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Open-label, Crossover Exploratory Study to Assess the dose-dependent effect of pyrimethamine ON The Pharmacokinetics of Endogenous biomarkers and Probe Drugs for assessment of drug-drug interactions mediated by MATE1/2K (Open-label, Crossover Exploratory Study to Assess the dose-dependent effect of pyrimethamine ON The Pharmacokinetics of Endogenous biomarkers and Probe Drugs for assessment of drug-drug interactions mediated by MATE1/2K)

OPEN-LABEL, CROSSOVER EXPLORATORY STUDY TO ASSESS THE DOSE DEPENDENT EFFECT OF PYRIMETHAMINE ON EXOGENOUS AND ENDOGENOUS MATE1/2K SUBSTRATES (OPEN-LABEL, CROSSOVER EXPLORATORY STUDY TO ASSESS THE DOSE DEPENDENT EFFECT OF PYRIMETHAMINE ON EXOGENOUS AND ENDOGENOUS MATE1/2K SUBSTRATES)

12

Age 23-38 years(Median 30 years) Height 165-183 cm(Median 167 cm) Weight 59.5-75.8kg(Median 65 kg) BMI 20.9-24.1 kg/m2(Median 23 kg/m2)

After screening, 12 participated in the study as subjects.

No

1. The mean and range of urinary volume and pH during the study period 2. Effect of pyrimethamine on the plasma concentrations of metformin The mean plasma concentrations of pyrimethamine at 10, 25, and 75 mg were 0.287, 0.781, and 2.47 microM, respectively. The pharmacokinetic parameters of metformin (AUC and the renal clearance CLr) were compared between the control and pyrimethamine administration periods. There was a significant increase in the AUC and decrease in the CLr of metformin in a pyrimethamine dose-dependent manner. 3. Effect of pyrimethamine on the plasma concentration and cumulative urinary excretion of endogenous metabolites The effect of pyrimethamine on the plasma concentrations and cumulative urinary excretion of m1A, creatinine, and 1-NMN, which are transported by OCT2 and MATE1/2K, was determined. All compounds showed a decrease in CLr following pyrimethamine administration. The CLr of m1A and 1-NMN decreased in a pyrimethamine dose-dependent manner, while the effect on CLr of creatinine was not clearly proportional to the pyrimethamine dose. 4. AUC ratio and CLr ratio between control and pyrimethamine administration periods The effect of pyrimethamine administration was determined by calculating the pharmacokinetic parameter ratios for each treatment relative to the control. Geometric means and 90% confidence intervals of the AUC ratio and CLr ratio were calculated. A notable reduction in CLr ratio of metformin was observed following pyrimethamine administration, even at the lowest doses. Conversely, a significant increase in AUC ratio was observed at intermediate doses and above. A decrease in the CLr ratio of m1A and creatinine was observed at the lowest dose, whereas a decrease in the CLr ratio of 1-NMN was observed at intermediate doses or higher. Unlike m1A and 1-NMN, pyrimethamine did not have a dose-dependent effect on the creatinine CLr ratio. Pyrimethamine slightly increased the AUC ratio of m1A and creatinine but showed a decreasing effect on 1-NMN. However, no dose dependence was observed for this effect. 5. Correlation of the CLr ratio between metformin and endogenous metabolites There was a strong correlation between the CLr ratio of metformin and endogenous metabolites, such as m1A and 1-NMN, but the correlation coefficient with the CLr ratio of creatine was lower than that of m1A and 1-NMN, although it was still statistically significant. 6. Estimation of inhibition constant (Ki,app) of pyrimethamine for CLr Using a nonlinear least squares method, Ki,app of pyrimethamine with respect to the total plasma concentrations was determined for metformin, m1A, and 1-NMN, and similar values were obtained for these three compounds. 7. Genotypes of the renal organic cation transporters The genotypes for OCT2 rs316019, MATE1 rs2289669, rs2453579,rs2252281, and MATE2-K rs12943590 in the subjects enrolled in this study were determined. The results for OCT2 rs316019 showed 10 individuals with the CC genotype and 2 with the AC genotype. For MATE1 rs2289669, four individuals had the GG genotype, six had the AG genotype, and two had the AA genotype. For rs2453579, six individuals had the CC genotype, five had the CA genotype, and one had the AA genotype. For rs2252281, eleven individuals had the TT genotype and one had the TC genotype. Finally, for MATE2-K rs12943590, four individuals had the GA genotype and two had the AA genotype. The test results were then stratified by genotype, and the CLr of each compound in the control period was compared, but no influence of genetic polymorphisms was observed. 8. Effect of pyrimethamine on AUC and CLr of pyridoxic acid The effect of pyrimethamine on pyridoxic acid, a substrate for organic anion transporters, was evaluated. Following administration of pyrimethamine, a dose-dependent decrease in the AUC was observed. The CLr of pyridoxic acid surpassed the glomerular filtration rate, suggesting that pyridoxic acid undergoes tubular secretion in the kidneys. The effect of pyrimethamine on CLr of this compound was comparable to the control, except at high doses, indicating that the decrease in CLr of metformin, m1A, 1-NMN, and creatinine caused by pyrimethamine is specific to organic cation transporters. 9. PBPK model of metformin, a probe substrate of OCT2/MATE1/2K The PBPK model for metformin developed by Nishiyama et al. was used in this study. The PBPK model for pyrimethamine was established based on the results of two clinical studies involving 50 mg pyrimethamine (QD)/250 mg metformin and 50 mg pyrimethamine (BID)/750-500 mg metformin. In this study, a successful model was used. Bioavailability was set at 0.90, based on literature information on the clinical pharmacokinetics of pyrimethamine, and the major elimination pathway was assumed to be hepatic metabolism since only 13% of the administered dose is excreted in the urine as an unchanged drug after oral administration. An in silico method was used to estimate the tissue distribution, and a common scaling factor was applied to estimate the Kp values in the main distribution organs (muscle, fat, and skin) to explain in vivo blood concentration changes. The impact of drug interactions was greater in the study by Oh et al. than in our previous study. The PBPK model analysis revealed that higher blood and kidney concentrations of pyrimethamine were responsible for this, resulting from BID administration owing to the long elimination half-life of pyrimethamine in the blood. The in vivo Ki value of pyrimethamine estimated by PBPK model analysis for the two clinical data sets was 0.2 microM using the dataset by Kusuhara et al., and 0.04 microM using in the data set by Oh et al. These values were in close agreement with the in vitro Ki values of 0.15 microM (MATE1), 0.094 microM (MATE2K), and 0.14 microM estimated by model-independent analysis of the present clinical data. The results obtained from this study were consistent with the findings of Kusuhara et al. and Oh et al., providing further validation of the utility of the PBPK model in understanding the complex interactions of drugs in vivo. 10. PBPK model of 1-NMN, an endogenous biomarker of OCT2/MATE1/2K When pyrimethamine or cimetidine, which inhibit MATEs, was administered, the CLr of 1-NMN decreased; however, the plasma concentration of 1-NMN decreased. Similar results were observed in this study. It can be inferred that this result is due to the inhibition of 1-NMN biosynthesis by these inhibitors, and a recent report that analyzed previously published clinical study data using a PBPK model also assumed an inhibition of biosynthesis. Therefore, in this study, the inhibition of NMN biosynthesis was considered in the PBPK model. Additionally, to represent diurnal fluctuations in 1-NMN, a model analysis that incorporates diurnal fluctuations in GFR, renal blood flow, and biosynthesis rate was performed. The study was based on the finding that the disappearance of 1-NMN from the plasma is related not only to renal elimination by OCT2/MATE but also to hepatic metabolism. Furthermore, the results of clinical studies showing saturation in the reabsorption from the urine were incorporated into the PBPK model. By simulating the blood concentration and cumulative urinary excretion of 1-NMN using parameters optimized through top-down analysis, clinical data were well reproduced. The in vivo Ki value obtained by top-down analysis using pyrimethamine as an inhibitor was approximately 0.2 microM for MATE, similar to that obtained when metformin was used as a substrate. In contrast, the Ki value for 1-NMN biosynthesis was even smaller at 0.05 microM. It is possible that relatively strong inhibition of the biosynthetic process by pyrimethamine underlies a reduction in NMN AUC during pyrimethamine administration periods.

Renal clearance of m1A and 1-NMN has significant potential as a quantitative biomarker for assessing drug-drug interactions mediated by MATE1/2K in the kidney. A physiologically-based pharmacokinetic (PBPK) models of metformin, 1-NMN and pyrimethamine were successfully developed, which could explain the observed data after parameter optimization.

Jan. 29, 2024

Oct. 09, 2020

https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.2022

No

no

https://jrct.niph.go.jp/latest-detail/jRCTs031180125

Furihata Kenichi

P-One Clinic, Keikokai Medical Corporation

View Tower Hachioji 4F, 8-1 Yokamachi Hachioji City, Tokyo

furihata@p1-clinic.or.jp

Ogoe Kazuaki

P-One Clinic, Keikokai Medical Corporation

View Tower Hachioji 4F, 8-1 Yokamachi Hachioji City, Tokyo

+81-42-625-5216

k-ogoe@p1-clinic.or.jp

Complete

April. 08, 2019

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

crossover assignment

basic science

a)Healthy Japanese men at >=20 but <40 years of age when the consent was obtained.
b)Persons whose body mass index (BMI) is >=18.5 but <25.0 at screening.
c)Persons who were judged appropriate as subjects by the investigator (sub-investigator) based on medical history and physical exam and laboratory tests at screening.
d)Subjects who can understand and comply with the protocol and from whom the written consent based on his or her own free will can be obtained.

a) Persons with a history of hypersensitivity to metformin or biguanide drug, pyrimethamine
b) Persons who are contraindicated for administration of metformin
c) Persons who are in the following state [Persons who are liable to cause lactic acidosis.]
(1) history of lactic acidosis
(2) renal dysfunction of moderate or higher
(3) dialysis patients (including peritoneal dialysis)
(4) severe liver dysfunction,
(5) shock, heart failure, myocardial infarction
(6) excessive alcohol intake
(7) Patients with gastrointestinal disorders such as vomiting, dehydration or diarrhea in which dehydration are a concern.
-Patients with severe ketosis, diabetic coma or precoma, type 1 diabetes [infusion, correction of rapid hyperglycemia by insulin is essential.]
-Severe infection, patients before and after surgery, patients with severe trauma [Administration of this drug is not suitable because it is desired to control blood glucose by insulin injection. Also, it is liable to cause lactic acidosis.]
-Patients with malnutrition, starvation, weakness, pituitary dysfunction or adrenal insufficiency
[May cause hypoglycemia. ]
-Persons who are contraindication of pyrimethamine administration or need careful administration
-Patients with megaloblastic anemia based on folate deficiency, patients with blood disorders or previous medical history, people with deficiency of folic acid or abnormal metabolism
-Person or parents, brothers who have a constitution prone to allergic symptoms such as bronchial asthma, rash, urticaria, or who have a history of hypersensitivity to other drugs.[Because there is description in interview form of fansidar (a combination agent containing sulphadoxin 500 mg and pyrimethamine 25 mg in 1 tablet, not single agent of pyrimethamine)]
d) Persons with lactose intolerance
e) Persons with hypotension (systolic blood pressure: <90 mmHg) or hypertension (systolic blood pressure: >=160 mmHg)
f) Persons who donated or lost 200 mL (1 unit) of blood within 4 weeks before administration of study drugs or 400 mL (2 units) of blood within 3 months before administration of study drugs.
g) Persons with a medical history/complication of severe nerve disease, cerebrovascular disease, liver disease, kidney disease, endocrine disease, cardiovascular disease, gastrointestinal disease (including digestive system disease which is considered to affect the absorption of study drugs), respiratory disease, metabolic disease, and anemia.
h) Persons with estimated creatinine clearance (eClcr, Cockcroft-Gault Equation) < 90 mL/min.
The person with low renal excretion ability of medicines
i) Persons who have been confirmed of a clinically severe abnormality based on medical examination or physical examination by the investigator or subinvestigator.
j) Persons with a clinically severe disease within 30 days before administration of study drugs.
k) Persons who took drugs, health food including St.John's wort, food 14 days prior to dosing and beverages including grapefruit, orange and apple (including food containing them), and nutritional supplements 7 days prior to dosing and cannot comply with prohibition of taking them during the study.
l) Persons who are smoking or taking nicotine within 30 days before administration of study drugs and who cannot comply with smoking cessation during the study period.
m) Persons who took alcohol/caffeine-containing food on the day before hospitalization in each study period and cannot comply with prohibition of taking them until the day of discharge in each study period.
n) Persons who tested positive in an alcohol breathe test/urine drug test at screening.
o) Persons who cannot discontinue the use of drugs other than study drugs from 2 weeks before administration of study drugs until the study completion.
p) Persons who are positive to hepatitis B surface (HBs) antigens, hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) antigens/antibodies.
q) Other persons who were judged inappropriate by the investigator or subinvestigator.

Male

None

Period I: On the day before administration of study drugs, the baseline data of endogenous substrates will be obtained by administrating placebo (excipient: lactose). A single dose of the probe drug cocktail (metformin) will be orally administered to subjects on the day of dosing.
Periods II, III and IV: Pyrimethamine will be given 1 hour prior to administration of probe drug orally. Subjects will be randomized to one of two of the following pyrimethamine (PYR) treatment sequences:
Sequence 1: Period II PYR 10 mg -> Period III PYR 25 mg -> Period IV PYR 75 mg
Sequence 2: Period II PYR 25 mg -> Period III PYR 10 mg -> Period IV PYR 75 mg


<Drug Dose>
Metformin: 500 mg
Pyrimethamine: 10, 25, or 75 mg

- Kinetic parameters of endogenous substrates during administration / non-administration of metformin (OCT 2 and MATE probe), pyrimethamine (MATE inhibitor)
- Measurement subjects: Pharmacokinetics (PK) of endogenous substrates metformin, pyrimethamine of other drug transporters and drug metabolizing enzymes including creatinine, N1-methyl nicotinamide, thiamine, other OCT2 and MATE 1 / 2K in plasma and urine, Evaluation of
- Evaluation of pharmacokinetics (PK) of metformin, pyrimethamine
- Measurement target: metformin in plasma and urine, pyrimethamine in plasma

- Genotyping (e.g., MATE1, MATE2-K, and OCT2) for PK of metformin, and endogenous substrates
- Concentrations of proteins in the plasma and urine specimens that could regulate the activities of drug transporters, and PK of metformin, and endogenous substrates

+81-3-5841-0818

Feb. 04, 2019

none