阅读说明：本技术 给予治疗的方法 (Methods of administering treatment ) 是由 J·德斯里沃 F·S·纳莫 于 2019-08-07 设计创作，主要内容包括：本发明涉及施用化合物1的疗法的改进方法,其涉及通过避免或禁忌联合CYP3A4/P-gp诱导剂例如利福平来增加化合物1的有效性。(The present invention relates to improved methods of therapy with the administration of compound 1, which involve increasing the effectiveness of compound 1 by avoiding or contraindicating the combination with CYP3a4/P-gp inducers such as rifampicin.)

1. Compound 1 for use in the treatment of a patient in need of compound 1 therapy, characterized in that said treatment comprises avoiding, contra-indicating or discontinuing: concomitant or co-administration with a CYP3A4/P-gp inducer.

2. Use of compound 1 in the manufacture of a medicament for treating a patient in need of therapy with compound 1, characterized in that said treatment comprises avoiding, contra-indicating or discontinuing: concomitant or co-administration with a CYP3A4/P-gp inducer.

3. A method of using compound 1 to administer a treatment to a patient in need of therapy with compound 1, comprising administering to the patient a therapeutically effective amount of compound 1, and avoiding, contraindicated, or discontinuing: concomitant or co-administration with a CYP3A4/P-gp inducer.

4. Compound 1 for use according to any one of the preceding claims, the use of compound 1 or a method, wherein a patient in need of therapy with compound 1 is in need of administration of a combination CYP3a4/P-gp inducer or in need of therapy with a combination CYP3a4/P-gp inducer.

5. Compound 1 for use according to any one of the preceding claims, the use of compound 1 or a method, wherein the use or method comprises the step of discontinuing the use of the combination CYP3a4/P-gp inducer prior to or simultaneously with the step of initiating therapy with compound 1.

6. Compound 1, the use of Compound 1, or the method for use according to any of the preceding claims, wherein the combined CYP3A4/P-gp inducer is rifampicin.

7. Compound 1, the use of compound 1, or a method for use according to claim 6, wherein said use or method further comprises the step of replacing rifampicin treatment with replacement therapy.

8. Compound 1, the use of compound 1, or the method for use according to any one of the preceding claims, wherein the patient in need of therapy with compound 1 is in need of rifampicin therapy.

9. Compound 1 for use according to any one of the preceding claims, the use of compound 1 or the method, wherein the patient in need of treatment with compound 1 has pulmonary fibrosis, for example idiopathic pulmonary fibrosis.

10. Compound 1 for use according to any one of the preceding claims, the use of compound 1 or the method, wherein the patient has active or latent TB.

11. Compound 1 for use according to any one of the preceding claims, the use of compound 1 or the method, wherein compound 1 is administered in a daily dose of at least 100 or at least 200 mg.

12. Compound 1 for use according to any one of the preceding claims, the use of compound 1 or the method, wherein compound 1 is administered in a daily dose of 200 to 600 mg.

13. A packaged product or kit comprising (i) compound 1, and (ii) a package insert, package label, instructions or other indicia including instructions for the concomitant use or co-administration of the avoidance or discontinuation or contraindication of association with a CYP3a4/P-gp inducer, particularly rifampicin.

14. The packaged product or kit of claim 14, further comprising one or more of the features of claims 1 to 13.

Background

Compound 1 is a small molecule drug of structural formula I under investigation.

The structures, names and syntheses are known and described in WO 2014/139882. Compound 1 is being developed as an autotaxin inhibitor and is being investigated for the treatment of pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (Maher et al, "Safety, tolerability, pharmacokinetics, and pharmacodynmics of GLPG1690, a novel autotaxin inhibitor, to clinical neuropathic pulmonary Fibrosis (FLORA): a phase 2a random plated membrane-controlled triple", Lancet Respiratory Medicine, 5.2018).

Rifampicin is an antibiotic used in the treatment of bacterial infections, and has a particular role in the treatment of Tuberculosis (TB).

Summary of The Invention

The invention described herein is based on the reduction in systemic exposure of compound 1 observed in patients also administered rifampicin.

Accordingly, in a first aspect the present invention provides compound 1 for use in the treatment of a patient in need of therapy with compound 1, characterised in that the treatment comprises avoiding, contra-indicating or discontinuing: concomitant or co-administration with a CYP3A4/P-gp inducer.

In a second aspect, the present invention also provides the use of compound 1 in the manufacture of a medicament for the treatment of a patient in need of therapy with compound 1, characterized in that the treatment comprises avoiding, contra-indicating or discontinuing: concomitant or co-administration with a CYP3A4/P-gp inducer.

In another aspect, the present invention provides a method of using compound 1 to administer a treatment to a patient in need of therapy with compound 1, comprising administering to the patient a therapeutically effective amount of compound 1, and avoiding, contraindicated, or discontinuing: concomitant or co-administration with a CYP3A4/P-gp inducer.

In a particular embodiment, the combined CYP3A4/P-gp inducer is rifampicin. Further embodiments will be apparent from the detailed description below.

Drawings

FIG. 1 mean values (. + -. SE) over time Compound 1 plasma concentrations (ng/mL) (Log-Linear Scale): the solid line represents data obtained on day 1 and the dashed line represents data obtained on day 12.

Detailed Description

Compound 1 is a small molecule Autotaxin (ATX) inhibitor having structural formula I.

The structures, names and syntheses are known and described in WO 2014/139882. Compound 1 is being investigated as an orally active agent for human medicine.

As used herein, a patient "in need of treatment with compound 1" or "in need of treatment with compound 1" is a patient who would benefit from administration of compound 1, who may have any disease or condition for which compound 1 treatment may be useful to ameliorate symptoms. In embodiments, a patient in need of treatment or therapy with compound 1 is a patient having a disease or a disorder that benefits from autotaxin inhibition. The disease or disorder includes a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a skin disease, and/or an abnormal angiogenesis-related disease.

In embodiments, the patient in need of treatment or therapy with compound 1 is a patient with a fibrotic disease. In a particular embodiment, the fibrotic disease is selected from Idiopathic Pulmonary Fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of different etiology, including iatrogenic drug-induced fibrosis, occupational and/or environmentally induced fibrosis, granulomatosis (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, pulmonary alveolar proteinosis, langerhans cell granulomatosis, lymphangiosarcoidosis, genetic disease (Hermansky-Pudlak syndrome, sarcoidosis, neurofibromatosis, metabolic storage disease, familial interstitial lung disease), radiation-induced fibrosis, Chronic Obstructive Pulmonary Disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, Acute Respiratory Distress Syndrome (ARDS), renal fibrosis, tubulointerstitial fibrosis, radiation-induced fibrosis, chronic inflammatory bowel disease, silicosis, asbestos-induced pulmonary fibrosis, Acute Respiratory Distress Syndrome (ARDS), renal fibrosis, tubuloint, Glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, Alport, intestinal fibrosis, liver fibrosis, cirrhosis, alcohol-induced liver fibrosis, toxicity/drug-induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, virus-induced liver fibrosis, and autoimmune hepatitis, corneal scarring, hypertrophic scarring, Dupuytren's disease, keloids, skin fibrosis, cutaneous scleroderma, systemic sclerosis, spinal cord injury/fibrosis, bone marrow fibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, wegener's granulomatosis, pelonese disease or chronic lymphocytic. More particularly, the fibrotic disease is Idiopathic Pulmonary Fibrosis (IPF).

In embodiments, the patient in need of treatment or therapy with compound 1 is a patient with a proliferative disease. In a specific embodiment, the proliferative disease is selected from the group consisting of cancer, leukemia, multiple myeloma, and psoriasis.

In embodiments, the patient in need of treatment or therapy with compound 1 is a patient with an inflammatory disease. In a particular embodiment, the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g., asthma), Chronic Obstructive Pulmonary Disease (COPD), and inflammatory bowel diseases (e.g., crohn's disease and ulcerative colitis). More particularly, the inflammatory disease is selected from rheumatoid arthritis and Chronic Obstructive Pulmonary Disease (COPD).

In embodiments, the patient in need of therapy or treatment with compound 1 is a patient with an autoimmune disease. In a particular embodiment, the autoimmune disease is selected from COPD, asthma (e.g. intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma), in particular chronic or refractory asthma (e.g. late asthma and airway hyperresponsiveness), bronchitis, including bronchial asthma, Systemic Lupus Erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (hashimoto's disease and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. In particular, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, type I diabetes and inflammatory bowel disease.

In a specific embodiment, the patient in need of treatment or therapy with compound 1 is a patient with a respiratory disease. In a particular embodiment, the respiratory disease is selected from asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, equal carbon dioxide hyperventilation, childhood asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema), pulmonary hypertension, interstitial pulmonary fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.

In a specific embodiment, the patient in need of treatment or therapy with compound 1 is a patient with a cardiovascular disease. In a particular embodiment, the cardiovascular disease is selected from the group consisting of cardiac arrhythmias (atrial or ventricular or both), atherosclerosis and its sequelae, angina pectoris, cardiac rhythm disorders, myocardial ischemia, myocardial infarction, cardiac or vascular aneurysm, vasculitis, stroke, peripheral occlusive arterial disease of a limb, organ or tissue, reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue, endotoxic, surgical or traumatic shock, hypertension, valvular heart disease, heart failure, blood pressure abnormalities, shock, vasoconstriction (including vasoconstriction associated with migraine), vascular abnormalities, inflammation, functional insufficiency limited to a single organ or tissue.

In a specific embodiment, the patient in need of treatment or therapy with compound 1 is a patient with a neurodegenerative disease. In a particular embodiment, the neurodegenerative disease is selected from the group consisting of alzheimer's disease and other dementias, brain cancer, degenerative neurological diseases, encephalitis, epilepsy, hereditary encephalopathy, head and brain malformations, hydrocephalus, stroke, parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), huntington's disease, and prion diseases.

In a specific embodiment, the patient in need of treatment or therapy with compound 1 is a patient with a skin disorder. In a particular embodiment, the skin disease is selected from atopic dermatitis, bullous disorders, collagenous diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, pruritus, urticaria, rosacea, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, kawasaki disease, rosacea, or Sjogren-Larsso syndrome. In a particular embodiment, the patient in need of treatment or therapy with compound 1 is a patient with scleroderma.

In a specific embodiment, the patient in need of treatment or therapy with compound 1 is a patient having a disease associated with abnormal angiogenesis. In a specific embodiment, the aberrant angiogenesis-related disease is selected from the group consisting of atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, diabetic retinopathy and glioblastoma multiforme.

Cytochrome P4503a4, also known by its gene name "CYP 3a 4", is a member of the monooxygenase cytochrome P450 family. The CYP3a4 protein is located in the endoplasmic reticulum, is primarily expressed in the liver and intestine, and is involved in the metabolism of selected drugs.

P-glycoprotein (P-gp) is also known as "multidrug resistance protein (MDR 1)" and its gene is named "ABCB 1". P-glycoproteins are members of a class of transporter molecules known as "ATP-binding cassette" transporters or simply "ABC" transporters. P-glycoprotein is located in cell membranes of various tissues, such as the intestine, kidney, liver and blood-brain barrier. P-glycoprotein transports substances administered to an individual, such as drugs (unaltered or after they are metabolized), out of the cells (efflux) so that they can be eliminated from the body.

The combined CYP3A4/P-gp inducer is a substance that increases CYP3A4 and P-gp mediated activity when administered to an individual. The combined CYP3A4/P-gp inducer reducing the availability of Compound 1 may be selected from phenytoin, carbamazepine, rifampicin, dexamethasone and St John's Wort. In one embodiment, the CYP3A4/P-gp inducer is selected from phenytoin, carbamazepine, and rifampin. In a specific embodiment, the CYP3A4/P-gp inducer is rifampicin.

Rifampin (also known as rifampin or rifamdin) is an antibiotic. "rifampicin indications" (prophylactic and/or therapeutic), i.e. indications for the use of rifampicin, include tuberculosis, meningococcal meningitis, leprosy, haemophilus influenzae, prussian disease, legionnaire's disease and severe staphylococcal infections.

In one embodiment, rifampin is indicated for the treatment of all forms of tuberculosis, including new onset, advanced, chronic, and resistant cases, even when used in combination with other active anti-tubercular drugs. Rifampicin is also effective against most atypical mycobacterial strains.

In one embodiment, rifampicin is indicated for use in the treatment, in particular prevention, of meningococcal meningitis, in asymptomatic carriers of neisseria meningitidis (n.

In one embodiment, rifampin is indicated for the treatment of Haemophilus influenzae infection (Haemophilus influenza), in particular for the treatment of asymptomatic carriers of Haemophilus influenzae (h.

In one embodiment, rifampin is indicated for the treatment of leprosy, typically in combination with at least one other active anti-leprosy drug, for the treatment of both polymicrobial and oligobacterial leprosy to effect transformation of the infected state into a non-infected state.

Patients in need of rifampicin treatment are patients who would benefit from rifampicin administration. Such patients may have any disease or disorder for which rifampicin treatment can be used to ameliorate symptoms. Such diseases or conditions include those caused by infection of organisms sensitive to rifampicin, such as rifampicin indications.

As used herein, the term "avoid" and other forms thereof are substitute terms for the terms discard, stop, refrain, and other forms thereof.

In a particular embodiment, the term "avoiding or administering rifampicin" includes or relates to avoiding rifampicin by looking for alternatives to rifampicin in patients in need of rifampicin treatment. Similarly, this may be the case for any other P-gp inducer intended for use in patients in need of compound 1 therapy.

As used herein, the term "interrupt" and other forms thereof are used as an alternative to the terms pause, stop, pause and disengage and other forms thereof.

As used herein, the term "contraindication" and other forms thereof, such as "contraindication" relate to instructions that include activities that are not entered into the contraindication.

Described herein (see example 1) is a human clinical study on the effect of combined administration of rifampicin on systemic exposure to compound 1. Rifampicin is a CYP3A4 and P-glycoprotein inducer. This study revealed an effect on the rate and extent of absorption, thereby significantly reducing the bioavailability of compound 1. Accordingly, aspects and embodiments are provided that relate to avoiding, contraindicating, and/or discontinuing the use of CYP3a4/P-gp inducers in patients in need of compound 1 treatment. In the embodiments described herein, concomitant or co-administration of a CYP3a4/P-gp inducing agent, such as rifampin, is avoided or contraindicated, or administration of a CYP3a4/P-gp inducing agent, such as rifampin, is discontinued, in a patient in need of compound 1 treatment, e.g., in a patient using or being administered compound 1, to avoid adverse drug interactions, e.g., to avoid a reduction in systemic exposure to compound 1, which potentially results in and thus avoids a reduction in efficacy (treatment) of compound 1 in said patient.

In some aspects, methods of administering compound 1 to a patient in need of treatment with compound 1 are provided that involve administering a therapeutically effective amount of compound 1 to the patient and avoiding the use of or administration (e.g., concomitant use or co-administration) of a CYP3a4/P-gp inducer in a patient who also requires treatment with the CYP3a4/P-gp inducer. In one embodiment, provided is the method of administering compound 1 to a patient in need of treatment with compound 1, involving administering a therapeutically effective amount of compound 1 to the patient and avoiding the use or administration (e.g., concomitant use or co-administration) of rifampicin. In another embodiment, the use or administration of a CYP3A4/P-gp inducer, such as rifampicin, is avoided by selecting an alternative therapy to use or administration of CYP3A4/P-gp inducer, such as rifampicin.

In some aspects, methods of administering compound 1 to a patient in need of treatment with compound 1 are provided that involve administering a therapeutically effective amount of compound 1 to the patient and discontinuing use of or administration (e.g., concurrent use or co-administration) of a CYP3a4/P-gp inducer in a patient also in need of treatment with the CYP3a4/P-gp inducer. In one embodiment, provided is the method of administering compound 1 to a patient in need of treatment with compound 1, involving administering a therapeutically effective amount of compound 1 to the patient and discontinuing use or administration (e.g., concomitant use or co-administration) of rifampicin.

In some embodiments, the use or administration of CYP3a4/P-gp inducing agent, such as rifampicin, is discontinued at or at the same time as the beginning of administration of compound 1. In other embodiments, a CYP3a4/P-gp inducing agent, such as rifampin, is discontinued at least 1 day, at least 2 days, or at least 3 days before compound 1 is started to be used or administered. In additional embodiments, a CYP3a4/P-gp inducing agent, such as rifampin, is discontinued at least 1 week, at least 2 weeks, or at least 3 weeks before compound 1 is started to be used or administered.

In another embodiment, the CYP3a4/P-gp inducing agent, such as rifampin, is discontinued within 1 day, within 2 days, or within 3 days after compound 1 is initially used or administered. These time periods may provide sufficient time for the CYP3a4/P-gp inducing agent to be gradually reduced and discontinued without side effects, such as when the CYP3a4/P-gp inducing agent is dexamethasone. Therefore, the time before interrupting the CYP3A4/P-gp inducer should be consistent with the safety discontinuation of the CYP3A4/P-gp inducer. In some embodiments, the CYP3a4/P-gp inducer is discontinued no later than one month, 3 weeks, 2 weeks, or 1 week after the start of therapy with compound 1.

In some aspects, methods of administering compound 1 to a patient in need of treatment with compound 1 are provided that involve administering a therapeutically effective amount of compound 1 to the patient and that are contraindicated for use or administration (e.g., concomitant use or co-administration) of a CYP3a4/P-gp inducer in a patient who also requires treatment with the CYP3a4/P-gp inducer. In one embodiment, provided is the method of administering compound 1 to a patient in need of treatment with compound 1, involving administering to the patient a therapeutically effective amount of compound 1, with the contraindication of use or administration (e.g., concomitant or coadministration) of rifampicin.

In another aspect, a packaged product or kit is provided comprising compound 1, optionally in a container, and a package insert, package label, instructions or other label comprising information, recommendations or instructions for: the concurrent use of compound 1 and rifampicin or CYP3a4/P-gp inducer in general, is avoided or discontinued or contraindicated, as described in the various aspects and embodiments herein. For example, a package insert, package label, instructions, or other label, for example, may include any one or more of the following information, suggestions, or instructions:

-informing or advising the patient that concurrent use of CYP3a4/P-gp inducer, such as rifampicin, should be avoided;

-informing or advising the patient that concurrent use of a CYP3a4/P-gp inducer, such as rifampicin, is contraindicated;

-informing or advising that the patient should discontinue concurrent use of a CYP3a4/P-gp inducing agent, e.g. rifampicin, e.g. discontinued at least 1 week, at least two weeks, at least 3 weeks or at least 4 weeks prior to compound 1 treatment;

-informing or advising the patient to concurrently administer a CYP3a4/P-gp inducing agent, such as rifampicin, to alter the therapeutic effect of compound 1, such as to decrease the therapeutic effect of compound 1, in which case the instructions may further indicate that concurrent administration is therefore contraindicated;

-instructing the patient to discontinue concurrent use of a CYP3a4/P-gp inducer, such as rifampicin;

instructing a patient in need of compound 1 therapy not to concurrently use or administer a CYP3a4/P-gp inducer, such as rifampicin;

concurrent use or administration of CYP3A4/P-gp inducer, e.g. rifampicin, is contraindicated.

The instructions or recommendations may also include recommendations for using replacement therapy instead of using CYP3a4/P-gp inducing agents such as rifampicin.

It is to be understood that the explicit wording included in the package insert, package label, instructions or other label may vary depending on the jurisdiction to which the package is authorized to be marketed, and thus encompasses any wording relating to avoiding, interrupting or contraindicating the concurrent use or administration of a P-gp inducing agent (e.g., rifampin) in a patient in need of treatment with compound 1.

In a related aspect or embodiment, a method of making or packaging a compound 1 medicament is provided, comprising packaging compound 1 (optionally in a container), together with a package insert, package label, instructions, or other label (including any one, two, three, or more of the foregoing instructions, recommendations, or recommendations).

Example 1

Phase I, open label, non-randomized, drug-drug interaction studies were performed in healthy male subjects to evaluate the effect of repeated doses of rifampicin on single dose Pharmacokinetics (PK) of compound 1, as well as to evaluate the safety and tolerability of single doses of compound 1 administered before or after oral doses of rifampicin.

Eighteen healthy male subjects received a single oral dose of 600mg of compound 1 on day 1. From day 2 to day 11, 600mg rifampicin was administered once daily (q.d.) to all subjects for 10 consecutive days. On day 12, subjects received a single oral dose of 600mg of compound 1 (see table 1). Follow-up was performed between day 15 and day 18.

TABLE 1 Compound 1 and Rifampicin administration regimen

Samples for determination of Compound 1

Blood samples for PK evaluation of compound 1 were collected on days 1, 2, 12, 13 (i.e., 1, 2, 3, 4, 5, 6, 7,8, 12, and 24 hours after compound 1 administration on days 1 and 12) and at follow-up. A 2mL blood sample for determination of compound 1 levels in plasma was collected by venipuncture (or indwelling catheter) in the arm into a vacuum tube containing lithium heparin and immediately cooled (ice bath).

Within 30 minutes after blood collection, plasma was separated by centrifugation at about 1,500g for 10 minutes at 4 ℃ and transferred to 2 polypropylene tubes, with at least 400 μ L of plasma in the first aliquot and the remaining volume in the second aliquot. After appropriate labeling, plasma samples were stored in clinical centers at-20 ℃ ± 10 ℃ within 2 hours after centrifugation and were protected from direct sunlight.

Pharmacokinetic assessment

Plasma concentrations were determined using validated tandem mass spectrometry liquid chromatography (LC/MS-MS) spectroscopy with a limit of quantitation for Compound 1 of 1.00ng/mL, cholesterol of 20.0mg/mL, and 4 β -hydroxycholesterol of 5.00 ng/mL. Using PhoenixNon-compartmental PK calculations were performed (version 6.4).

The following parameters for compound 1 were determined from each concentration-time curve in plasma:

C_maxmaximum observed plasma concentration

t_max:C_maxTime of occurrence

AUC_0-tArea under the plasma concentration-time curve from time zero to the time corresponding to the last observed quantifiable concentration, calculated by the linear up-log down-trapezoidal rule

AUC_0-24hArea under the plasma concentration-time curve from time zero to 24 hours after administration, calculated by the linear up-log down-trapezoidal rule

C_24hPlasma concentrations observed 24 hours after administration

The induction of CYP3A4 by rifampicin was evaluated using the 4-beta-hydroxycholesterol/cholesterol ratio as a marker and proved to be effective.

Pharmacokinetic analysis

Each subject listed the plasma concentration and PK parameters for Compound 1 on a daily basis (day 1: Compound 1 before Rifampicin multiple doses; day 12: Compound 1 after Rifampicin multiple doses). Descriptive statistics of plasma concentrations and PK parameters were calculated daily. Mean (± SE) concentration-time curves were generated on a daily basis.

Evaluation of drug interactions

Mixed effects model was performed on the following natural log (ln) transformed PK parameters for compound 1, with days as fixed effect and subjects as random effect: c_max、C_24h、AUC_0-tAnd AUC_0-24h. The point estimate (point estimate) is calculated as the geometric mean of the respective ratios of each parameter at day 1 relative to the parameter at day 12 and is expressed as a percentage. The 90% Confidence Interval (CI) of the point estimate was calculated using the mean square error of the analysis of variance.

Due to t_maxIs a discrete variable that depends on the chosen blood sampling time, so the daily effect is evaluated using a non-parametric test (Wilcoxon's signed rank test).

Pharmacokinetic results

Compound 1 plasma concentrations

Mean values (± SE) are illustrated in fig. 1 (log linear scale).

On days 1 and 12, the mean maximum concentration of compound 1 was reached 2 hours after administration, which was 7,870ng/mL and 1,180ng/mL, respectively.

The elimination of compound 1 appeared biphasic before and after multiple rifampicin intakes (figure 1). Visual inspection of the log-linear mean concentration-time curves showed a slight difference in apparent elimination rate when comparing day 12 to day 1, indicating no effect on the elimination rate of compound 1 and therefore no effect on compound 1 clearance.

Pharmacokinetic parameters of Compound 1

The results of the statistical analysis of individual compound 1PK parameters with descriptive statistics and drug-drug interaction assessments are summarized in table 2.

TABLE 2 summary of statistical analysis of pharmacokinetic parameters and drug-drug interaction assessment of Compound 1

PE-Point estimation

N-number of subjects with data

For C_max、C_24h、AUC_0-tAnd AUC_0-24hThe arithmetic mean (CV%) is given. For Tmax, the median (min, max) is given

^aFor C_max、C_24h、AUC_0-tAnd AUC_0-24hPE% [ 90% CI ]]Is a point estimate of the least squares geometric mean ratio of compound 1 on day 12 to day 1, t_max ^bp-value N-17, since 1 subject only had evaluable data for up to 12 hours

Statistical analysis showed C_maxAnd AUC have significant daily effects, while t_maxNo significant effect was observed (p-value 0.7226).

As shown by the Point Estimate (PE), multiple rifampicin intakes resulted in a significant decrease in bioavailability of compound 1: c_maxAnd AUC_0-24hThe respective significant reduction is 6.0-and 9.3-fold (83.2 and89.2%). For t_maxNo effect indicates an effect on the absorption rate.

Compound 1PK parameters (C)_maxAnd AUC) to moderate to high with CV% between 46.7% and 53.8%.

The objective of this study was to study the effect of multiple oral doses of rifampicin on a single dose PK of compound 1.

After a single 600mg oral dose, the maximum plasma concentration of compound 1 was rapidly (2 hours) reached, with a relevant mean value of 7,870 ng/mL.

Administration of rifampicin (600mg, daily) once daily for 10 days resulted in a decrease in bioavailability of Compound 1 (C)_maxAnd AUC_0-24h6.0 and 9.3-fold, respectively) without observed p-t_maxA significant effect of (a). Comparison of the plasma profiles showed no effect on the apparent elimination rate of compound 1.