• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    IN VITRO method to calculate the dosage of the drug adalimumab or biosimilars to be administered for the treatment of inflammatory bowel diseases. The invention relates to an in vitro method for calculating the appropriate dosage and dosage range of adalimumab or its biosimilars to be administered to a patient with inflammatory bowel disease. Said method comprises the application of a mathematical formula based on three individual patient factors: (i) the body mass index (BMI), (ii) the amount of fecal calprotectin and (iii) the presence or absence of anti-adalimumab antibodies. . This method allows the dosage to be adapted to the patient's situation, increasing the success of therapy by achieving therapeutic serum concentrations of the drug. The invention also proposes a dosage schedule for adalimumab or its biosimilars, preferably to be administered during the maintenance phase of the treatment, which allows reaching plasma therapeutic drug concentrations. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2785326A1
    申请号:ES201930298
    申请日:2019-04-02
    公开日:2020-10-06
    发明作者:Hernández José Germán Sánchez；Díaz Noemí Rebollo；Hernández María Victoria Calvo；Núñez José Fernando Muñoz；Pérez Antonio Rodríguez
    申请人:FUNDACION INST DE ESTUDIOS DE CIENCIAS de la SALUD DE CASTILLA Y LEON；
    IPC主号:
    专利说明:

    [0003] ADALIMUMAB OR BIOSIMILARES TO BE ADMINISTERED FOR THE TREATMENT OF
    [0005] The present invention falls within the field of pharmacology, pharmacokinetics and therapeutic methods based on the administration of adalimumab or its biosimilars, such as those against inflammatory bowel diseases. Specifically, the invention relates to an in vitro method for calculating the adalimumab drug dosage regimen to be administered individually to each patient to successfully treat inflammatory bowel diseases and achieve therapeutic serum concentrations of the drug, which makes it possible to ensure the efficacy and safety of the treatment.
    [0007] BACKGROUND OF THE INVENTION
    [0009] Inflammatory bowel disease (IBD) is a chronic pathology that affects approximately 0.3% of the Spanish population and it is expected that the prevalence will continue to increase steadily over the next few years, as the incidence of this disease has multiplied by 10 in the last 25 years and currently about 2,000 new cases are detected per year, with an annual increase of 2.5%. The consequences of poor control of this disease are devastating for the patient: diarrhea, abdominal pain, bleeding, infections, etc., and many of them end up requiring a partial or total colectomy or steroid rescue. The treatment options for these diseases are very limited, so optimizing the currently available therapies is essential to make them efficient.
    [0011] One of the drugs most used in the treatment of these diseases is adalimumab or HUMIRA®, a human monoclonal antibody that blocks tumor necrosis factor (TNF) by interrupting the inflammatory cascade. The dosage of this drug according to its technical sheet is a fixed dose of 40 mg for 14 days subcutaneously, being able to intensify to 40 mg for 7 more days in case of lack of response to the previous scheme.
    [0012] However, this approved dosage is often insufficient to achieve therapeutic success, so it would be necessary to administer higher doses and even, in the worst case, it could lead to a lack of response to the drug with the consequent loss of a line of treatment, which are very limited in these pathologies.
    [0014] In particular, patients with obesity and those with high inflammatory activity are those who have the highest probability of being underdosed. In such patients the dosage of 40 mg / 14 days is insufficient. In the studies carried out for the approval of the drug, it was dosed at a dose of 0.5 mg / kg in a population that is not very representative of the obese, so the standard approved dose of 40 mg has not been validated for this specific population of patients. In fact, there are studies that show a lower efficacy of this treatment in obese individuals and the consequent need to administer higher doses to this subgroup of patients. Furthermore, it is widely demonstrated that the high inflammatory load (defined by the levels of C-reactive protein and fecal calprotectin) significantly increases the elimination of the drug and therefore the need to administer higher doses.
    [0016] In the same way, patients with low body mass indexes (BMI) would be receiving doses that could be toxic. For all these reasons, it is of special interest to have tools or methods that allow adapting the dosage to the individualized situation of each patient, in order to increase the success of the therapy by reaching therapeutic serum concentrations of the drug. These methods would make it possible to precisely and individually adjust the dosage of adalimumab in order to optimize the treatment of patients receiving this drug, for example those with IBD, and achieve a more effective, safe and less immunogenic therapy.
    [0018] With this objective, different studies have been published that have evaluated the influence of different anthropomorphic parameters, such as weight, on this and on different indications. Thus, in relation to the factors that allow predicting the need for an increase in the dose of adalimumab, it has been described that in patients with Crohn's disease the body mass index (BMI), the levels of C-reactive protein (CRP) or the response to a previous treatment with infliximab are determining parameters. In particular, it has been concluded that high BMI values and Prior absence of response to infliximab-based treatment is indicative of the need for an increase in the adalimumab dose. The BMI has also been postulated as an independent factor in predicting dose escalation (Bultman E., et al., 2012, Aliment Pharmacol Ther, 35 (3): 335-341). In this way, BMI has been identified as a factor that affects independently and inversely proportional to serum levels of adalimumab.
    [0020] Likewise, comparative studies have been carried out of the minimum values of adalimumab and infliximab achieved between doses in patients with Crohn's disease or ulcerative colitis, based on a series of parameters that include anthropomorphic parameters, such as BMI, and biochemical parameters, such as levels. fecal calprotectin (FPC) or PCR. The results of these studies showed that there is no significant variation in infliximab trough levels as a function of BMI, although there is a tendency to achieve lower trough levels of adalimumab in patients with a BMI over 30 (Bond A., et al. ., 2016, European Journal of Gastroenterology & Hepatology, 28 (3): 271-276).
    [0022] Bhalme M., et al. analyzed the association between BMI and loss of response to anti-TNF antibodies, particularly infliximab and adalimumab. The objective was to determine the efficacy of this type of treatment in obese patients with Crohn's disease. The authors of this study indicate that increases in BMI are associated with an increased risk of loss of response to adalimumab and, therefore, with a greater probability of needing a dose increase, but they do not appear to affect the response to infliximab ( Bhalme M., et al., 2013, European Journal of Gastroenterology and Hepatology, 25 (5): 543-549).
    [0024] On the other hand, Lie M., et al. showed the results of a pharmacokinetic study of adalimumab in patients with Crohn's disease, in which the effect of different patient factors on the serum levels reached by the drug was analyzed. The analysis of the results indicated that the baseline BMI values and the CRP concentration at week 28 of treatment make it possible to predict, weakly, but significantly, the level of adalimumab in that week of treatment (Lie M., et al. , 2014, Aliment Pharmacol Ther, 40 (10): 1202-1208).
    [0025] Finally, Ternant D., et al. conducted a pharmacokinetic study of adalimumab using MONOLIX 4.3.2 software, and in which the values of the following parameters were determined: volume of distribution (13.5 l), plasma clearance (0.42 ld-1 ) and first order absorption constant (0.15 d-1). These authors indicate how the presence of anti-adalimumab antibodies is associated with an increase in drug clearance of up to 5.5 times (Ternant D., et al., 2015, European Journal of Clinical Phar, 71 (9): 1155- 1157). On the other hand, the weight of the patient is mentioned in this same study as one of the variables noted at the time of conducting the trial, but no reference is made to its particular influence on the clearance of the drug. Therefore, this study does not propose any method that allows personalizing the dose of adalimumab based on the particular parameters of each patient.
    [0027] Therefore, it would be desirable to have a method to calculate an individualized dosage schedule for adalimumab or its biosimilars, which allows the administration of a personalized dose regimen that guarantees the achievement of therapeutic plasma levels of the drug in each IBD patient.
    [0029] DESCRIPTION OF THE INVENTION
    [0031] The present invention relates to an in vitro method for calculating the appropriate dosage (D) and dosage range (n) of the drug adalimumab, or of a biosimilar drug, to be administered to an individual suffering from inflammatory bowel disease (IBD). Said method comprises the application of a mathematical formula that allows calculating the most appropriate individualized dosage scheme for the drug based, mainly, on three factors of the patient: (i) the body mass index (BMI), (ii) the inflammatory load of the patient, defined by the amount of fecal calprotectin (FPC) and (iii) the presence or absence of anti-adalimumab (anti-ADA) antibodies. This method allows the dosage to be adapted to the individualized situation of each patient, thus increasing the success of the therapy by achieving therapeutic serum concentrations of the drug.
    [0033] The invention therefore proposes an algorithm or mathematical formula that allows adjusting the dosage of adalimumab or its biosimilars based on the calculation of population pharmacokinetic parameters together with the patient's BMI, the concentration of CPF and the presence or absence of anti-ADA, which allows optimizing the patient's treatment, preferably during the maintenance phase, and therefore their response to it.
    [0035] The advantages derived from the method described in the present invention are:
    [0037] - It allows to precisely adjust the dosage to be administered to each patient, since it is calculated based on anthropomorphic, pharmacokinetic and biochemical parameters, which leads to the optimization of treatment in each individual and the achievement of a more effective, safe therapy and less immunogenic.
    [0039] - It allows a dynamic dosage of the drug, that is, if the patient loses or gains body mass or there are changes in their inflammatory activity, they may benefit from changes in their dosage schedule, thus preventing a lack of response to treatment before they occur clinical manifestations.
    [0041] - Greater treatment efficacy is achieved, since patients treated according to the dosage schedule calculated as indicated in the present invention reach therapeutic serum concentrations of the drug.
    [0043] - Greater safety is achieved, since reaching therapeutic concentrations of the drug avoids the immunogenicity derived from it (which is inversely proportional to the serum concentration of the drug), whose clinical manifestations are local reactions at the infusion point, bronchospasm , fever...
    [0045] - Greater treatment efficiency is achieved, since by optimizing it, patients remain in this treatment line for longer, avoiding resorting to successive more expensive treatment lines.
    [0047] - The quality of life of the patient is improved, because the outbreaks of the disease, relapses and surgeries caused as a result of the loss of response to treatment decrease.
    [0048] Thus, one aspect of the invention refers to an in vitro method , hereinafter "method of the invention", to calculate the appropriate dosage (D) and the dosage range (-n-) of the drug adalimumab or its biosimilars to administer, during the maintenance phase after the induction phase of treatment, to an individual suffering from an inflammatory bowel disease comprising the following stages:
    [0050] to. to determine, in a biological sample isolated from the individual, (i) the amount of fecal calprotectin (FPC) and (ii) the presence or absence of anti-diadalimumab (anti-ADA) antibodies,
    [0051] b. calculate the body mass index (BMI) of that individual,
    [0052] c. apply, with the values obtained in steps (a) and (b), the following formula:
    [0054] C (p, ^ / ml) = RX (fX D / Vd) X ( ka / ( ka -ke)) X ( e ~ keXn- e ~ kaXn)
    [0056] where C is the target or desired concentration (included and selected within the range [7.5 - 12 p, g / ml]), F is the bioavailability of the drug, Vd is the volume of distribution of the drug (preferably in liters), D is the dose (preferably in mg), -u is the dosage interval (preferably in hours) and R is the accumulation factor calculated according to the formula:
    [0058] R = 1 / (1 -e _fce ^), and
    [0060] where Ka = 0.0062 h-1, and
    [0061] Ke = (CL / F) / (Vd / F),
    [0062] where Vd / F = 12.4 l, and
    [0063] CL / F (l / h) = 0.015 (l / h) * ((CPF (mg / Kg) / 30) °, ° 63) * ((BMI (Kg / m2) / 22) °, 967)) * 4.8 (anti-ADA) and where anti-ADA = 1 when the presence of antibodies is determined or anti-ADA = 0 when the absence of antibodies is determined in step (a), and
    [0065] d. Solve for the values of D and -u in the formula indicated in step (c).
    [0067] The dose "D" is the dose that must be administered to the individual to reach therapeutic concentrations of the drug in serum (C) and must be adjusted to the available presentations of the drug (thus, once cleared, D in the formula of the invention will have a value of D = 40 or 80 mg).
    [0069] ■ u is the dosage interval (preferably in hours), that is, the dosage interval with which the desired concentration (C) would be reached with the chosen dose (D) (according to the previous paragraph). This value should be within an easy-to-use time frame, for example one week, 10 days, two weeks, or three weeks.
    [0071] The term "in vitro" means that the method of the invention is carried out entirely outside the human or animal body.
    [0073] The method of the invention makes it possible to calculate or determine, based on the individual parameters indicated in steps (a) and (b), the optimal and personalized dose regimen or dosage scheme to be administered to each patient during the maintenance phase. treatment.
    [0075] As used in the proposed formula, "Ka" is the absorption constant of the drug, and its value is 0.0062 h-1. The absorption constant is the probability that the drug is absorbed in the unit of time analyzed.
    [0077] As used in the proposed formula, "Ke" is the drug removal constant, which is the percentage of drug removed each hour. Its value is calculated in the present invention by applying the following formula:
    [0079] Ke = (CL / F) / (Vd / F)
    [0081] where (Vd / F) is the volume of distribution of the drug (Vd) divided by its bioavailability (F) and its value is 12.4 l; and where (CL / F) is the drug's plasma clearance (CL) divided by its bioavailability (F). (CL / F) is calculated according to the formula:
    [0083] CL / F (l / h) = 0.015 (l / h) * ((CPF (mg / Kg) / 30) °, ° 63) * ((BMI (Kg / m2) / 22) °, 967)) * 4.8 (anti-ADA) and where anti-ADA = 1 when the presence of antibodies is determined or anti-ADA = 0 when the absence of antibodies is determined in step (a).
    [0084] The "clearance" or "plasma clearance" (CL) is the volume of plasma that becomes drug-free per unit of time. In the present invention, this factor is expressed in liters per hour (l / h).
    [0086] "Bioavailability" (F) is the fraction of the administered drug dose that reaches the bloodstream unchanged. It depends, among other factors, on the route of administration, pharmaceutical form, interactions with other drugs or with food, degradation in the stomach or metabolic processes that take place in the intestine or liver. It is expressed as a percentage with respect to the bioavailability of the intravenous route, which is 100%. It therefore refers to the amount of drug available to carry out its action. The F for adalimumab is between 60-64% (ie, F = 0.6 or F = 0.64).
    [0088] The "volume of distribution" (Vd) relates the amount of drug in the body to the concentration of drug in the blood or plasma.
    [0090] "Fecal calprotectin" (FPC) is a protein from leukocytes that appears in the intestinal mucosa when there is inflammation and can be detected, for example, but not limited to, in the stool. This protein is a biomarker that makes it possible to assess intestinal inflammatory activity in patients with, for example, but not limited to, ulcerative colitis or Crohn's disease, in a simple, fast and non-invasive way, so its quantification is very useful in clinical practice . The determination of the amount of CPF is thus a tool that allows diagnosing inflammatory bowel disease, evaluating the response to treatment and predicting the course of the disease. An elevated PFC result is correlated with endoscopic inflammatory activity in both Crohn's disease and ulcerative colitis. In turn, a decrease in the PFC value after medical treatment has a good correlation with the clinical response and with mucosal healing in inflammatory bowel disease.
    [0092] Obtaining biological samples to determine the amount of CPF can be done, but without limitations, by collecting a stool sample. Harvesting in any special container is not required, although it will preferably be done in a sterile container, nor the use of preservatives. Preferably, the isolated biological sample for the determination of the amount of CPF is faeces. collected from the first bowel movement of the day. Such samples can be stored, for example, at room temperature or in a refrigerator for up to 3 days before analysis.
    [0094] The amount of CPF can be determined, for example, directly by evaluating the soluble protein levels in the collected and isolated samples. Protein levels can be measured, for example but not limited to, by incubation with a specific antibody, preferably labeled (with, for example, an enzyme, a secondary antibody, radioisotopes, magnetic or fluorescent labels) and more preferably immobilized, in assays. such as Western blot, electrophoresis, immunoprecipitation, protein arrays preferably antibody-based microarrays , immunofluorescence, ELISA or any other immunoenzymatic or immunoassay method, immunohistochemistry, by incubation with a specific ligand, NMR or any other diagnostic imaging technique, techniques chromatography preferably combined with mass spectrometry, or by lateral flow devices or Luminex. To carry out these techniques, probes, ligands, enzymes, substrates and / or antibodies that recognize and specifically bind to the CPF or to a fragment thereof can be used.
    [0096] The amount of CPF can alternatively be determined by measuring the expression levels of its mRNA. The mRNA expression levels can be measured, for example but not limited to, by PCR, RT-PCR, RTLCR, qRT-PCR, Northern blot or hybridization array, or any other method of nucleic acid amplification; DNA microarrays made with oligonucleotides deposited by any mechanism; DNA microarrays made with oligonucleotides synthesized in situ by photolithography or any other mechanism; in situ hybridization using specific probes labeled with any labeling method; using electrophoresis gels; by membrane blotting and hybridization with a specific probe; by NMR or any other diagnostic imaging technique using paramagnetic nanoparticles or any other type of detectable nanoparticles functionalized with antibodies or by any other means.
    [0098] On the other hand, the analysis of antidrug antibodies is clinically relevant for the individualization of treatment. For the determination of the presence or absence of anti-ADA antibodies, the biological sample can be contacted with the drug, preferably the biological sample is added to a support, more preferably to a well, where the drug has previously been immobilized, preferably adalimumab. After incubation with the sample, we proceed to the detection of anti-ADA. Such detection can be accomplished by, for example, binding to a labeled secondary antibody, preferably biotin.
    [0100] In the present invention, the presence or absence of anti-adalimumab (anti-ADA) antibodies can be determined by, for example, immunoassay, preferably by ELISA, more preferably by solid phase ELISA. The ELISA method also allows the quantification of the serum concentration of anti-ADA. An ELISA kit that is commercially available for this purpose is, for example, Promonitor®, Proteomika S.L., distributed by Grifols S.A.®, which could be used in the method described here to determine the presence or absence of anti-ADA. However, other techniques for determining the presence or absence of anti-ADA that could alternatively be employed in the present invention are, but are not limited to, radioimmunoassay, variable mobility assay, reporter gene assay, or enzyme immunoassay.
    [0102] Radioimmunoassay is mainly used in the liquid phase, being more sensitive compared to ELISA. Furthermore, it does not interact with other immunoglobulins and allows IgG4 to be detected, with the disadvantage of being more complex due to the use of radioisotopes.
    [0104] The variable mobility assay has high sensitivity and specificity, is capable of detecting all immunoglobulin subtypes and allows the identification of antibodies in the presence of the drug with lower detection levels compared to the rest of the techniques.
    [0106] The term "isolated biological sample", as used in the present invention, refers to any biological tissue and / or fluid extracted from an individual. Biological samples can be obtained by any method known to those skilled in the art. Preferably , the isolated biological sample of the present invention is feces, blood, more preferably peripheral blood, serum or plasma. In another preferred embodiment of the method of the invention, the isolated biological sample for determining the amount of CPF is feces and the isolated biological sample for determining the presence or absence of anti-ADA is serum. These biological samples can be fresh, frozen, fixed or fixed and embedded in paraffin.
    [0108] The drug "adalimumab" or "ADA" is a human monoclonal antibody included in the group of drugs called biological treatment. It is used for the treatment of, among other pathologies, rheumatoid arthritis, Crohn's disease, psoriatic arthritis, psoriasis, hidradenitis suppurative and ulcerative colitis Administration of adalimumab is generally performed by subcutaneous injection Adalimumab is commercially available, for example under the name "Humira®" (Abbott Laboratories, North Chicago, Illinois, USA). Its CAS number is 331731-18-1 It has a bioavailability of 64% and its half-life is between 10 and 20 days.
    [0110] A “biosimilar” or “similar biological medicine” drug or medicine is a medicine of biotechnological origin, produced in accordance with specific requirements established by the European Medicines Agency (EMEA) regarding quality, efficacy and safety, and which has proven to be comparable to the innovative reference medicine. It is therefore a biological medicine equivalent in quality, efficacy and safety to an original biological medicine, called a reference product. The dosage and route of administration must be the same, and the biosimilar is authorized for all or some of the indications approved for the reference biological. Examples of adalimumab biosimilar drugs are, but are not limited to, Amgevita®, Cyltezo®, Halimatoz®, Hefiya®, Hulio®, Hyrimoz®, Imraldi®, Solymbic®.
    [0112] The "maintenance phase of treatment", as indicated in the present invention, refers to the phase of treatment after the induction phase. The induction phase is the initial phase in which the patient is treated with high doses of the drug for at least 12 weeks in order to treat the acute phase of the disease. The maintenance phase is the phase after the treatment phase itself in order to control the symptoms of the disease and prevent relapses of the same.
    [0114] The term "subject", "individual" or "patient" as used in the present invention refers to an animal, preferably a mammal, more preferably a human. Therefore, in a preferred embodiment of the method of the invention, the individual is a human.
    [0115] By "inflammatory bowel disease" or "IBD" is understood the set of diseases that affect the digestive tract causing chronic inflammatory processes in any of its parts (from the mouth to the anus). The symptoms of IBD appear in the form of flare-ups that occur throughout the life of the patient at more or less long intervals, depending on the severity and the treatment administered. The pathologies encompassed within IBD are, for example but without limitation, Crohn's disease, ulcerative colitis, indeterminate colitis, collagenous colitis or lymphocytic colitis. Preferably, the inflammatory bowel disease referred to in the method of the invention is ulcerative colitis or Crohn's disease.
    [0117] Crohn's disease is characterized by chronic inflammation of any part of the digestive tract, although generally the most affected areas are the small intestine (enteritis), specifically the end of the small intestine (ileum), and the large intestine ( colitis), specifically the beginning of the large intestine (cecum). The symptoms usually appear in the form of outbreaks that alternate with phases of remission where no symptoms occur although the pathology is still present. During outbreaks, diarrhea (sometimes with bleeding), abdominal pain, weight loss, fatigue and fever are common. The duration of outbreaks is usually between 2 and 4 weeks. When the disease is not controlled, there may be cases of intestinal perforation and abscesses in the abdomen, in which it is necessary to resort to surgery.
    [0119] "Ulcerative or ulcerative colitis" is a disease characterized by an inflammation of the walls of the large intestine that causes small ulcers that are the cause of pain associated with this pathology. It can affect a more or less extensive part of the large intestine (proctitis, proctosigmoiditis, left colitis, extensive colitis) or the entire colon (pancolitis). Like Crohn's disease, symptoms appear in flare-ups that alternate with phases of inactivity. The severity and type of symptoms depend on how affected the large intestine is. The most common symptoms are diarrhea (with bloody stools, mucus, and pus), abdominal pain, continuous feeling of having a stool (urgency), urgency to have a bowel movement, and occasionally nausea and vomiting.
    [0121] In another preferred embodiment of the method of the invention, the individual suffers from obesity.
    [0122] By "obesity" is understood a BMI equal to or greater than 30.
    [0124] The BMI is calculated, in the present invention, as follows: weight (Kg) / height (cm) 2.
    [0126] Steps (a) to (d) of the method of the invention can be totally or partially automated, for example, but not limited to, by means of a robotic equipment for the determination of the amount of CPF, the presence or absence of anti-ADA, the calculation of the BMI and / or the application of the proposed formula, as well as to solve the values of D and -u according to stage (d).
    [0128] In another preferred embodiment of the method of the invention, step (c) and / or (d) is carried out by its implementation in software, more preferably in MONOLIX ™ or NONMEM ™ software.
    [0130] In addition to the steps specified above, the method of the invention may comprise other additional steps, for example, but not limited to, related to the pre-treatment of biological samples prior to their analysis or to the treatment of biochemical, anthropomorphic and pharmacokinetics collected from the individual.
    [0132] Another aspect of the invention relates to a computer program or software to implement the method of the invention.
    [0134] The method described in the present invention has allowed the inventors to design a suitable and individualized dosage schedule of the drug adalimumab or its biosimilars to be administered to an individual suffering from IBD, which allows obtaining therapeutic concentrations of the drug in plasma, which ensures the effectiveness of the treatment.
    [0136] As used in the present invention, "therapeutic serum or plasma concentrations" (C) of the drug adalimumab or its biosimilars are understood to mean drug concentrations in serum or plasma within the therapeutic range or margin of 7.5 to 12 p, g / ml.
    [0137] Thus, another aspect of the present invention refers to the use of adalimumab or its biosimilars for the preparation of a drug for the treatment of IBD, where said drug is administered to the patient according to the following dosage schedule (which has been obtained by the method of the invention described above):
    [0139] - 40 mg for 14 days in patients with a body mass index less than 23, - 40 mg for 14 days in patients with a body mass index between 23 and 25,
    [0140] - 40 mg for 10 days in patients with a body mass index between 23 and 25 when they also present an amount of fecal calprotectin in stool greater than 100 mg / kg,
    [0141] - 40 mg for 10 days in patients with a body mass index between 25 and 30, or
    [0142] - 40 mg for 7 days or 80 mg for 14 days in patients with a body mass index greater than or equal to 30.
    [0144] In a preferred embodiment of this aspect of the invention, the administration of 80 mg referred to above is performed by two injections of 40 mg of adalimumab each.
    [0146] In another preferred embodiment, the IBD is ulcerative colitis or Crohn's disease.
    [0148] In another preferred embodiment, the patient is human.
    [0150] In another preferred embodiment, the drug is administered during the maintenance phase of treatment.
    [0152] In another preferred embodiment, the drug is administered subcutaneously, that is, said drug is formulated for subcutaneous administration. Preferably, the medicament to which this aspect of the invention relates is an injection which is presented in liquid form (as a solution).
    [0154] The drug can be administered both alone and in combination with other medications or compositions that are indicated for the treatment of IBD. So, Said medicine can be used together with other active principles or therapies as a combination therapy. The other active principles can be part of the same composition or they can be provided by means of a different composition, being able to be administered at the same time (simultaneous administration) or at different times (sequential administration).
    [0156] The term "treatment", as understood in the present invention, refers to combating the effects caused as a consequence of the disease or pathological condition of interest in a subject (preferably a mammal, and more preferably a human) including:
    [0158] (i) inhibiting the disease or pathological condition, that is, arresting its development; (ii) alleviating the disease or pathological condition, that is, causing regression of the disease or pathological condition or its symptomatology;
    [0159] (iii) stabilize the disease or pathological condition.
    [0161] Throughout the description and claims the word "comprise" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration and are not intended to be limiting of the present invention.
    [0163] EXAMPLES
    [0165] The invention will be illustrated below by means of tests carried out by the inventors that show the effectiveness of the proposed method.
    [0167] EXAMPLE 1. Design of a dosing schedule for adalimumab based on BMI in patients with inflammatory bowel disease.
    [0169] Adalimumab is a monoclonal antibody approved for the treatment of inflammatory bowel disease (IBD). Although the drug dosage was determined based on weight in clinical trials, its prescribing information indicates using the standard regimen of 40 mg / 14 days.
    [0170] With the therapeutic range (MT) of target trough plasma concentrations (Cmin) in IBD: [7.5-12] p, g / ml, it has been observed that many obese patients are underdosed. Therefore, the objective of the present study was to design and validate a dosage schedule based on body mass index (BMI), and other pharmacokinetic and biochemical parameters of its own, for adalimumab in patients with IBD.
    [0172] A prospective study was carried out with a first phase of 26 months duration (October 2015-December 2017) to design the dosage scheme and a second phase of 4 months (January-April 2018) for its validation.
    [0174] Patients diagnosed with IBD (ulcerative colitis (UC) and Crohn's disease (CD)) under treatment with adalimumab with pharmacokinetic monitoring (MDD) were included in the study. Those patients who showed non-adherence due to lack of concordance with previous MDD and the population pharmacokinetic model (popPK) used, which was confirmed with the prescriber and / or personal interview with the patients, were excluded.
    [0176] Anthropometric data (sex, age, weight, height and BMI) and inflammation markers (C-reactive protein (CRP), fecal calprotectin (FPC) and albumin) on the day of sample extraction were recorded.
    [0178] For the design of the dosing scheme, the estimated plasma clearance value of the drug (CL) was used from the popPK model developed at the center (a non-linear model of mixed effects implemented in NONMEM ™ was developed through population pharmacokinetic analysis, assuming a one-compartment behavior with first-order absorption and elimination) defined by the equation:
    [0180] CL / F (l / h) = 0.015 (l / h) * ((CPF (mg / Kg) / 30) °, ° 63) * ((BMI (Kg / m2) / 22) °, 967)) * 4.8 (anti-ADA) and where anti-ADA = 1 if there is the presence of anti-adalimumab (anti-ADA) and anti-ADA = 0 otherwise.
    [0182] With the formula of the population CL, simulations were performed varying the BMI values, setting the CPF to the median value of the population (30 mg / Kg), for the following Dosing schedules: 40mg / 14 days, 40mg / 10 days, 40mg / 7 days and 80mg / 14 days. With these simulations, the cut-off points to reach Cmin within the MT were established. Both the popPK model and the simulations were performed with the NONMEM ™ software
    [0184] For validation, the percentage of patients who reached Cmin within the therapeutic MT was calculated according to the proposed dosage schedule.
    [0186] 100 patients (53% women) with a median age (range) of 43 (18-84) years diagnosed with CD (N = 81) and UC (N = 19) were included in the first phase of the study. A total of 196 TDM of Cmin were performed with a mean of 9.6. ^ G / ml (± 5.10). The mean BMI was 23.98 Kg / m2 ± 4.63 and the median CPF was 50mg / Kg (<15 3150). 4 patients developed anti-drug (anti-AD) antibodies.
    [0188] The proposed dosage scheme once the maintenance phase was reached based on BMI (Kg / m2) was:
    [0190] • 40 mg / 14 days if BMI <23;
    [0191] • 40 mg / 14 days if 23 <BMI <25 (or 40 mg / 10 days if high inflammatory load);
    [0192] • 40 mg / 10 days if 25 <BMI <30;
    [0193] • 40 mg / 7 days or 80 mg / 14 days if BMI> 30.
    [0195] Understanding as a high inflammatory load CPF> 100 mg / Kg.
    [0197] For validation, 21 patients (52.3% women) diagnosed with CD (N = 15) and UC (N = 6) with a mean BMI of 26.1 Kg / m2 ± 4.63 were included. All patients received adalimumab at the proposed doses, reaching a Cmin within the MT in 85.7% of the patients. 1 patient presented high Cmin while 2 were below MT, although they were justified by the high concentrations of CPF.
    [0199] In conclusion, the adalimumab administration regimen in IBD at a standard dose of 40mg / 14 days underdoses overweight patients. The dosing scheme proposed here based on BMI ensures that minimum drug plasma concentrations are achieved within the therapeutic range in all patients.
    权利要求:
    Claims (9)
    [1]
    1. In vitro method to calculate the adequate dosage (D) and the posological interval (■ n-) of the drug adalimumab or its biosimilars to be administered, during the maintenance phase after the induction phase of treatment, to an individual suffering from an inflammatory bowel disease, comprising the following stages:
    to. to determine, in a biological sample isolated from the individual, (i) the amount of fecal calprotectin (FPC) and (ii) the presence or absence of anti-diadalimumab (anti-ADA) antibodies,
    b. calculate the body mass index (BMI) of that individual,
    c. apply, with the values obtained in steps (a) and (b), the following formula:
    C (p, g / ml) = RX (fX D / Vd) X ( ka / ( ka -ke)) X ( e ~ keXn- e ~ kaXn)
    where C is the target concentration that consists of a value that is selected within the range 7.5 - 12 p, g / ml, F is the bioavailability of the drug, Vd is the volume of distribution of the drug, D is the dose, - u is the dosage interval and R is the accumulation factor calculated according to the formula:
    R = 1 / (1 -e _fceH and
    where Ka = 0.0062 h-1, and
    Ke = (CL / F) / (Vd / F),
    where Vd / F = 12.4 l, and
    CL / F (l / h) = 0.015 (l / h) * ((CPF (mg / Kg) / 30) ° '063) * ((BMI (Kg / m2) / 22) °' 967)) * 4 , 8 (anti-ADA) and where anti-ADA = 1 when the presence of antibodies is determined or anti-ADA = 0 when the absence of antibodies is determined in step (a), and
    d. Solve for the values of D and -u in the formula indicated in step (c).
    [2]
    2. Method according to claim 1, wherein the individual is a human.
    [3]
    3. Method according to either of claims 1 or 2, wherein the isolated biological sample to determine the amount of CPF is feces and the isolated biological sample to determine the presence or absence of anti-ADA is serum.
    [4]
    4. Method according to any one of claims 1 to 3, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
    [5]
    Method according to any one of claims 1 to 4, wherein the individual suffers from obesity.
    [6]
    6. Use of adalimumab or its biosimilars for the manufacture of a drug for the treatment of an inflammatory bowel disease where said drug is administered to the patient according to the following dosage schedule:
    - 40 mg for 14 days in patients with a body mass index less than 23, - 40 mg for 14 days in patients with a body mass index between 23 and 25,
    - 40 mg for 10 days in patients with a body mass index between 23 and 25 when they also present an amount of fecal calprotectin in stool greater than 100 mg / kg,
    - 40 mg for 10 days in patients with a body mass index between 25 and 30, or
    - 40 mg for 7 days or 80 mg for 14 days in patients with a body mass index greater than or equal to 30.
    [7]
    7. Use according to claim 6, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
    [8]
    8. Use according to any of claims 6 or 7, wherein the patient is a human.
    [9]
    9. Use according to any one of claims 6 to 8, wherein the drug is administered during the maintenance phase of the treatment.
    类似技术:
    公开号 | 公开日 | 专利标题
    Jürgens et al.2011|Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn's disease
    Huet et al.2008|Portal hypertension and primary biliary cirrhosis: effect of long-term ursodeoxycholic acid treatment
    Yadav et al.2017|Genetic factors interact with tobacco smoke to modify risk for inflammatory bowel disease in humans and mice
    Sheedfar et al.2014|Increased hepatic CD36 expression with age is associated with enhanced susceptibility to nonalcoholic fatty liver disease
    White2018|Vitamin D deficiency and the pathogenesis of Crohn’s disease
    Schäfer et al.2016|Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia
    WO2015153864A2|2015-10-08|Methods for treating inflammatory conditions
    Bull et al.2018|Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies
    Wang et al.2012|Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients
    Kitsios et al.2013|High-sensitivity C-reactive protein levels and metabolic disorders in obese and overweight children and adolescents
    US20160178584A1|2016-06-23|Methods for diagnosing and assessing kidney disease
    Lucena et al.2020|Drug-induced liver injury in older people
    Jensen et al.2016|Dietary fat drives whole-body insulin resistance and promotes intestinal inflammation independent of body weight gain
    Shah2015|Managing alcoholic liver disease
    Polyzos et al.2016|Activin A and follistatin in patients with nonalcoholic fatty liver disease
    US20180306797A1|2018-10-25|Methods of detecting ceramide
    Kroiss et al.2016|Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma
    Fontana et al.2011|Development and progression of portal hypertensive gastropathy in patients with chronic hepatitis C
    Kramer et al.2019|A clinical model for identifying an inflammatory phenotype in mood disorders
    BR112020003573A2|2020-09-01|non-invasive diagnosis of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and / or liver fibrosis
    WO2014190170A1|2014-11-27|Biomarker composite test for hepatic vein pressure gradient and cirrhosis treatment
    Marsillach et al.2005|The role of circulating monocyte chemoattractant protein-1 as a marker of hepatic inflammation in patients with chronic liver disease
    ES2785326B2|2021-05-07|IN VITRO METHOD TO CALCULATE THE DOSAGE OF THE ADALIMUMAB OR BIOSIMILAR DRUG TO BE ADMINISTERED FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASES
    US20120128580A1|2012-05-24|Preselection of subjects for therapeutic treatment with elesclomol based on hypoxic status
    Xu et al.2021|Serum lipocalin-2 is a potential biomarker for the clinical diagnosis of nonalcoholic steatohepatitis
    同族专利:
    公开号 | 公开日
    ES2785326B2|2021-05-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2020-10-06| BA2A| Patent application published|Ref document number: 2785326 Country of ref document: ES Kind code of ref document: A1 Effective date: 20201006 |
    2021-05-07| FG2A| Definitive protection|Ref document number: 2785326 Country of ref document: ES Kind code of ref document: B2 Effective date: 20210507 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201930298A|ES2785326B2|2019-04-02|2019-04-02|IN VITRO METHOD TO CALCULATE THE DOSAGE OF THE ADALIMUMAB OR BIOSIMILAR DRUG TO BE ADMINISTERED FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASES|ES201930298A| ES2785326B2|2019-04-02|2019-04-02|IN VITRO METHOD TO CALCULATE THE DOSAGE OF THE ADALIMUMAB OR BIOSIMILAR DRUG TO BE ADMINISTERED FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASES|
    [返回顶部]