the regulatory requirement, animal studies, at least in one species, are required to establish microdose in humans, but at a much reduced level. Further, if human screening of compounds is done earlier in the drug development process, fewer animal studies are required before Phase I clinical trials. Thus, further animal studies can be avoided with compounds having unsuitable pharmacokinetic profiles.

• Capecitabine is an adjuvant treatment for colon cancer and for the treatment of metastatic breast cancer in patients whose pathology did not improve during treatment with other therapeutic agents.

• Capecitabine is a prodrug, and it is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine phosphorylase, which is generally expressed at high levels in tumors.

Capecitabine

• Clinical and pharmacokinetics studies for capecitabine are performed in patients with cancer.

• Standard dosing is 1,250 mg/m2 orally twice daily, morning and evening, for 14 consecutive days in 3-week cycles.

• For an average healthy male volunteer weight (70 kg) and height (170 cm) this would mean 2150 mg per dose (4300 mg per day). Corporal Area = 1,809 m2

Capecitabine

Metabolic activation of capacitabine in humans

Reiner et al, 1998

Adverse effects

• Asthenia/ fatigue• Diarrhea• Lymphopenia• Leukopenia• Mucositis• Nausea• Neutropenia • Thrombocytopenia• Vomit • Hand Foot Syndrome

Committee of Ethics in Research approval the pilot study protocol

Item V- CER evaluation

The Committee of Ethics in Research of the Faculty of Medical Sciences of

UNICAMP, obeying the evaluations of the previously designated members for the

present case and attending all of dispositions of Resolutions 196/96 and

complementary, decided to approve without restrictions the Research Protocol,

the informed consent, as well as all the attached files included in the research

proposal.

April 10th, 2010

2nd World Congress on Bioavailability

& Bioequivalence 2011 (BABE 2011)

Presentation of the results of the two pilot studies of

capecitabine on 16 healthy male volunteers

June 6th 2011

August 10th 2011

CONEP had received from the National Agency of Sanitary Vigilance

(ANVISA) a note warning about the approval from the Committee of

Ethics in Research of clinical studies that violated the ethical concepts

of resolution CNS 196/96.

In response, CONEP released a note stating the following:

“Healthy individuals should not enroll on bioequivalence studies of

drugs with high toxic potential (chemotherapeutics); Studies with these

agents should only be performed on patients that may benefit from the

studied drug.”

National Commission on Ethics in Research (CONEP)

- Evaluated the safety of a capecitabine bioequivalence study (150 mg tablet) using 8 healthy male volunteers under fasting and non-fasting conditions. - The study was initially conducted with an open, randomized, two-period crossover design in a 2-week washout with fasted volunteers. - After the fasted study a new protocol was submitted to the Ethics Committee to evaluate the non-fasted study. - The volunteers were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests .- A single capecitabine tablet (150mg) was given in each interment. - The drug was well tolerated by the volunteers, and they presented no adverse reactions. The biochemical and hematological parameters presented no clinically relevant alterations. - Results indicate that it is safe to perform capecitabine bioequivalence studies in healthy male volunteers.

Item 2 – Relative bioavailability/ bioequivalence studies with drugs present on attachment I must respect the general measures described on this note as well as specific measures to each drug described on the same attachment.

Item 3.1 – Based on the toxic potential of these drugs the investigators must decide on the participation of patients or healthy volunteers, as well as the most adequate dose to use in the study.

Attachment I – Drugs that must have bioavailability/ bioequivalence studies conducted accordingly to this note

Technical Note 05/2012

Capecitabine

Study population

Male volunteers

Female volunteers with definitive sterilization

Oral dose 150 mg

Item 2 – Relative bioavailability/ bioequivalence studies with drugs present on attachment I must be conducted on patients of the target population of the studied drug; patients must be receiving treatment to a pathology to which the reference drug is indicated. These studies must respect the technical aspects depicted on this note.

Attachment I – Drugs that must have bioavailability/ bioequivalence studies conducted on patients.

Technical Note 06/2012

Azacitidine Ganciclovir Temozolomide

Chlorambucil Goserelin Testosterone

Clozapine Leuprorelin Topotecan

Doxorubicin Melphalan Triptorelin

Etoposide Mercaptopurine Vorinostat

Everolimus Nabilone

Felbamate Nilutamide

December 13th, 2012

6.2.1. Phase I, single agent dose and schedule finding trials

– Non-clinical data and, when available, data from healthy volunteers

should be used to design the studies to be conducted in patients

– Based on preclinical tolerability and toxicology findings and the

assumed pharmacology of the compound, early trials may sometimes be

conducted in healthy volunteers.

European Medicines Agency

To evaluate bioequivalence between two formulations of capecitabine (test and reference) in healthy male volunteers

Objective

Why evaluate on healthy volunteers?

Capecitabine is employed for the treatment of metastatic cancer, therefore the prognosis of these patients is usually reserved. To expose these critical patients to either ineffective or toxic doses of the drug (due to unforeseen infra or supra-bioavailability of the test formulation), to experimental procedures such as internment, venous puncture and blood collection to evaluate bioequivalence should be ethically re-evaluated. Furthermore, studies performed in patients are with therapeutic doses, using several tablets for each administration (generally a combination of both 150 and 500 mg tablets), a procedure that limits the discrimination between dosage forms.

• The clinical protocols were approved by the university IRB.

• The studies were conducted using an open, randomized, two-period (150 mg single administration of Xeloda; F. Hoffmann-La Roche Ltd., vs a test formulation) crossover design with a one-week washout interval, in two groups, with food.

• All male subjects were negative for HIV, HCV and HBV. The laboratory tests (biochemical and hematological parameters) were performed on average three days after the first confinement, and 7 days after the second confinement.

Methods

• Subjects: Seventy-two healthy male volunteers were recruted

• Hematological evaluation: Hemoglobin, Hematocrit, Erythrocyte Count, VCM, HbCM, White Cell and Platelet Count

• Biochemistry: Total Cholesterol, Triglycerides, Total Proteins, Albumin, Uric Acid, Total Bilirubins (Direct and Indirect), Alkaline Phosphatase, SGOT (AST), SGPT (ALT), Urea, Creatinine, Fasting Blood Glucose

• Physical exam and EKG.

Methods

• Dose: 150mg single-dose on each treatment with a one-week washout period between treatments.

• Volunteers had a standardized breakfast 30 minutes before drug administration.

• Blood samples were collected at 0:10, 0:15, 0:20, 0:30, 0:40, 0:50, 1:00, 1:10, 1:20, 1:30, 1:40, 1:50, 2:00, 2:30, 3:00, 3:30, 4:00, 5:00, 6:00 and 7:00h after drug administration

Methods

• HPLC coupled to tandem mass spectrometry

• Deuterated capecitabine

Determination of Capecitabine

CapecitabineM.W. 359.93 g/mol

Capecitabine-d11M.W. 371.08 g/mol

http://www.caymanchem.com/images/catalog/screen/10010681.png

• Three drop-outs due to time unavailability.

• The drug was well tolerated by the 69 volunteers

that concluded the study.

• One volunteer had a mild headache.

• Three individuals presented hypertriglyceridemia.

Results

• To determinate if hypertriglyceridemia was due to capecitabine, plasma

samples remaining from the analitical study were evaluated for

triglycerides.

• Two out of the 3 volunteers had hypertriglyceridemia before the first

and the second dose of capecitabine, and did not have significant

variation through out the treatment day.

• The volunteer that had normal triglycerides before treatments only

presented mildly elevated levels (273 mg/dL) 8 days after the second

dose (discharge evaluation). It resolved without treatment, as evaluated

30 days after the last dose.

Results

It is safe to perform capicetabine (150mg)

bioequivalence study in healthy male volunteers.

Conclusion

John Robert Vane Oswaldo Vital Brazil João Garcia Leme

Missed but not forgotten

reflexões e contribuições à farmacologia

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