Introduction

Lafutidine is a novel antiulcer drug that exhibits long-lasting gastric antisecretory effects due to the blockade of the histamine H2 receptor [1]. It is used in the treatment of gastric ulcers, duodenal ulcers, and gastric mucosal lesions associated with acute gastritis and acute exacerbation of chronic gastritis [2]. Lafutidine-based therapy may also be a potential new triple therapy for eradicating Helicobacter pylori infection [3]. Lafutidine has been shown to exhibit potent gastroprotective activity in addition to its gastric acid antisecretory effect [4–6]. Moreover, lafutidine has a protective effect on anticancer drug-induced mucositis in the stomach and lower gastrointestinal tract [7, 8]. Lafutidine might be useful for preventing gastrointestinal toxicities during adjuvant chemotherapy for gastric cancer [9], and it might effectively prevent chemotherapy-induced mucositis by activating intestinal mucus cells [10]. The gastroprotective activity of lafutidine is associated with the activation of capsaicin-mediated sensory nerves [11].

Lafutidine was first approved in Japan in 2005. Lafutidine was non-inferior to famotidine in healing of reflux esophagitis, was superior to famotidine in terms of symptom relief of reflux esophagitis, and showed similar efficacy in the clinical improvement of reflux esophagitis compared to omeprazole [12].

Lafutidine has an elimination half-life (t 1/2) of 1.9–3.2 h and a time to maximum plasma concentration (T max) of 0.9–2.1 h according to previous reports [6, 12–14]. Though there are some pharmacokinetic (PK) studies in Indian [13], Korean [8], and Japanese [12] subjects, to the authors’ knowledge, there is little published information on its PKs in healthy Chinese subjects, especially on the effect of food on its PK properties.

Therefore, we conducted three studies to evaluate lafutidine’s PK properties in 12 healthy Chinese subjects. These including a single-dose study, a multiple-dose study, and a food effect study, which were to evaluate the dose linearity, steady-state PKs, and the effect of food on the PK properties of lafutidine. The tolerability and the effect of sex on the PK properties were also evaluated.

Methods

Subjects

Three PK studies, a single-dose dose-ascending study, a single-dose food interaction study, and a repeat-dose (steady-state) study were conducted in 12 healthy volunteers (6 male, 6 female). The criteria for inclusion were healthy adults, aged between 18 and 40 years, with a body mass index (BMI) of between 19 and 24. Enrollment was voluntary and all participants provided written consent before being enrolled. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013.

People who met any of the following circumstances were excluded from the study: people who had a history of drug abuse or who were obviously drinking or smoking on the day of testing (if we could smell or see it); people who had attended another drug trial within 3 months; people who were allergic to a drug which is similar to the study drug; people who were donated blood within 3 months. Subjects whose adherence was poor, who could not use the medicine regularly, or who were not willing to continue the clinical trials could exit the study.

Study Design

Study 1: Dose-Ascending Study

This was a single-dose, three-period, three-dose level (10, 20, 40 mg), three-sequence cross-over study under fasting conditions (overnight fast) to evaluate the dose linearity of lafutidine PK. The washout between periods was 7 days. Randomization was balanced for gender. Three sequences took a single dose of lafutidine tablets (10, 20, or 40 mg) according to the randomization list. Patients were administrated lafutidine tablets with 250 mL of room-temperature water, and took the same standard meal 4 h after administration. Blood samples were taken before and then at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 7, 9, 12, and 16 h post-dose.

Study 2: Multiple-Dose Study

This study was intended to evaluate steady-state PK properties of lafutidine. All 12 subjects received 10 mg lafutidine tablets twice a day at 07:00 and 19:00 over 6 days. Volunteers were told to fast 2 h before administration and 2 h after administration, which is the recommended mode of bioavailability (BA) and bioequivalency (BE) guidelines. According to a previous study [6, 13] of the t 1/2 of lafutidine, 3 days was enough to reach the steady-state plasma concentration. Blood samples were collected before the fourth, fifth, and sixth doses to determine the minimum plasma concentration at steady state (C min) and the time to reach steady state. After the morning dose (under fasted conditions) on day 6, blood samples were taken at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 7, 9, 12, and 16 h post-dose.

Study 3: Food Interaction Study

This was a two-period, two-sequence, cross-over study to evaluate the effect of food on the PK properties of lafutidine. The washout between periods was 7 days. Randomization was balanced for gender. One sequence received the same standard food (a cup of milk, creamy bread, two eggs, two pieces of sausage, and a spoon of vegetable salad; 37.05 g protein, 59.3 g fat, and 63.80 g carbohydrate; 937.1 calories in total) in 30 min and then received a single dose of 10 mg lafutidine tablets 30 min after the meal, while the other sequence were administrated in fasted condition (overnight fast). All volunteers took the same standard meal 4 h after the administration of lafutidine and appetite was strictly controlled. The standard meal in the second period was consistent with the first period. Blood samples were taken before and then at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 7, 9, 12, and 16 h post-dose.

The drug product used in all three studies was 10 mg lafutidine tablets (Yue Kang Pharmaceutical Group Co., Ltd. SprL005-01). Subjects were administrated lafutidine with 250 mL of room-temperature water. The meal in the test was a standard meal.

Analytical Methods

A sensitive and specific liquid chromatography electrospray ionization mass spectrometry (LC–ESI–MS) method has been developed and validated for the identification and quantification of lafutidine in human plasma [1]. The established lower limit of quantitation (LLOQ, 5 ng/mL) was sufficiently low to conduct this PK study for lafutidine tablets. Calibration curves exhibited a good linearity from 5 to 1000 ng/mL with correlation coefficient r 2 > 0.99 for lafutidine. The intra- and interday precision of the quality control samples was <6.81% and 6.68%, respectively. The accuracy ranged from 90.29% to 109.04%. These indicated that the quantitative method was reliable and accurate.

Tolerability Assessments

All adverse events were monitored and recorded till the end of the study. In the single-dose and food effect studies, vital signs consisting of body temperature, heart rate, respiratory rate, and blood pressure were monitored 30 min before and at 0.5, 1, 2, 4, 8, 12, 14, and 16 h after administration. In the multiple-dose study, vital signs were monitored pre-dose and at 0.5, 2, 4, 8, 12, 24, 48, and 72 h after the last administration of lafutidine tablets. Standard laboratory tests and electrocardiogram (ECG) were conducted at the beginning and end of the study.

PK Parameters

The PK parameters of lafutidine were determined by a non-compartmental model using Drug and Statistics (DAS), which is approved by the Chinese Pharmacological Society [15]. The following PK parameters were calculated: C max, T max, area under the concentration–time curve from time zero to the last measurable concentration (AUC0–t ) or infinity (AUC0–∞), AUCss, i.e., AUC0–t at steady state, t 1/2, apparent oral clearance (CL), and apparent volume of distribution (V).

Statistical Analysis

SPSS (Statistical Product and Service Solutions, SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Analysis of variance (ANOVA) was used to compare PK parameters between male and female subjects, between fasted and fed conditions, and between different dose groups. The linearity of lafutidine PK parameters was assessed by examining C max, AUC0–t , and AUC0–∞ as a function of single-dose administration. In the multiple-dose phase, one-way ANOVA was used to determine when plasma concentrations had reached steady state and whether the multiple-dose PK parameters were consistent with those in the single-dose phase. All PK parameters were based on ln-transformed data. All calculations were done on ln-transformed PK parameters with differences as geometric mean ratios (GMRs). A P value less than 0.05 was considered statistically significant.

Results

Subjects

All subjects enrolled in the study completed the physical examination and ECG which proved they were healthy. All enrolled subjects completed the trial. All eligible subjects were healthy Chinese adults with a mean age of 23.42 years (range 19–27 years), a mean weight 59.33 kg (men were ≥50 kg and women were ≥45 kg), and a mean height 166 cm (range 155–175 cm). The results of the routine physical examination and biochemical tests suggested that the renal function and ECG of all participants were normal, that they were in a good mental state, and that the menstruation of female subjects was regular. Participants had not taken any other medication 2 weeks before the trial or during the trial and had not had donated blood or undergone a blood test in last 3 months. Female subjects were not in the menstrual period during the test.

PK Properties

Study 1

Plasma concentration–time profiles over 16 h after three single doses (10, 20, and 40 mg) of lafutidine tablets are shown in Fig. 1. These profiles were used to obtain PK parameters, as shown in Table 1. Over the dose range studied, the C max and AUC0–∞ increased in proportion to dose (r 2 = 1 and 0.9998, respectively; Figs. 4 and 5).

Fig. 1
figure 1

Single-dose study. Mean (standard deviation) plasma concentration versus time curve for the 3 doses in 12 healthy volunteers

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Table 1 Pharmacokinetic parameters of lafutidine in plasma following single-dose administration of lafutidine tablet in healthy Chinese subjects (n = 12)
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Study 2

The mean plasma concentration–time profiles of lafutidine after multiple 10-mg doses twice a day are shown in Fig. 2, and the mean [standard deviation (SD)] steady-state PK parameters after multiple doses of lafutidine are shown in Table 2. The PK behavior between single dose and multiple dose were similar.

Fig. 2
figure 2

Multiple-dose study. Mean (standard deviation) plasma concentration versus time curve after multiple doses of lafutidine 10 mg twice daily for 6 days

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Table 2 Pharmacokinetic parameters of lafutidine in plasma following multiple-dose administration of lafutidine tablet in healthy Chinese subjects (n = 12)
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Study 3

The mean plasma concentration–time profiles of lafutidine in fasted and fed states are shown in Fig. 3, and the mean (SD) steady-state PK parameters of the two states are shown in Table 3. The GMRs with 90% confidence intervals (CI) of C max and AUC0–∞ are displayed in Table 4. From these tables we can see that the values of C max and AUC0–∞ were not significantly different between the fasting and fed conditions since they were inside the predetermined range. However, the C max and AUC0–∞ values of female subjects in the fed condition were slightly higher than those in fasted conditions, and C max values of male subjects were slightly lower than those in the fasted state. In addition, the absorption half-life (K a) in the fed state was much less than in the fasted state (P < 0.05), and the T max values were greater than those in the fasted state (P < 0.05). The results indicated that food may reduce the rate of absorption of lafutidine, but it has less influence on the degree of absorption and the rate of elimination.

Fig. 3
figure 3

Food effect study. Mean (standard deviation) plasma concentration versus time curve in fasted and fed states

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Table 3 Pharmacokinetic parameters of lafutidine in plasma following fasted and fed administration of lafutidine tablet in healthy Chinese subjects (n = 12)
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Table 4 GMRs with 90% CI of C max and AUC0–∞ of oral lafutidine 10 mg in the fasted and fed condition in healthy subjects
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Gender Effects

P values for PK parameters in each dose were not significantly different (P > 0.05) except several abnormities, including C max, C min, and T max in multiple-dose study and C max in the 20-mg-dose study (P < 0.05). The GMRs with 90% CI of C max and AUC0–∞ are displayed in Table 5. They were significantly different between female and male subjects since the 90% CIs were outside of the predetermined range, both in single- and multiple-dose studies; this phenomenon was perhaps due to the small number of subjects.

Table 5 GMRs with 90% CI of C max and AUC0–∞ of male and female
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Safety

Lafutidine appeared to be well tolerated during the study. No participants dropped out and no serious adverse events were observed. No adverse events appeared with the increase of the dose. Clinical laboratory assessments, vital signs, physical examinations, and ECG remained within normal limits for all subjects.

Discussion

To the authors’ knowledge, this was the first study to examine the PK parameters of lafutidine, including the effect of food, in Chinese subjects. The parameters in this study had similar values of C max, AUC0–t , AUC0–∞, and T max compared to a previous study in Indian subjects [13] after 10 mg of oral lafutidine tablets. However, the t 1/2 was longer in the healthy Chinese volunteers (2.76 ± 0.45 h) than in the Indian subjects (2.05 ± 1.01 h). The observed effect of food was contrary to a previous study in which lafutidine was rapidly absorbed in the absence of a lag time after postprandial oral administration [12]. The reasons for this phenomenon are unclear.

In study 1, the C max (Fig. 4) and AUC0–∞ (Fig. 5) increased in proportion to dose (r 2 = 1 and 0.9998, respectively). There were no significant differences in t 1/2, average residence time (MRT), and T max among the groups. This indicates that the PK of oral lafutidine tablets are consistent with first-order kinetics. In study 2, C max,ss and AUCss were greater than the C max and AUC0–∞ after oral administration of lafutidine tablets (10 mg). T 1/2 was longer than in the single-dose study. The degrees of fluctuation (DF) were small and the valley plasma concentration (i.e., C min) was steady. The T max and MRT were not significantly different when compared with the single-dose study. This indicated that the PK behavior between single-dose and multiple-dose studies were similar. In study 3, C max and AUC0–∞ were not significantly different between fasted and fed conditions since they were inside of the predetermined range. However, the values of C max and AUC0–∞ of female participants under fed conditions were slightly higher than those under fasted conditions, and the C max of male participants under fed conditions was slightly lower than that under fasted conditions. We conjectured that this observation was due to the small number of subjects. And gender may have little effect on food.

Fig. 4
figure 4

Linear correlation between C max (n = 12) and increasing doses of lafutidine tablets. C max maximum plasma concentration

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Fig. 5
figure 5

Linear correlation between mean AUC0–∞ (n = 12) and increasing doses of lafutidine tablets. AUC 0–∞ area under the concentration–time curve from time zero to infinity

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The assessment of gender effect found that there was no significant difference in PK parameters between the two sexes in general (P > 0.05), except for several abnormities. The 90% CIs around the GMRs of C max and AUC0–∞ were outside the predetermined range. This may be because of the small size of sample or the difference in participants’ weights. However, gender may also have an effect on lafutidine. Thus, further studies on this are required. It may not be necessary to adjust the dose since all subjects showed good tolerability in the study.

The small size of sample was a limitation of the study. Furthermore, the subjects in this study were young, healthy Chinese adults and therefore not representative of all ages.

Conclusions

The PK parameters (AUC and C max) of single doses of lafutidine displayed linear PK properties in the dose range of 10–40 mg. Estimated PK parameters after the administration of multiple doses of 10 mg lafutidine for 6 consecutive days appeared to be consistent with those from single doses, indicating no significant accumulation of lafutidine tablets with multiple dosing. Food can reduce the rate of absorption of lafutidine, but it has less of an influence on the degree of absorption and the rate of elimination in healthy Chinese subjects. No adverse events appeared with the increased doses.